{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:16:41Z","timestamp":1785428201548,"version":"3.56.0"},"reference-count":165,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Key Research and Development Program of China","award":["\uff082023YFC3404304, 2024YFC3406800\uff09"],"award-info":[{"award-number":["\uff082023YFC3404304, 2024YFC3406800\uff09"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["(82260154, 82460153, 82400891)"],"award-info":[{"award-number":["(82260154, 82460153, 82400891)"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["(82260154, 82460153, 82400891)"],"award-info":[{"award-number":["(82260154, 82460153, 82400891)"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Hainan Provincial Health and Health Technology Innovation Joint Project","award":["(WSJK2025MS163)"],"award-info":[{"award-number":["(WSJK2025MS163)"]}]},{"name":"Hainan Provincial Science and Technology Talent Innovation Project","award":["(KJRC2023B08)"],"award-info":[{"award-number":["(KJRC2023B08)"]}]},{"name":"Hainan Provincial Outstanding Talent Team Building Program, and the Hainan Provincial Department of Education","award":["(Hnky2025ZD-8)"],"award-info":[{"award-number":["(Hnky2025ZD-8)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Clear cell renal cell carcinoma (ccRCC) accounts for approximately 75% of renal cell carcinomas and is defined by near-universal VHL inactivation, leading to constitutive HIF stabilisation, metabolic reprogramming, and an immunologically distinct tumour microenvironment (TME). Although ccRCC is characterised by abundant immune infiltration, this paradoxically correlates with poor prognosis, reflecting a TME that imposes interconnected physical, immunological, and metabolic barriers to effective immunotherapy. Chimeric antigen receptor (CAR)-based therapies have revolutionised the treatment of haematological malignancies, but their translation to ccRCC has encountered substantial hurdles. The first-in-human trial targeting carbonic anhydrase IX (CAIX) was limited by on-target off-tumour toxicity and CAR immunogenicity\u2014lessons that fundamentally reshaped the field. CD70 has since emerged as the dominant clinical target, expressed in over 80% of ccRCCs with a highly restricted normal tissue distribution. The phase I COBALT-RCC trial of CTX130, an allogeneic CRISPR-Cas9-edited CD70-directed CAR-T cell product, provided formal proof of concept, achieving disease control in 81.3% of heavily pretreated patients and a durable complete response now exceeding three years\u2014the first such sustained remission reported for any CAR-T cell product in a solid malignancy. Nevertheless, the low frequency of durable responses and universal loss of CAR-T cell persistence by day 28 underscore that major barriers remain. Beyond CD70, the field has diversified across multiple platforms, including CAR\u2013natural killer (NK) cells, CAR\u2013natural killer T (NKT) cells, and CAR\u2013macrophages, each offering distinct biological advantages. This review synthesises current knowledge of the ccRCC TME, the preclinical landscape of CAR-based therapies, and emerging clinical evidence from more than 30 registered trials. We discuss target antigens; engineering strategies to overcome TME barriers, including cytokine armouring, chemokine receptor co-expression, switch receptors, and metabolic reprogramming; and rational combination approaches. We argue that the convergence of optimised target selection, cellular engineering, combination strategies, and biomarker-driven trial design may ultimately improve outcomes for patients with ccRCC. However, achieving a cure remains an aspirational goal, and significant barriers must first be overcome.<\/jats:p>","DOI":"10.3390\/cancers18132051","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T01:03:56Z","timestamp":1782349436000},"page":"2051","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chimeric Antigen Receptor\u2013Immune Cell-Based Therapies for Clear Cell Renal Cell Carcinoma: Latest Advancements and Directions"],"prefix":"10.3390","volume":"18","author":[{"given":"Xuyuan","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Kidney Transplantation, The Second Affiliated Hospital of Hainan Medical University, Haikou 570311, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Kidney Transplantation, The Second Affiliated Hospital of Hainan Medical University, Haikou 570311, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Kidney Transplantation, The Second Affiliated Hospital of Hainan Medical University, Haikou 570311, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6982-3154","authenticated-orcid":false,"given":"Shanda","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Kidney Transplantation, The Second Affiliated Hospital of Hainan Medical University, Haikou 570311, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Kidney Transplantation, The Second Affiliated Hospital of Hainan Medical University, Haikou 570311, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Kidney Transplantation, The Second Affiliated Hospital of Hainan Medical University, Haikou 570311, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojie","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, The