{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:03:38Z","timestamp":1789376618398,"version":"build-2803163510"},"reference-count":240,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Gastrointestinal (GI) malignancies account for approximately one-quarter of new cancer diagnoses and more than one-third of cancer-related deaths worldwide, yet as of August 2026, only one CAR-T therapy has received regulatory approval for a solid tumor indication anywhere in the world. The recent CT041-ST-01 phase II trial of satricabtagene autoleucel, the first randomized CAR-T trial conducted in a solid tumor, demonstrated a significant improvement in progression-free survival for patients with advanced gastric cancer (median 3.25 vs. 1.77 months; hazard ratio (HR) 0.37, p &lt; 0.001). While this landmark study established the clinical feasibility of CAR-T therapy in solid tumors, it also underscored the biological barriers that continue to limit durable responses. GI tumors are characterized by heterogeneous antigen expression, dense desmoplastic stroma, inefficient immune-cell trafficking, profoundly immunosuppressive tumor microenvironments, and progressive T-cell dysfunction, all of which are further compounded by the logistical and economic challenges of autologous cell manufacturing. In this narrative review, we organize these obstacles within a unified four-barrier engineering framework and critically examine the strategies being developed to overcome each of them. We discuss advances in multi-antigen and logic-gated CAR architectures, stromal remodeling through fibroblast activation protein (FAP)-targeted approaches and extracellular matrix-degrading enzymes, chemokine receptor engineering, regional delivery, hypoxia-responsive CARs, cytokine-armored and persistence-enhanced constructs, dominant-negative and switch receptors, metabolic reprogramming, and intrinsic checkpoint disruption. We also review emerging manufacturing platforms, including allogeneic CAR-T and CAR-natural killer (CAR-NK) cells, induced pluripotent stem cell-derived products, CAR-macrophages, and in vivo CAR generation, together with engineering strategies designed to improve safety and scalability. Rather than relying on a single technological advance, the future of CAR-based therapy for GI malignancies will likely depend on integrating multiple engineering approaches to address the diverse biological barriers within the tumor microenvironment. By synthesizing current preclinical and early clinical evidence, this review provides a translational framework for the next generation of CAR-based cellular therapies in gastrointestinal oncology.<\/jats:p>","DOI":"10.3390\/ph19091449","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T08:10:23Z","timestamp":1789373423000},"page":"1449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Barriers and Blueprints: Next-Generation Engineering Strategies for CAR-T Cell Therapy in Gastrointestinal Tumors"],"prefix":"10.3390","volume":"19","author":[{"given":"Mariam","family":"Ismail","sequence":"first","affiliation":[{"name":"Department of Medicine, Houston Methodist Hospital, Houston, TX 77030, USA"},{"name":"Faculty of Medicine, Delta University for Science and Technology, Gamasa 7730103, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noran","family":"Al-Gizey","sequence":"additional","affiliation":[{"name":"College of Medicine, University of Baghdad, Baghdad 12114, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaid","family":"Alabed","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nour","family":"Mustafa","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebtesam","family":"Al-Najjar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Houston Methodist Hospital, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazan","family":"Hamdaneh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Methodist Healthcare System of San Antonio, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nehal","family":"Eid","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2337-8351","authenticated-orcid":false,"given":"Abdullah","family":"Esmail","sequence":"additional","affiliation":[{"name":"Department of Medicine, Houston Methodist Hospital, Houston, TX 77030, USA"},{"name":"Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1053\/j.gastro.2020.02.068","article-title":"Global Burden of 5 Major Types of Gastrointestinal Cancer","volume":"159","author":"Arnold","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e70245","DOI":"10.1002\/cncr.70245","article-title":"Gastrointestinal cancer statistics in 2022 and projection to 2050: GLOBOCAN estimates across 185 countries","volume":"132","author":"Danpanichkul","year":"2026","journal-title":"Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S2468-1253(23)00366-7","article-title":"Global, regional, and national lifetime risks of developing and dying from gastrointestinal cancers in 185 countries: A population-based systematic analysis of GLOBOCAN","volume":"9","author":"Wang","year":"2024","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S0140-6736(24)02848-4","article-title":"Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): A randomised, open-label, phase 3 trial","volume":"405","author":"Elez","year":"2025","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1001\/jamaoncol.2021.0275","article-title":"Assessment of pembrolizumab therapy for the treatment of microsatellite instability\u2013high gastric or gastroesophageal junction cancer among patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 clinical trials","volume":"7","author":"Chao","year":"2021","journal-title":"JAMA Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1111\/imr.13273","article-title":"Hurdles race for CAR T-cell therapy in digestive tract cancer","volume":"320","author":"Kronig","year":"2023","journal-title":"Immunol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e15593","DOI":"10.1200\/JCO.2026.44.16_suppl.e15593","article-title":"Clinical outcomes of immune checkpoint inhibitors in combination with tyrosine kinase inhibitors in metastatic MSS\/pMMR colorectal cancer: A systematic review and meta-analysis","volume":"44","author":"Maurya","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1038\/s41577-025-01229-3","article-title":"Microenvironmental regulation of solid tumour resistance to CAR T cell therapy","volume":"26","author":"Lamplugh","year":"2025","journal-title":"Nat. Rev. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1016\/S0140-6736(25)00860-8","article-title":"Claudin-18 isoform 2-specific CAR T-cell therapy (satri-cel) versus treatment of physician\u2019s choice for previously treated advanced gastric or gastro-oesophageal junction cancer (CT041-ST-01): A randomised, open-label, phase 2 trial","volume":"405","author":"Qi","year":"2025","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1001\/jama.2024.19462","article-title":"CAR T cells and T-cell therapies for cancer: A translational science review","volume":"332","author":"Brudno","year":"2024","journal-title":"JAMA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1111\/imr.13255","article-title":"Next-generation chimeric antigen receptors for T-and natural killer-cell therapies against cancer","volume":"320","author":"Li","year":"2023","journal-title":"Immunol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/nrd4597","article-title":"The pharmacology of second-generation chimeric antigen receptors","volume":"14","author":"Hamieh","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1073\/pnas.90.2.720","article-title":"Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors","volume":"90","author":"Eshhar","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"10024","DOI":"10.1073\/pnas.86.24.10024","article-title":"Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity","volume":"86","author":"Gross","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/s41571-023-00754-1","article-title":"Long-term outcomes following CAR T cell therapy: What we know so far","volume":"20","author":"Cappell","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Garcia-Robledo, J.E., Cabrera-Salcedo, S., Brandauer, A.M., Romano, F., Rengifo-Martinez, J., Toro-Pedroza, A., Victoria, J.S., Rios-Serna, L.J., Loukanov, A., and Cardona, A.F. (2025). Engineering the next generation of CAR T- cells: Precision modifications, logic gates and universal strategies to overcome exhaustion and tumor resistance. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1698442"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1517\/14712598.2015.1046430","article-title":"TRUCKs: The fourth generation of CARs","volume":"15","author":"Chmielewski","year":"2015","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1038\/nm.4478","article-title":"A novel chimeric antigen receptor containing a JAK\u2013STAT signaling domain mediates superior antitumor effects","volume":"24","author":"Kagoya","year":"2018","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1056\/NEJMoa1709866","article-title":"Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia","volume":"378","author":"Maude","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1056\/NEJMoa1707447","article-title":"Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma","volume":"377","author":"Neelapu","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1056\/NEJMoa2213614","article-title":"Ide-cel or standard regimens in relapsed and refractory multiple myeloma","volume":"388","author":"Ailawadhi","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"107419","DOI":"10.1016\/j.pharmthera.2019.107419","article-title":"Clinical investigation of CAR T cells for solid tumors: Lessons learned and future directions","volume":"205","author":"Bagley","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_23","unstructured":"CARsgen Therapeutics Holdings Limited (2026). CARsgen Announces Approval of Satri-cel, the World\u2019s First CAR T-Cell Therapy Product for Solid Tumors, PR Newswire."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/s41575-025-01062-y","article-title":"CAR T cell therapies in gastrointestinal cancers: Current clinical trials and strategies to overcome challenges","volume":"22","author":"Abken","year":"2025","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Al Shaer, N.S.H., Masoud, I., Tleyjeh, A., Al-Attas, A.A., Al-Attas, M.A., Khan, M.I., and Yaqinuddin, A. (2026). CAR-T cells in solid tumors: Engineering, biomarkers, translational pathways and the road ahead. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1796675"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/s41571-022-00704-3","article-title":"Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours","volume":"20","author":"Flugel","year":"2023","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"152411","DOI":"10.1016\/j.seminoncol.2025.152411","article-title":"Tumor tough, therapy smarter: Rethinking CAR-T for pancreatic cancer","volume":"52","author":"Guirguis","year":"2025","journal-title":"Semin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/imm.70094","article-title":"Barriers and Strategies to Enhance CAR-T Cell Infiltration in Solid Tumours: A Systematic Review","volume":"178","author":"Zhang","year":"2026","journal-title":"Immunology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1177\/10430342251372041","article-title":"Genetic Engineering in CAR T Cells for Solid Tumors: Current State, Barriers and Future Developments","volume":"36","author":"Garnica","year":"2025","journal-title":"Hum. Gene Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0016-5085(03)00689-9","article-title":"Glypican-3: A novel serum and histochemical marker for hepatocellular carcinoma","volume":"125","author":"Capurro","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1111\/febs.12126","article-title":"Glypican-3: A marker and a therapeutic target in hepatocellular carcinoma","volume":"280","author":"Filmus","year":"2013","journal-title":"FEBS J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1038\/s41591-023-02452-y","article-title":"Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: Phase 1\/2 trial interim results","volume":"29","author":"Hassan","year":"2023","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1080\/07357907.2021.1943747","article-title":"Mesothelin is Commonly Expressed in Pancreatic Adenocarcinoma but Unrelated to Cancer Aggressiveness","volume":"39","author":"Weidemann","year":"2021","journal-title":"Cancer Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"14827","DOI":"10.1073\/pnas.93.25.14827","article-title":"Guanylyl cyclase C is a selective marker for metastatic colorectal tumors in human extraintestinal tissues","volume":"93","author":"Carrithers","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/S0140-6736(10)61121-X","article-title":"Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial","volume":"376","author":"Bang","year":"2010","journal-title":"Lancet"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/S1470-2045(18)30904-5","article-title":"Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): An updated report from a multicentre, open-label, phase 2a, multiple basket study","volume":"20","author":"Hurwitz","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/s41571-024-00874-2","article-title":"Claudin 18.2 as a novel therapeutic target","volume":"21","author":"Nakayama","year":"2024","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9650","DOI":"10.1038\/s41467-025-61858-z","article-title":"On-target off-tumor toxicity of claudin18.2-directed CAR-T cells in preclinical models","volume":"16","author":"Birocchi","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2224","DOI":"10.1038\/s41591-024-03037-z","article-title":"Claudin18.2-specific CAR T cells in gastrointestinal cancers: Phase 1 trial final results","volume":"30","author":"Qi","year":"2024","journal-title":"Nat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"114650","DOI":"10.1016\/j.jconrel.2026.114650","article-title":"Next generation CAR-T cells to tackle down solid tumors","volume":"391","author":"Abreu","year":"2026","journal-title":"J. Control. Release"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1186\/s12943-025-02334-6","article-title":"Strategies to overcome tumour relapse caused by antigen escape after CAR T therapy","volume":"24","author":"Lu","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e2317283121","DOI":"10.1073\/pnas.2317283121","article-title":"Tumor resistance to anti-mesothelin CAR-T cells caused by binding to shed mesothelin is overcome by targeting a juxtamembrane epitope","volume":"121","author":"Liu","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e001875","DOI":"10.1136\/jitc-2020-001875","article-title":"Shed antigen-induced blocking effect on CAR-T cells targeting Glypican-3 in Hepatocellular Carcinoma","volume":"9","author":"Sun","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Cao, M., Alvarez, J., Mitra, R., Xu, M., Baybutt, T.R., Sun, Z., Taylor, O., Doermann, A.S., Staudt, R.E., and Waldman, S.A. (2026). IFN\u03b3-induced antigen loss in chimeric antigen receptor-T cell therapy. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1772472"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6245","DOI":"10.1158\/0008-5472.CAN-04-4244","article-title":"Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling","volume":"65","author":"Capurro","year":"2005","journal-title":"Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Rappaport, J.A., and Waldman, S.A. (2018). The Guanylate Cyclase C-cGMP Signaling Axis Opposes Intestinal Epithelial Injury and Neoplasia. Front. Oncol., 8.","DOI":"10.3389\/fonc.2018.00299"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1158\/1055-9965.EPI-14-0440","article-title":"The paracrine hormone for the GUCY2C tumor suppressor, guanylin, is universally lost in colorectal cancer","volume":"23","author":"Wilson","year":"2014","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1200\/JCO-25-01090","article-title":"Guanylyl Cyclase 2C-Targeted Chimeric Antigen Receptor T-Cell Therapy in Patients With Metastatic Colorectal Cancer","volume":"44","author":"Qi","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e014286","DOI":"10.1136\/jitc-2025-014286","article-title":"Clinical trial landscape of CAR-based cell therapy for gastrointestinal malignancies","volume":"14","author":"Li","year":"2026","journal-title":"J. Immunother. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"116783","DOI":"10.1016\/j.intimp.2026.116783","article-title":"Recent advances in chemokine-directed strategies to improve CAR-T cell infiltration into solid tumors","volume":"181","author":"Hu","year":"2026","journal-title":"Int. Immunopharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.ymthe.2016.10.016","article-title":"Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer","volume":"25","author":"Mohammed","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4124","DOI":"10.1158\/0008-5472.CAN-15-2973","article-title":"FAP Promotes Immunosuppression by Cancer-Associated Fibroblasts in the Tumor Microenvironment via STAT3-CCL2 Signaling","volume":"76","author":"Yang","year":"2016","journal-title":"Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1038\/nm.3833","article-title":"Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes","volume":"21","author":"Caruana","year":"2015","journal-title":"Nat. Med."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Das, S., Valton, J., Duchateau, P., and Poirot, L. (2023). Stromal depletion by TALEN-edited universal hypoimmunogenic FAP-CAR T cells enables infiltration and anti-tumor cytotoxicity of tumor antigen-targeted CAR-T immunotherapy. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1172681"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/s41586-019-0985-x","article-title":"NR4A transcription factors limit CAR T cell function in solid tumours","volume":"567","author":"Chen","year":"2019","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"eabn7336","DOI":"10.1126\/scitranslmed.abn7336","article-title":"BLIMP1 and NR4A3 transcription factors reciprocally regulate antitumor CAR T cell stemness and exhaustion","volume":"14","author":"Jung","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3345","DOI":"10.7150\/thno.107908","article-title":"Supercharging CAR-T cells through transcriptional and epigenetic armoring","volume":"15","author":"Qin","year":"2025","journal-title":"Theranostics"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1111\/imr.13252","article-title":"Coengineering specificity, safety, and function into T cells for cancer immunotherapy","volume":"320","author":"Ash","year":"2023","journal-title":"Immunol. Rev."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Zhang, X., Kong, Y.-J., Li, J.-Y., Li, H.-H., and Chen, L. (2026). Systematic optimization of PD-L1 and CLDN18.2 CAR-T designs identifies a bicistronic dual-target, double-CD3\u03b6 architecture with enhanced antitumor activity in gastric cancer. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1805471"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e012822","DOI":"10.1136\/jitc-2025-012822","article-title":"Tandem CAR-T cells targeting mesothelin and MUC16 overcome tumor heterogeneity by targeting one antigen at a time","volume":"13","author":"Birocchi","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Wang, H., Wang, X., Ye, X., Ju, Y., Cao, N., Wang, S., and Cai, J. (2022). Nonviral mcDNA-mediated bispecific CAR T cells kill tumor cells in an experimental mouse model of hepatocellular carcinoma. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-09861-1"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"7622","DOI":"10.7150\/thno.43991","article-title":"Tandem CAR-T cells targeting CD70 and B7-H3 exhibit potent preclinical activity against multiple solid tumors","volume":"10","author":"Yang","year":"2020","journal-title":"Theranostics"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e012318","DOI":"10.1136\/jitc-2025-012318","article-title":"Engineering single-vector logic-gated CAR T cells with transgene sizes beyond current limitations","volume":"14","author":"Rommel","year":"2026","journal-title":"J. Immunother. Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1001\/jamaoncol.2024.3891","article-title":"Chimeric Antigen Receptor T Cells Targeting CD19 and GCC in Metastatic Colorectal Cancer: A Nonrandomized Clinical Trial","volume":"10","author":"Chen","year":"2024","journal-title":"JAMA Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1200\/JCO.2025.43.4_suppl.175","article-title":"A phase 1 dose-escalation study of GCC19CART: A novel CAR T-cell therapy for metastatic colorectal cancer in the United States","volume":"43","author":"Keenan","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1200\/JCO.2023.41.16_suppl.2519","article-title":"A phase I\/II trial investigating safety and efficacy of autologous TAC01-HER2 in relapsed or refractory solid tumors","volume":"41","author":"Schlechter","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1186\/s12967-023-04080-z","article-title":"FAP-targeted CAR-T suppresses MDSCs recruitment to improve the antitumor efficacy of claudin18.2-targeted CAR-T against pancreatic cancer","volume":"21","author":"Liu","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1016\/j.ymthe.2020.07.017","article-title":"Dual Targeting of Mesothelin and CD19 with Chimeric Antigen Receptor-Modified T Cells in Patients with Metastatic Pancreatic Cancer","volume":"28","author":"Ko","year":"2020","journal-title":"Mol. Ther."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"eabe7378","DOI":"10.1126\/scitranslmed.abe7378","article-title":"SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma","volume":"13","author":"Choe","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"eabd8836","DOI":"10.1126\/scitranslmed.abd8836","article-title":"SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models","volume":"13","author":"Su","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"eaba1624","DOI":"10.1126\/science.aba1624","article-title":"Synthetic cytokine circuits that drive T cells into immune-excluded tumors","volume":"378","author":"Allen","year":"2022","journal-title":"Science"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1038\/s41586-023-05778-2","article-title":"Co-opting signalling molecules enables logic-gated control of CAR T cells","volume":"615","author":"Tousley","year":"2023","journal-title":"Nature"},{"key":"ref_73","first-page":"e16381","article-title":"MSLN and CLDN18.2 dual-target CAR-T therapy: Enhancing cancer treatment with improved efficacy and safety","volume":"43","author":"Yang","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e007426","DOI":"10.1136\/jitc-2023-007426","article-title":"HER2 and HLA-A*02 dual CAR-T cells utilize LOH in a NOT logic gate to address on-target off-tumor toxicity","volume":"11","author":"Bassan","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e2312374120","DOI":"10.1073\/pnas.2312374120","article-title":"Dual-inhibitory domain iCARs improve the efficiency of the AND-NOT gate CAR T strategy","volume":"120","author":"Bangayan","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Manry, D., Bolanos, K., DiAndreth, B., Mock, J.Y., and Kamb, A. (2022). Robust In Vitro Pharmacology of Tmod, a Synthetic Dual-Signal Integrator for Cancer Cell Therapy. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.826747"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Partin, A.C., Bruno, R., Shafaattalab, S., Vander Mause, E., Winters, A., Daris, M., Gahrs, C., Jette, C.A., DiAndreth, B., and Sandberg, M.L. (2024). Geometric parameters that affect the behavior of logic-gated CAR T cells. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1304765"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"TPS2699","DOI":"10.1200\/JCO.2024.42.16_suppl.TPS2699","article-title":"EVEREST-2: A seamless phase 1\/2 study of A2B694, a mesothelin (MSLN) logic-gated Tmod CAR T-cell therapy, in patients with solid tumors that show MSLN expression and human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH)","volume":"42","author":"Punekar","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"TPS2673","DOI":"10.1200\/JCO.2026.44.16_suppl.TPS2673","article-title":"A logic-gated chimeric antigen receptor T-cell (CAR T) therapy with an armored, membrane-tethered IL-12 booster in patients with advanced solid tumors with HLA-A*02 loss of heterozygosity (LOH): EVEREST-2, a phase 1\/2 study","volume":"44","author":"Punekar","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e16408","DOI":"10.1200\/JCO.2025.43.16_suppl.e16408","article-title":"EVEREST-1: Safety and efficacy data of A2B530, a logic-gated Tmod chimeric antigen receptor T-cell (CAR T) therapy, in patients with solid tumors associated with carcinoembryonic antigen (CEA) expression and with human leukocyte antigen (HLA) loss of heterozygosity (LOH)","volume":"43","author":"Molina","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"eabm0306","DOI":"10.1126\/scitranslmed.abm0306","article-title":"A carcinoembryonic antigen-specific cell therapy selectively targets tumor cells with HLA loss of heterozygosity in vitro and in vivo","volume":"14","author":"Sandberg","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1007\/s00262-017-2034-7","article-title":"The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity","volume":"66","author":"Thistlethwaite","year":"2017","journal-title":"Cancer Immunol. Immunother. CII"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"TPS2677","DOI":"10.1200\/JCO.2025.43.16_suppl.TPS2677","article-title":"Logic-gated, allogeneic Tmod chimeric antigen receptor T-cell (CAR T) therapy targeting epidermal growth factor receptor (EGFR) in advanced solid tumors with human leukocyte antigen (HLA) loss of heterozygosity (LOH): DENALI-1 trial","volume":"43","author":"Kirtane","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e012435","DOI":"10.1136\/jitc-2025-012435","article-title":"Allele-specific HLA LOH in solid tumors: Distinct patterns by tumor type and potential prognostic relevance","volume":"13","author":"Sewastianik","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e001033","DOI":"10.1136\/bmjonc-2025-001033","article-title":"BASECAMP-1 screening study: A model for efficient enrolment in precision oncology clinical trials","volume":"5","author":"Hecht","year":"2026","journal-title":"BMJ Oncol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1016\/j.cell.2018.03.038","article-title":"Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses","volume":"173","author":"Cho","year":"2018","journal-title":"Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1186\/s13046-023-02912-w","article-title":"Immunotheranostic target modules for imaging and navigation of UniCAR T-cells to strike FAP-expressing cells and the tumor microenvironment","volume":"42","author":"Loureiro","year":"2023","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Soto, K.E., Loureiro, L.R., Bartsch, T., Arndt, C., Kegler, A., Mitwasi, N., Drewitz, L., Hoffmann, L., Saleh, H.A., and Crespo, E. (2023). Targeting colorectal cancer cells using AND-gated adaptor RevCAR T-cells. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1302354"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Nagy, L., Mez\u0151si-Csapl\u00e1r, M., Rebenku, I., Vereb, G., and Sz\u00f6\u0151r, \u00c1. (2024). Universal CAR T cells targeted to HER2 with a biotin-trastuzumab soluble linker penetrate spheroids and large tumor xenografts that are inherently resistant to trastuzumab mediated ADCC. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1365172"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"8579","DOI":"10.1200\/JCO.2026.44.16_suppl.8579","article-title":"Initial safety and efficacy of A2B694, a logic-gated mesothelin (MSLN)\u2013targeted Tmod chimeric antigen receptor T-cell (CAR T) therapy in patients with advanced solid tumors with HLA-A*02 loss of heterozygosity (LOH)","volume":"44","author":"Molina","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"218618","DOI":"10.1016\/j.canlet.2026.218618","article-title":"Desmoplasia and Therapeutic Resistance in Pancreatic Ductal Adenocarcinoma","volume":"654","author":"Ghanwatkar","year":"2026","journal-title":"Cancer Lett."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1001\/jama.2021.13027","article-title":"Pancreatic cancer: A review","volume":"326","author":"Park","year":"2021","journal-title":"JAMA"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1038\/s41590-025-02134-6","article-title":"Macrophages and fibroblasts as regulators of the immune response in pancreatic cancer","volume":"26","author":"Shakiba","year":"2025","journal-title":"Nat. Immunol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/imm.13496","article-title":"Heterogeneous cancer-associated fibroblasts: A new perspective for understanding immunosuppression in pancreatic cancer","volume":"167","author":"Zhang","year":"2022","journal-title":"Immunology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"20212","DOI":"10.1073\/pnas.1320318110","article-title":"Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti\u2013PD-L1 immunotherapy in pancreatic cancer","volume":"110","author":"Feig","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Gorchs, L., and Kaipe, H. (2021). Interactions between cancer-associated fibroblasts and T cells in the pancreatic tumor microenvironment and the role of chemokines. Cancers, 13.","DOI":"10.3390\/cancers13122995"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"217475","DOI":"10.1016\/j.canlet.2025.217475","article-title":"FAP upregulates PD-L1 expression in cancer-associated fibroblasts to exacerbate T cells dysfunction and suppress anti-tumor immunity","volume":"612","author":"Wei","year":"2025","journal-title":"Cancer Lett."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1158\/0008-5472.CAN-23-3252","article-title":"Dissecting FAP+ cell diversity in pancreatic cancer uncovers an interferon-response subtype of cancer-associated fibroblasts with tumor-restraining properties","volume":"85","author":"Cumming","year":"2025","journal-title":"Cancer Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1158\/2159-8290.CD-20-1484","article-title":"Identification of functional heterogeneity of carcinoma-associated fibroblasts with distinct IL6-mediated therapy resistance in pancreatic cancer","volume":"12","author":"McAndrews","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"3532","DOI":"10.1111\/cas.16285","article-title":"Fibroblast activation protein constitutes a novel target of chimeric antigen receptor T-cell therapy in solid tumors","volume":"115","author":"Meng","year":"2024","journal-title":"Cancer Sci."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Xin, L., Gao, J., Zheng, Z., Chen, Y., Lv, S., Zhao, Z., Yu, C., Yang, X., and Zhang, R. (2021). Fibroblast Activation Protein-\u03b1 as a Target in the Bench-to-Bedside Diagnosis and Treatment of Tumors: A Narrative Review. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.648187"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2800","DOI":"10.1158\/0008-5472.CAN-14-3041","article-title":"Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells","volume":"75","author":"Lo","year":"2015","journal-title":"Cancer Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1158\/2326-6066.CIR-13-0027","article-title":"Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity","volume":"2","author":"Wang","year":"2014","journal-title":"Cancer Immunol. Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1084\/jem.20130110","article-title":"Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia","volume":"210","author":"Tran","year":"2013","journal-title":"J. Exp. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"3915","DOI":"10.1016\/j.ymthe.2024.08.018","article-title":"TALEN-edited allogeneic inducible dual CAR T cells enable effective targeting of solid tumors while mitigating off-tumor toxicity","volume":"32","author":"Dharani","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1038\/s41419-025-08405-2","article-title":"A new strategy for CAR-T therapy in solid tumors: IL-15-autocrine signaling augments tumor stroma depletion and promotes a T(SCM) subset in the TME","volume":"17","author":"Pang","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1158\/2326-6066.CIR-25-0349","article-title":"The Allogeneic FAP-CAR-IL15 iNKT Therapy MiNK-215 Remodels the Tumor Stroma to Enhance Antitumor Immunity","volume":"14","author":"Chantzoura","year":"2026","journal-title":"Cancer Immunol. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"2556714","DOI":"10.1080\/2162402X.2025.2556714","article-title":"Anti-FAP CAR-NK cells as a novel targeted therapy against cervical cancer and cancer-associated fibroblasts","volume":"14","author":"Polten","year":"2025","journal-title":"Oncoimmunology"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1158\/2326-6066.CIR-25-0663","article-title":"Targeted Lipid Nanoparticle Delivery of FAP-CAR mRNA Enables Potent In Vivo T-cell Engineering against Pancreatic Tumors","volume":"14","author":"Bajbouj","year":"2026","journal-title":"Cancer Immunol. Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"e70310","DOI":"10.1002\/jev2.70310","article-title":"Heparanase-Loaded CAR T Extracellular Vesicles Remodel the Colorectal Tumour Microenvironment and Boost T Cell Antitumor Immunity","volume":"15","author":"Zhu","year":"2026","journal-title":"J. Extracell. Vesicles"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1038\/s41423-024-01228-9","article-title":"Specific ECM degradation potentiates the antitumor activity of CAR-T cells in solid tumors","volume":"21","author":"Zheng","year":"2024","journal-title":"Cell. Mol. Immunol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"eadr2151","DOI":"10.1126\/scitranslmed.adr2151","article-title":"OX40\u2013heparan sulfate binding facilitates CAR T cell penetration into solid tumors in mice","volume":"17","author":"Zhang","year":"2025","journal-title":"Sci. Transl. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1002\/eji.201948457","article-title":"CXCR2-modified CAR-T cells have enhanced trafficking ability that improves treatment of hepatocellular carcinoma","volume":"50","author":"Liu","year":"2020","journal-title":"Eur. J. Immunol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s00018-025-05972-7","article-title":"CCR2\/CXCR6 enhances tumor infiltration and antitumor efficacy of MSLN CAR-T cells","volume":"83","author":"Zhang","year":"2025","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/s00262-024-03909-w","article-title":"CCR5 and IL-12 co-expression in CAR T cells improves antitumor efficacy by reprogramming tumor microenvironment in solid tumors","volume":"74","author":"Tian","year":"2025","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1186\/s12967-025-06866-9","article-title":"Enhanced homing and efficacy of HER2-CAR T cells via CXCR5\/CCR6 co-expression for HER2-positive NSCLC","volume":"23","author":"Hu","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"117673","DOI":"10.1016\/j.bcp.2026.117673","article-title":"Enhancement of B7-H3 chimeric antigen receptor-T cell efficacy via the coexistence effect of IL-7, IL-15 and CCL19 for pancreatic and lung xenograft tumors","volume":"245","author":"Zhang","year":"2026","journal-title":"Biochem. Pharmacol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1038\/cgt.2016.14","article-title":"Regional CAR-T cell infusions for peritoneal carcinomatosis are superior to systemic delivery","volume":"23","author":"Katz","year":"2016","journal-title":"Cancer Gene Ther."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"e012292","DOI":"10.1136\/jitc-2025-012292","article-title":"Intraperitoneal CAR T-cell therapy for peritoneal carcinomatosis from gastroesophageal cancer: Preclinical investigations to a phase I clinical trial (NCT06623396)","volume":"13","author":"Restle","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1038\/s43018-026-01124-3","article-title":"Hypoxia-responsive CEA-targeted CAR T cells in CEA-positive solid tumors through intraperitoneal or intravenous infusion: A phase 1 trial","volume":"7","author":"Gao","year":"2026","journal-title":"Nat. Cancer"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"3514","DOI":"10.1200\/JCO.2026.44.16_suppl.3514","article-title":"Phase I study of intraperitoneal fast-manufactured IL-9-secreting CEACAM5-targeted CAR-T cells in advanced colorectal cancer with peritoneal metastases","volume":"44","author":"Zhang","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"3149","DOI":"10.1158\/1078-0432.CCR-14-1421","article-title":"Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor-Modified T-cell Therapy for CEA+ Liver Metastases","volume":"21","author":"Katz","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/s41417-019-0104-z","article-title":"HITM-SIR: Phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy and selective internal radiation therapy for CEA+ liver metastases","volume":"27","author":"Katz","year":"2020","journal-title":"Cancer Gene Ther."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1158\/0008-5472.CAN-23-1038","article-title":"Hypoxia-Responsive CAR-T Cells Exhibit Reduced Exhaustion and Enhanced Efficacy in Solid Tumors","volume":"84","author":"Zhu","year":"2024","journal-title":"Cancer Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"e002755","DOI":"10.1136\/jitc-2021-002755","article-title":"Conditioned CAR-T cells by hypoxia-inducible transcription amplification (HiTA) system significantly enhances systemic safety and retains antitumor efficacy","volume":"9","author":"He","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"e012321","DOI":"10.1136\/jitc-2025-012321","article-title":"Envirotune-CAR-T: A hypoxia-responsive and glutamine-enhanced CAR-T cell therapy for overcoming tumor microenvironment-mediated suppression","volume":"13","author":"Li","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"108235","DOI":"10.1016\/j.phrs.2026.108235","article-title":"Overexpression of HIF-1\u03b1 via small activating RNA enhances CAR-T cell function in hypoxic microenvironments","volume":"229","author":"Huang","year":"2026","journal-title":"Pharmacol. Res."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1111\/imm.13888","article-title":"Co-Expression of Dominant-Negative TGF-\u03b2 Receptor 2 Enhances the Therapeutic Efficacy of Novel TREM1\/DAP12-BB-Based CAR-T Cells in Solid Tumours","volume":"174","author":"Zhu","year":"2025","journal-title":"Immunology"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"3130","DOI":"10.1172\/JCI83092","article-title":"Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition","volume":"126","author":"Cherkassky","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"11593","DOI":"10.1038\/s41467-025-66737-1","article-title":"Multiplex gene-editing strategy to engineer allogeneic EGFR-targeting CAR T-cells with improved efficacy against solid tumors","volume":"16","author":"Murray","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/s41577-026-01280-8","article-title":"Progress in the development of cytokine armoured CAR T cells","volume":"26","author":"Prasad","year":"2026","journal-title":"Nat. Rev. Immunol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1038\/s41586-024-08261-8","article-title":"Interleukin-15-armoured GPC3 CAR T cells for patients with solid cancers","volume":"637","author":"Steffin","year":"2025","journal-title":"Nature"},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Shi, H., Li, A., Dai, Z., Xue, J., Zhao, Q., Tian, J., Song, D., Wang, H., Chen, J., and Zhang, X. (2023). IL-15 armoring enhances the antitumor efficacy of claudin 18.2-targeting CAR-T cells in syngeneic mouse tumor models. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1165404"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1158\/1078-0432.CCR-23-1872","article-title":"Cooperative armoring of CAR and TCR T cells by T cell\u2013restricted IL15 and IL21 universally enhances solid tumor efficacy","volume":"30","author":"Nguyen","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1158\/2326-6066.CIR-19-0293","article-title":"Glypican-3\u2013specific CAR T cells coexpressing IL15 and IL21 have superior expansion and antitumor activity against hepatocellular carcinoma","volume":"8","author":"Batra","year":"2020","journal-title":"Cancer Immunol. Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"eaec2632","DOI":"10.1126\/sciadv.aec2632","article-title":"IL-7\/IL-15\/IL-21 cytokine-fusion scaffold generates highly functional CAR T cells enriched in long-lived T memory stem cells","volume":"12","author":"Cole","year":"2026","journal-title":"Sci. Adv."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1038\/s41591-022-01726-1","article-title":"PSMA-targeting TGF\u03b2-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: A phase 1 trial","volume":"28","author":"Narayan","year":"2022","journal-title":"Nat. Med."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"e008261","DOI":"10.1136\/jitc-2023-008261","article-title":"Armored TGF\u03b2RIIDN ROR1-CAR T cells reject solid tumors and resist suppression by constitutively-expressed and treatment-induced TGF\u03b21","volume":"12","author":"Tran","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1016\/j.ymthe.2024.12.014","article-title":"Potentiating CAR-T cell function in the immunosuppressive tumor microenvironment by inverting the TGF-\u03b2 signal","volume":"33","author":"Zheng","year":"2025","journal-title":"Mol. Ther."},{"key":"ref_140","first-page":"e14502","article-title":"Effectiveness of CAR-T cells engineered with TGF-\u03b2r\/IL-9R domain-swapped chimeric receptor and membrane-bound IL-2 for treatment of CEA+ solid tumors","volume":"44","author":"Zhao","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"4121","DOI":"10.4049\/jimmunol.1203085","article-title":"Human T cells engineered to express a programmed death 1\/28 costimulatory retargeting molecule display enhanced antitumor activity","volume":"191","author":"Ankri","year":"2013","journal-title":"J. Immunol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1158\/0008-5472.CAN-15-2524","article-title":"A chimeric switch-receptor targeting PD1 augments the efficacy of second-generation CAR T cells in advanced solid tumors","volume":"76","author":"Liu","year":"2016","journal-title":"Cancer Res."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"e2510017","DOI":"10.71150\/jm.2510017","article-title":"Development of tri-cistronic CLDN18. 2 CAR-T cells incorporating PD-1\/CD28 switch and cyclophilin A for enhanced solid tumor immunotherapy","volume":"64","author":"Lee","year":"2026","journal-title":"J. Microbiol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.jcyt.2022.10.006","article-title":"Cytotoxic activity of anti-mucin 1 chimeric antigen receptor T cells expressing PD-1-CD28 switch receptor against cholangiocarcinoma cells","volume":"25","author":"Supimon","year":"2023","journal-title":"Cytotherapy"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"e014970","DOI":"10.1136\/jitc-2026-014970","article-title":"Chimeric switch scaffold protein augments CAR synapse formation and signaling networks","volume":"14","author":"Park","year":"2026","journal-title":"J. Immunother. Cancer"},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"152438","DOI":"10.1016\/j.seminoncol.2025.152438","article-title":"Genome editing of immune checkpoints: CRISPR-mediated PD-1 inhibition in cancer","volume":"53","author":"Mohammad","year":"2026","journal-title":"Semin. Oncol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1038\/s41423-021-00749-x","article-title":"Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors","volume":"18","author":"Wang","year":"2021","journal-title":"Cell. Mol. Immunol."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"e16061","DOI":"10.1200\/JCO.2023.41.16_suppl.e16061","article-title":"Phase I clinical trial using a unique immunotherapeutic combination of MUC1-targeted CAR-T cells with PD-1-knockout in the treatment of patients with advanced esophageal cancer","volume":"41","author":"Chen","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"2692","DOI":"10.1016\/j.ymthe.2026.01.028","article-title":"Enhancing adoptive T cell therapy by disrupting the SKI-SMAD2\/3 axis to counteract TGF-\u03b2-mediated immunosuppression","volume":"34","author":"Jin","year":"2026","journal-title":"Mol. Ther."},{"key":"ref_150","doi-asserted-by":"crossref","unstructured":"Frlic, T., and Pavlin, M. (2025). Metabolic reprogramming of CAR T cells: A new frontier in cancer immunotherapy. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1688995"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1158\/2326-6066.CIR-25-1490","article-title":"Reprogramming CAR with cytokine signaling increases the efficacy of CAR-T cell therapy in solid tumour treatment and confers sustained immune memory","volume":"14","author":"Sun","year":"2026","journal-title":"Cancer Immunol. Res."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"419","DOI":"10.3892\/or.2016.4807","article-title":"Aberrant expression of B7-H4 correlates with poor prognosis and suppresses tumor-infiltration of CD8+ T lymphocytes in human cholangiocarcinoma","volume":"36","author":"Zhao","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"e57","DOI":"10.1016\/S2352-3026(24)00273-4","article-title":"Accelerating and optimising CAR T-cell manufacture to deliver better patient products","volume":"12","author":"Agliardi","year":"2025","journal-title":"Lancet Haematol."},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"Feng, Y., Yang, Z., Zhou, Y., Liang, Y., and Zhao, H. (2025). From innate-like to innate: The next wave of off-the-shelf CAR immunotherapies. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1691743"},{"key":"ref_155","doi-asserted-by":"crossref","unstructured":"Yerinde, C., Siegmund, B., Glauben, R., and Weidinger, C. (2019). Metabolic Control of Epigenetics and Its Role in CD8(+) T Cell Differentiation and Function. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02718"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1016\/j.tibs.2024.10.005","article-title":"A two-way relationship between histone acetylation and metabolism","volume":"49","author":"Charidemou","year":"2024","journal-title":"Trends Biochem. Sci."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1111\/imm.13575","article-title":"Metabolic plasticity and regulation of T cell exhaustion","volume":"167","author":"Li","year":"2022","journal-title":"Immunology"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"2640","DOI":"10.1158\/0008-5472.CAN-21-4052","article-title":"Intracellular Acetyl CoA Potentiates the Therapeutic Efficacy of Antitumor CD8+ T Cells","volume":"82","author":"Chowdhury","year":"2022","journal-title":"Cancer Res."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"eadj3020","DOI":"10.1126\/science.adj3020","article-title":"Nutrient-driven histone code determines exhausted CD8(+) T cell fates","volume":"387","author":"Ma","year":"2025","journal-title":"Science"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/s41467-020-20696-x","article-title":"Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming","volume":"12","author":"Wang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/s41586-019-1805-z","article-title":"c-Jun overexpression in CAR T cells induces exhaustion resistance","volume":"576","author":"Lynn","year":"2019","journal-title":"Nature"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"eadw7685","DOI":"10.1126\/sciimmunol.adw7685","article-title":"Modulating AP-1 enables CAR T cells to establish an intratumoral stemlike reservoir and overcomes resistance to PD-1 blockade","volume":"11","author":"Snyder","year":"2026","journal-title":"Sci. Immunol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1158\/2159-8290.CD-22-1350","article-title":"SUV39H1 Ablation Enhances Long-term CAR T Function in Solid Tumors","volume":"14","author":"Fuentealba","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13148-026-02085-1","article-title":"Epigenetic editing to advance CAR T cell therapy","volume":"18","author":"Horvathova","year":"2026","journal-title":"Clin. Epigenet."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0140-6736(24)02462-0","article-title":"Induced pluripotent stem-cell-derived CD19-directed chimeric antigen receptor natural killer cells in B-cell lymphoma: A phase 1, first-in-human trial","volume":"405","author":"Ghobadi","year":"2025","journal-title":"Lancet"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"218257","DOI":"10.1016\/j.canlet.2026.218257","article-title":"Programmable Smart CAR-T design: A new paradigm in precision immunotherapy driven by logic gates, conditional activation, allogeneic strategies, and artificial intelligence","volume":"640","author":"Wen","year":"2026","journal-title":"Cancer Lett."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1016\/j.ccell.2025.09.013","article-title":"Engineered natural killer cells for cancer therapy","volume":"43","author":"Rezvani","year":"2025","journal-title":"Cancer Cell"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1038\/s41590-023-01659-y","article-title":"Forks in the road for CAR T and CAR NK cell cancer therapies","volume":"24","author":"Dagher","year":"2023","journal-title":"Nat. Immunol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1126\/science.285.5428.727","article-title":"Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA","volume":"285","author":"Bauer","year":"1999","journal-title":"Science"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"0023","DOI":"10.34133\/cancomm.0023","article-title":"Harnessing the Power of CAR-NK Cells for Solid Tumors: Challenges, Innovations, and Future Frontiers in Immunotherapy","volume":"46","author":"An","year":"2026","journal-title":"Cancer Commun."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1056\/NEJMoa1910607","article-title":"Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors","volume":"382","author":"Liu","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1038\/s41591-023-02785-8","article-title":"Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: A phase 1\/2 trial","volume":"30","author":"Marin","year":"2024","journal-title":"Nat. Med."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/s43018-025-00940-3","article-title":"Safety and feasibility of 4-1BB co-stimulated CD19-specific CAR-NK cell therapy in refractory\/relapsed large B cell lymphoma: A phase 1 trial","volume":"6","author":"Lei","year":"2025","journal-title":"Nat. Cancer"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00262-025-04196-9","article-title":"NKG2D CAR-NK adoptive cellular immunotherapy combined with or without PD-1 blockade in the treatment of patients with metastatic colorectal cancer: An exploratory study","volume":"74","author":"Wang","year":"2025","journal-title":"Cancer Immunol. Immunother. CII"},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"4509","DOI":"10.1016\/j.ymthe.2025.05.026","article-title":"Intraperitoneal infusion of NKG2D CAR-NK cells induces endogenous CD8(+) T cell activation in patients with advanced colorectal cancer","volume":"33","author":"Li","year":"2025","journal-title":"Mol. Ther."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1053\/j.gastro.2021.12.281","article-title":"Off-the-Shelf Prostate Stem Cell Antigen-Directed Chimeric Antigen Receptor Natural Killer Cell Therapy to Treat Pancreatic Cancer","volume":"162","author":"Teng","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1186\/s12967-024-05851-y","article-title":"Repurposing anti-mesothelin CAR-NK immunotherapy against colorectal cancer","volume":"22","author":"Torchiaro","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_178","doi-asserted-by":"crossref","unstructured":"Yang, L., Pham, K., Xi, Y., Wu, Q., Liu, D., Robertson, K.D., and Liu, C. (2025). Exploring Glypican-3 targeted CAR-NK treatment and potential therapy resistance in hepatocellular carcinoma. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0317401"},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.ymthe.2017.12.012","article-title":"Development of GPC3-specific chimeric antigen receptor-engineered natural killer cells for the treatment of hepatocellular carcinoma","volume":"26","author":"Yu","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s13046-026-03722-6","article-title":"Dual CAR-NK cells targeting PD-L1 and ErbB2 (HER2) exhibit cooperative CAR signaling and counteract solid tumor heterogeneity","volume":"45","author":"Schuldt","year":"2026","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_181","doi-asserted-by":"crossref","unstructured":"Hou, Y., Hu, S., Liu, C., Chen, X., Wang, Y., Li, Y., Fu, Z., Feng, C., Gong, Y., and Liu, Z. (2025). Beyond CAR-T Cells: Exploring CAR-NK, CAR-M, and CAR-\u03b3\u03b4 T strategies in solid tumor immunotherapy. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1675807"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"8809","DOI":"10.1038\/s41467-025-63863-8","article-title":"Selective HLA knockdown and PD-L1 expression prevent allogeneic CAR-NK cell rejection and enhance safety and anti-tumor responses in xenograft mice","volume":"16","author":"Liu","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"5516","DOI":"10.1016\/j.ymthe.2025.08.014","article-title":"Preclinical development and a phase 1 trial of IMC001, an EpCAM-targeted CAR-T cell therapy, in patients with advanced gastric cancer","volume":"33","author":"Fang","year":"2025","journal-title":"Mol. Ther."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"2671","DOI":"10.1007\/s12015-026-11156-y","article-title":"Induced Pluripotent Stem Cell-Derived NK Cells as an Off-the-Shelf Platform for Cancer Immunotherapy: Opportunities, Challenges, and Clinical Translation","volume":"22","author":"Manshadi","year":"2026","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1016\/j.stem.2025.05.007","article-title":"Preferential tumor targeting of HER2 by iPSC-derived CAR T cells engineered to overcome multiple barriers to solid tumor efficacy","volume":"32","author":"Hosking","year":"2025","journal-title":"Cell Stem Cell"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"e2517786122","DOI":"10.1073\/pnas.2517786122","article-title":"Targeting orthotopic and metastatic pancreatic cancer with allogeneic stem cell-engineered mesothelin-redirected CAR-NKT cells","volume":"122","author":"Li","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1080\/07357907.2025.2548603","article-title":"Tandem Dual CAR-T Cells Targeting HER2 and Mesothelin Enhance anti-Tumor Effects in Pancreatic Cancer","volume":"43","author":"Jiang","year":"2025","journal-title":"Cancer Investig."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1186\/s13287-021-02648-4","article-title":"Targeted integration of EpCAM-specific CAR in human induced pluripotent stem cells and their differentiation into NK cells","volume":"12","author":"Tang","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1158\/2159-8290.CD-24-0102","article-title":"CD70-Targeted Allogeneic CAR T-Cell Therapy for Advanced Clear Cell Renal Cell Carcinoma","volume":"14","author":"Pal","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41423-018-0024-0","article-title":"NETosis, complement, and coagulation: A triangular relationship","volume":"16","author":"Boelens","year":"2019","journal-title":"Cell. Mol. Immunol."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"116981","DOI":"10.1016\/j.intimp.2026.116981","article-title":"Development of super V\u03b42 T cells for relapsed\/refractory acute myeloid Leukemia via non-viral site-specific integration","volume":"185","author":"Liu","year":"2026","journal-title":"Int. Immunopharmacol."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"e011890","DOI":"10.1136\/jitc-2025-011890","article-title":"Comparative efficacy and safety of PSCA CAR-engineered V\u03b41 \u03b3\u03b4 T cells for immunotherapy of pancreatic cancer","volume":"13","author":"Li","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_193","doi-asserted-by":"crossref","unstructured":"Niedzielska, M., Chalmers, A., Popis, M.C., Altman-Sharoni, E., Addis, S., Beulen, R., Rudqvist, N.P., Chantzoura, E., Purbhoo, M.A., and Chand, D. (2025). CAR-iNKT cells: Redefining the frontiers of cellular immunotherapy. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1625426"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"e179014","DOI":"10.1172\/JCI179014","article-title":"Off-the-shelf invariant NKT cells expressing anti-PSCA CAR and IL-15 promote pancreatic cancer regression in mice","volume":"135","author":"Dai","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/j.stem.2024.03.018","article-title":"Human anti-PSCA CAR macrophages possess potent antitumor activity against pancreatic cancer","volume":"31","author":"Shah","year":"2024","journal-title":"Cell Stem Cell"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12943-025-02538-w","article-title":"Synergistic innate-adaptive immunity by NKG2D-specific CAR-macrophages drives durable remission in hepatocellular carcinoma","volume":"25","author":"Zhao","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/349329a0","article-title":"Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice","volume":"349","author":"Bix","year":"1991","journal-title":"Nature"},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1016\/j.stem.2024.06.011","article-title":"Genetic ablation of adhesion ligands mitigates rejection of allogeneic cellular immunotherapies","volume":"31","author":"Hammer","year":"2024","journal-title":"Cell Stem Cell"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1182\/blood.2022016204","article-title":"Genome-edited allogeneic donor \u201cuniversal\u201d chimeric antigen receptor T cells","volume":"141","author":"Qasim","year":"2023","journal-title":"Blood"},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"3453","DOI":"10.1038\/s41467-022-30896-2","article-title":"Endowing universal CAR T-cell with immune-evasive properties using TALEN-gene editing","volume":"13","author":"Jo","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"101991","DOI":"10.1016\/j.jcyt.2025.10.001","article-title":"A differentiated and durable allogeneic strategy applicable to cell therapies","volume":"28","author":"Jetley","year":"2026","journal-title":"Cytotherapy"},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1097\/CJI.0000000000000413","article-title":"Clinical Grade Manufacture of CYAD-101, a NKG2D-based, First in Class, Non-Gene-edited Allogeneic CAR T-Cell Therapy","volume":"45","author":"Michaux","year":"2022","journal-title":"J. Immunother."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1200\/JCO.2021.39.3_suppl.74","article-title":"Updated data from the alloSHRINK phase 1 first-in-Human study evaluating CYAD-101, an innovative non-Gene-Edited allogeneic CAR-T, in metastatic colorectal cancer","volume":"39","author":"Prenen","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"4508","DOI":"10.1200\/JCO.2025.43.16_suppl.4508","article-title":"ALLO-316 in advanced clear cell renal cell carcinoma (ccRCC): Updated results from the phase 1 TRAVERSE study","volume":"43","author":"Srour","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"e71918","DOI":"10.1002\/cam4.71918","article-title":"A Novel Strategy to Produce CAR-\u03b3\u03b4 T Cells via Site-Directed Gene Integration by a Combination of CRISPR\/Cas9 and AAV","volume":"15","author":"Dong","year":"2026","journal-title":"Cancer Med."},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1182\/blood-2017-08-752162","article-title":"The potential role of \u03b3\u03b4 T cells after allogeneic HCT for leukemia","volume":"131","author":"Handgretinger","year":"2018","journal-title":"Blood"},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/s41573-025-01291-5","article-title":"In vivo chimeric antigen receptor (CAR)-T cell therapy","volume":"25","author":"Bot","year":"2026","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"e2509698123","DOI":"10.1073\/pnas.2509698123","article-title":"Lipid nanoparticle-mediated in vivo generation of panCAR immune cells for solid tumor immunotherapy","volume":"123","author":"Yin","year":"2026","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"114379","DOI":"10.1016\/j.jconrel.2025.114379","article-title":"In vivo nano-engineering T cells for CAR-T therapy","volume":"388","author":"Shi","year":"2025","journal-title":"J. Control. Release"},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"115043","DOI":"10.1016\/j.jconrel.2026.115043","article-title":"Rapid receptor internalization potentiates CD7-targeted lipid nanoparticles for efficient mRNA delivery to T cells and in vivo CAR T-cell engineering","volume":"396","author":"Zeng","year":"2026","journal-title":"J. Control. Release"},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"e011759","DOI":"10.1136\/jitc-2025-011759","article-title":"T cell-specific non-viral DNA delivery and in vivo CAR-T generation using targeted lipid nanoparticles","volume":"13","author":"Bimbo","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"TPS4218","DOI":"10.1200\/JCO.2025.43.16_suppl.TPS4218","article-title":"A first-in-human study of MT-303, an innovative in vivo mRNA chimeric antigen receptor (CAR) therapy targeting GPC3, in adults with hepatocellular carcinoma","volume":"43","author":"Humphries","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"eady6730","DOI":"10.1126\/scitranslmed.ady6730","article-title":"In vivo generation of CAR myeloid cells through erythrocyte-mediated mRNA delivery for cancer immunotherapy","volume":"18","author":"Nie","year":"2026","journal-title":"Sci. Transl. Med."},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/mt.2010.24","article-title":"Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2","volume":"18","author":"Morgan","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"10743","DOI":"10.1038\/s41467-024-53220-6","article-title":"PSCA-targeted BPX-601 CAR T cells with pharmacological activation by rimiducid in metastatic pancreatic and prostate cancer: A phase 1 dose escalation trial","volume":"15","author":"Stein","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"3596","DOI":"10.1158\/0008-5472.CAN-15-0159","article-title":"Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice","volume":"75","author":"Liu","year":"2015","journal-title":"Cancer Res."},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"e008566","DOI":"10.1136\/jitc-2023-008566","article-title":"Systemically administered low-affinity HER2 CAR T cells mediate antitumor efficacy without toxicity","volume":"12","author":"Shabaneh","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1158\/1535-7163.MCT-22-0073","article-title":"Development of Highly Effective Anti-Mesothelin hYP218 Chimeric Antigen Receptor T Cells With Increased Tumor Infiltration and Persistence for Treating Solid Tumors","volume":"21","author":"Tomar","year":"2022","journal-title":"Mol. Cancer Ther."},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"TPS788","DOI":"10.1200\/JCO.2025.43.4_suppl.TPS788","article-title":"EVEREST-2: A seamless phase 1\/2 study of A2B694, a logic-gated Tmod chimeric antigen receptor T-cell (CAR T) therapy, in patients with pancreatic cancer (PANC) or other mesothelin (MSLN)-expressing solid tumors and human leukocyte antigen (HLA)\u2013A*02 loss of heterozygosity (LOH)","volume":"43","author":"Spencer","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"eaau5907","DOI":"10.1126\/scitranslmed.aau5907","article-title":"The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on\/off switch for CAR T cells","volume":"11","author":"Mestermann","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1016\/j.ccell.2022.08.008","article-title":"High-performance multiplex drug-gated CAR circuits","volume":"40","author":"Li","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"eabb6295","DOI":"10.1126\/scitranslmed.abb6295","article-title":"Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide","volume":"13","author":"Jan","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"e2405085121","DOI":"10.1073\/pnas.2405085121","article-title":"Dual ON\/OFF-switch chimeric antigen receptor controlled by two clinically approved drugs","volume":"121","author":"Shui","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1016\/j.ymthe.2019.03.011","article-title":"Adoptive Transfer of NKG2D CAR mRNA-Engineered Natural Killer Cells in Colorectal Cancer Patients","volume":"27","author":"Xiao","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1053\/j.gastro.2018.03.029","article-title":"Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial","volume":"155","author":"Beatty","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"S580","DOI":"10.1016\/j.annonc.2025.08.1514","article-title":"945P A phase I trial of KD-496, a CLDN18.2\/NKG2D dual targeting CAR-T, in patients with gastrointestinal cancers","volume":"36","author":"Qi","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1007\/s00262-025-04039-7","article-title":"Enhancing mesothelin CAR T cell therapy for pancreatic cancer with an oncolytic herpes virus boosting CAR target antigen expression","volume":"74","author":"Aboalela","year":"2025","journal-title":"Cancer Immunol. Immunother. CII"},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1200\/JCO.2026.44.16_suppl.2508","article-title":"Objective response rates with Ori-C101, an armored GPC3-directed CAR-T, in heavily pretreated advanced HCC: Updated results from the phase Ib BEACON study","volume":"44","author":"Fan","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"102175","DOI":"10.1016\/j.eclinm.2023.102175","article-title":"RUNX-3-expressing CAR T cells targeting glypican-3 in patients with heavily pretreated advanced hepatocellular carcinoma: A phase I trial","volume":"63","author":"Fu","year":"2023","journal-title":"eClinicalMedicine"},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"3979","DOI":"10.1158\/1078-0432.CCR-19-3259","article-title":"Chimeric antigen receptor-glypican-3 T-cell therapy for advanced hepatocellular carcinoma: Results of phase I trials","volume":"26","author":"Shi","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_231","doi-asserted-by":"crossref","first-page":"e1440169","DOI":"10.1080\/2162402X.2018.1440169","article-title":"CD133-directed CAR T cells for advanced metastasis malignancies: A phase I trial","volume":"7","author":"Wang","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_232","doi-asserted-by":"crossref","unstructured":"Yang, C., You, J., Pan, Q., Tang, Y., Cai, L., Huang, Y., Gu, J., Wang, Y., Yang, X., and Du, Y. (2023). Targeted delivery of a PD-1-blocking scFv by CD133-specific CAR-T cells using nonviral Sleeping Beauty transposition shows enhanced antitumour efficacy for advanced hepatocellular carcinoma. BMC Med., 21.","DOI":"10.1186\/s12916-023-03016-0"},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1016\/j.ymthe.2019.04.020","article-title":"Combined antitumor effects of sorafenib and GPC3-CAR T cells in mouse models of hepatocellular carcinoma","volume":"27","author":"Wu","year":"2019","journal-title":"Mol. Ther."},{"key":"ref_234","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1200\/JCO.2026.44.16_suppl.2557","article-title":"Long-term follow-up of satricabtagene autoleucel (satri-cel) as sequential therapy after first-line treatment for advanced gastric cancer: A subgroup analysis","volume":"44","author":"Liu","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_235","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1200\/JCO.2026.44.16_suppl.2543","article-title":"Safety and preliminary efficacy of a novel armored mesothelin-targeted CAR-T therapy in advanced solid tumors","volume":"44","author":"Qi","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1158\/1078-0432.CCR-25-2907","article-title":"Ibrutinib and PD-1 Blockade Potentiate Mesothelin-Targeting CAR T-cell Therapy in Preclinical Models of Pancreatic Cancer","volume":"32","author":"Armstrong","year":"2026","journal-title":"Clin. Cancer Res."},{"key":"ref_237","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1016\/j.ymthe.2025.12.068","article-title":"Dual-targeting CD133\/PD-L1 CAR-T plus \u03b1PD-1 overcomes immunosuppressive microenvironment and enhanced by radiation pre-conditioning","volume":"34","author":"Yao","year":"2026","journal-title":"Mol. Ther."},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"e2403002121","DOI":"10.1073\/pnas.2403002121","article-title":"Proton radiation boosts the efficacy of mesothelin-targeting chimeric antigen receptor T cell therapy in pancreatic cancer","volume":"121","author":"Amit","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1007\/s11426-025-2885-x","article-title":"Pursuing precise cancer therapy: Tumor microenvironment-triggered hydrogen bond self-assembly enables photoreaction transition from type II to type I","volume":"69","author":"Ye","year":"2026","journal-title":"Sci. China Chem."},{"key":"ref_240","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1007\/s00262-025-04267-x","article-title":"Preclinical evaluation of CAR-T cell immunotherapy with a fully human EpCAM-specific scFv against pancreatic cancer","volume":"75","author":"Fan","year":"2025","journal-title":"Cancer Immunol. Immunother."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/9\/1449\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T08:14:18Z","timestamp":1789373658000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/9\/1449"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,12]]},"references-count":240,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ph19091449"],"URL":"https:\/\/doi.org\/10.3390\/ph19091449","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,12]]}}}