Second Affiliated Hospital of Hainan Medical University, Haikou 570311, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuona","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Physiology, Zhejiang Chinese Medical University, Hangzhou 310053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongtao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Kidney Transplantation, The Second Affiliated Hospital of Hainan Medical University, Haikou 570311, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kase, A.M., George, D.J., and Ramalingam, S. (2023). Clear Cell Renal Cell Carcinoma: From Biology to Treatment. Cancers, 15.","DOI":"10.3390\/cancers15030665"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kim, M.C., Jin, Z., Kolb, R., Borcherding, N., Chatzkel, J.A., Falzarano, S.M., and Zhang, W. (2021). Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma. Cancers, 13.","DOI":"10.3390\/cancers13225856"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/s41581-025-00983-w","article-title":"Immunological features of clear-cell renal-cell carcinoma and resistance to immune checkpoint inhibitors","volume":"21","author":"Burgers","year":"2025","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1001\/jama.2024.12848","article-title":"Renal Cell Carcinoma: A Review","volume":"332","author":"Rose","year":"2024","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1056\/NEJMoa1200690","article-title":"Safety, activity, and immune correlates of anti-PD-1 antibody in cancer","volume":"366","author":"Topalian","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Zhu, Z., Jin, Y., Zhou, J., Chen, F., Chen, M., Gao, Z., Hu, L., Xuan, J., Li, X., and Song, Z. (2024). PD1\/PD-L1 blockade in clear cell renal cell carcinoma: Mechanistic insights, clinical efficacy, and future perspectives. Mol. Cancer, 23.","DOI":"10.1186\/s12943-024-02059-y"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Wang, M., Zhao, Y., Xu, K., Liu, C., Zhong, H., Wu, Y., Zhang, K., and Wei, S. (2025). Cancer-associated fibroblasts in clear cell renal cell carcinoma: Functional heterogeneity, tumor microenvironment crosstalk, and therapeutic opportunities. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1617968"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kouro, T., Sasada, T., and Imai, K. (2025). Mechanistic insights into the limited function of CAR-T cells in solid tumors and potential solutions. Int. Immunopharmacol., 161.","DOI":"10.1016\/j.intimp.2025.115010"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"E162","DOI":"10.1002\/ajh.26123","article-title":"Humanized CD19-targeted chimeric antigen receptor T (CAR-T) cells for relapsed\/refractory pediatric acute lymphoblastic leukemia","volume":"96","author":"Wang","year":"2021","journal-title":"Am. J. Hematol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Vo, M.C., Tran, V.D., Nguyen, V.T., Ruzimurodov, N., Trung, D.T., Kim, S.K., Jung, S.H., and Lee, J.J. (2025). Challenges and limitations of chimeric antigen receptor T-cell therapies in solid tumors: Why are approvals restricted to hematologic malignancies?. J. Hematol. Oncol., 18.","DOI":"10.1186\/s13045-025-01744-9"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.clgc.2023.12.003","article-title":"CD70 is Consistently Expressed in Primary and Metastatic Clear Cell Renal Cell Carcinoma","volume":"22","author":"Huang","year":"2024","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_12","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_13","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.tips.2024.07.002","article-title":"\u2018Living drugs\u2019 target CD70 in advanced renal tumors","volume":"45","author":"Wagner","year":"2024","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2800","DOI":"10.1200\/JCO.23.02082","article-title":"Bempegaldesleukin Plus Nivolumab Versus Sunitinib or Cabozantinib in Previously Untreated Advanced Clear Cell Renal Cell Carcinoma: A Phase III Randomized Study (PIVOT-09)","volume":"42","author":"Tannir","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1634\/theoncologist.2015-0143","article-title":"Hypertension and Circulating Cytokines and Angiogenic Factors in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma Treated With Sunitinib: Results From a Phase II Trial","volume":"20","author":"Bilen","year":"2015","journal-title":"Oncologist"},{"key":"ref_16","first-page":"275","article-title":"CAR NK cell therapy for solid tumors: Potential and challenges","volume":"8","author":"Yu","year":"2025","journal-title":"Antib. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1182\/blood.2022016201","article-title":"Natural killer T cells and other innate-like T lymphocytes as emerging platforms for allogeneic cancer cell therapy","volume":"141","author":"Courtney","year":"2023","journal-title":"Blood"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"And\u00f3n, F.T., Rosales S\u00e1nchez, A., Pensado-L\u00f3pez, A., Garc\u00eda-Campelo, R., and Takimoto, C.H. (2026). Engineering macrophages for effective and safe targeting of CD47 cancer cells in the tumor microenvironment. J. Immunother. Cancer, 14.","DOI":"10.1136\/jitc-2025-014457"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41581-020-00359-2","article-title":"Clear cell renal cell carcinoma ontogeny and mechanisms of lethality","volume":"17","author":"Jonasch","year":"2021","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1016\/j.cell.2018.02.020","article-title":"Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal","volume":"173","author":"Mitchell","year":"2018","journal-title":"Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1056\/NEJMoa2103425","article-title":"Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease","volume":"385","author":"Jonasch","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1016\/j.apsb.2015.05.007","article-title":"HIF-1\u03b1 pathway: Role, regulation and intervention for cancer therapy","volume":"5","author":"Masoud","year":"2015","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Garcia, J., Hurwitz, H.I., Sandler, A.B., Miles, D., Coleman, R.L., Deurloo, R., and Chinot, O.L. (2020). Bevacizumab (Avastin\u00ae) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat. Rev., 86.","DOI":"10.1016\/j.ctrv.2020.102017"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Wang, Y., Lu, J., Lin, B., Chen, J., Lin, F., Zheng, Q., Xue, X., Wei, Y., Chen, S., and Xu, N. (2025). Integrated analysis of MIOX gene in prognosis of clear-cell renal cell carcinoma. Cell Death Dis., 16.","DOI":"10.1038\/s41419-025-07698-7"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Zhang, J., and Zhang, Q. (2018). VHL and Hypoxia Signaling: Beyond HIF in Cancer. Biomedicines, 6.","DOI":"10.3390\/biomedicines6010035"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Yang, G., Cheng, J., Xu, J., Shen, C., Lu, X., He, C., Huang, J., He, M., Cheng, J., and Wang, H. (2024). Metabolic heterogeneity in clear cell renal cell carcinoma revealed by single-cell RNA sequencing and spatial transcriptomics. J. Transl. Med., 22.","DOI":"10.1186\/s12967-024-04848-x"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1038\/s41586-024-07812-3","article-title":"Mitochondrial complex I promotes kidney cancer metastasis","volume":"633","author":"Bezwada","year":"2024","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zhan, M., Zhao, B., Chen, H., Wu, J., Shi, R., Gao, F., Zhao, L., and Zhu, J. (2025). Metabolic reprogramming in clear cell renal cell carcinoma: Core pathways and targeted therapeutic strategies. Front. Genet., 16.","DOI":"10.3389\/fgene.2025.1752384"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1158\/1078-0432.CCR-14-1425","article-title":"pVHL\/HIF-regulated CD70 expression is associated with infiltration of CD27+ lymphocytes and increased serum levels of soluble CD27 in clear cell renal cell carcinoma","volume":"21","author":"Ruf","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.cell.2018.03.043","article-title":"Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal","volume":"173","author":"Turajlic","year":"2018","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.ymthe.2020.09.034","article-title":"Olaparib Suppresses MDSC Recruitment via SDF1\u03b1\/CXCR4 Axis to Improve the Anti-tumor Efficacy of CAR-T Cells on Breast Cancer in Mice","volume":"29","author":"Sun","year":"2021","journal-title":"Mol. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.arbres.2024.02.013","article-title":"Dysregulation in CD39\/CD73 Axis May Trigger the Upsurge of the Immune Suppressive Agent Adenosine in OSA Patients","volume":"60","author":"Alfaro","year":"2024","journal-title":"Arch. Bronconeumol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Li, H.R., Xiong, J., Wang, C.H., Hu, L.B., Wang, Y.B., Ping, Q.R., Yang, M., Tan, J., Li, T.T., and Yang, Y. (2025). CAR-T cell therapy for solid tumors: HIF-1\u03b1 as a potential enhancement strategy. Autoimmunity, 58.","DOI":"10.1080\/08916934.2025.2579069"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.ccell.2021.02.013","article-title":"Progressive immune dysfunction with advancing disease stage in renal cell carcinoma","volume":"39","author":"Braun","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.ccell.2021.02.015","article-title":"Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma","volume":"39","author":"Bi","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1016\/j.tem.2025.08.009","article-title":"CD8(+) T cell stressors converge on shared metabolic-epigenetic networks","volume":"37","author":"Shangguan","year":"2025","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Komahashi, M., Horaguchi, S., Tsuji, K., Hoshino, D., Kishida, T., Usui, K., Nakaigawa, N., Sato, S., Hamana, H., and Kishi, H. (2026). Tumor-reactive TCRs within exhausted TILs reveal cancer type-specific immune landscapes in renal cell carcinoma. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1729388"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Cao, L., Meng, X., Zhang, Z., Liu, Z., and He, Y. (2024). Macrophage heterogeneity and its interactions with stromal cells in tumour microenvironment. Cell Biosci., 14.","DOI":"10.1186\/s13578-024-01201-z"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Guo, F., Gao, Y., Zhou, P., Wang, H., Ma, Z., Wang, X., Wang, X., Feng, X., Wang, Y., and Han, Z. (2024). Single-cell analysis reveals that TCF7L2 facilitates the progression of ccRCC via tumor-associated macrophages. Cell Signal, 124.","DOI":"10.1016\/j.cellsig.2024.111453"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1158\/2159-8290.CD-19-0273","article-title":"A FATal Combination: Fibroblast-Derived Lipids and Cancer-Derived Autotaxin Promote Pancreatic Cancer Growth","volume":"9","author":"Biffi","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.actbio.2022.01.040","article-title":"Targeting extracellular matrix glycation to attenuate fibroblast activation","volume":"141","author":"Jang","year":"2022","journal-title":"Acta Biomater."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Li, S., Zhou, X., Feng, H., Huang, K., Chen, M., Lin, M., Lin, H., Deng, Z., Chen, Y., and Liao, W. (2025). Deciphering the Immunomodulatory Function of GSN (+) Inflammatory Cancer-Associated Fibroblasts in Renal Cell Carcinoma Immunotherapy: Insights From Pan-Cancer Single-Cell Landscape and Spatial Transcriptomics Analysis. Cell Prolif., 58.","DOI":"10.1111\/cpr.70062"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.immuni.2022.02.001","article-title":"Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer","volume":"55","author":"Meylan","year":"2022","journal-title":"Immunity"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Xu, W., Lu, J., Tian, X., Ye, S., Wei, S., Wang, J., Anwaier, A., Qu, Y., Liu, W., and Chang, K. (2024). Unveiling the impact of tertiary lymphoid structures on immunotherapeutic responses of clear cell renal cell carcinoma. MedComm, 5.","DOI":"10.1002\/mco2.461"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Wang, Y.Q., Chen, W.J., Zhou, W., Dong, K.Q., Zuo, L., Xu, D., Chen, J.X., Chen, W.J., Li, W.Y., and Liu, Z.C. (2024). Integrated analysis of tertiary lymphoid structures and immune infiltration in ccRCC microenvironment revealed their clinical significances: A multicenter cohort study. J. Immunother. Cancer, 12.","DOI":"10.1136\/jitc-2023-008613"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Oxburgh, L. (2022). The Extracellular Matrix Environment of Clear Cell Renal Cell Carcinoma. Cancers, 14.","DOI":"10.3390\/cancers14174072"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Zvirblyte, J., Nainys, J., Juzenas, S., Goda, K., Kubiliute, R., Dasevicius, D., Kincius, M., Ulys, A., Jarmalaite, S., and Mazutis, L. (2024). Single-cell transcriptional profiling of clear cell renal cell carcinoma reveals a tumor-associated endothelial tip cell phenotype. Commun. Biol., 7.","DOI":"10.1038\/s42003-024-06478-x"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Arreola, A., Payne, L.B., Julian, M.H., de Cubas, A.A., Daniels, A.B., Taylor, S., Zhao, H., Darden, J., Bautch, V.L., and Rathmell, W.K. (2018). Von Hippel-Lindau mutations disrupt vascular patterning and maturation via Notch. JCI Insight, 3.","DOI":"10.1172\/jci.insight.92193"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/s41581-023-00800-2","article-title":"Metabolic alterations in hereditary and sporadic renal cell carcinoma","volume":"20","author":"Coffey","year":"2024","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1158\/1078-0432.CCR-18-2882","article-title":"Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan-Kynurenine-Aryl Hydrocarbon Axis","volume":"25","author":"Labadie","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Saad, S.H., Kashanchi, A., Zadeh, M.A., Williams, A., and Batrakova, E.V. (2025). Exosome-Mediated Crosstalk Between Cancer Cells and Tumor Microenvironment. Cells, 14.","DOI":"10.3390\/cells14221750"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Huang, Y., Sun, H., and Guo, P. (2023). Research Progress of Tumor Microenvironment Targeted Therapy for Clear Cell Renal Cell Carcinoma. Cancer Control, 30.","DOI":"10.1177\/10732748231155700"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.ccell.2016.03.004","article-title":"Exosome-Transmitted lncARSR Promotes Sunitinib Resistance in Renal Cancer by Acting as a Competing Endogenous RNA","volume":"29","author":"Qu","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.euf.2025.04.001","article-title":"Management of Metastatic Renal Cell Carcinoma: Guideline Updates","volume":"11","author":"Scavuzzo","year":"2025","journal-title":"Eur. Urol. Focus"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Capitanio, U., Fallara, G., Raggi, D., Nocera, L., Larcher, A., Belladelli, F., Rowe, I., Briganti, A., Salonia, A., and Karakiewicz, P. (2022). Pembrolizumab in advanced renal cell carcinoma: A meta-analysis providing level 1a evidence. Curr. Probl. Cancer, 46.","DOI":"10.1016\/j.currproblcancer.2022.100875"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1016\/j.cell.2023.03.016","article-title":"Fibroblasts in cancer: Unity in heterogeneity","volume":"186","author":"Chhabra","year":"2023","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Rysz, J., \u0141awi\u0144ski, J., Franczyk, B., and Gluba-Sagr, A. (2025). Immune Checkpoint Inhibitors in Clear Cell Renal Cell Carcinoma (ccRCC). Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26125577"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Darzi, A., Shokouhfar, M., Farajee, N., Ghafari, A., Deldar, F., Eini, P., Vanan, A.G., and Bahrami, N. (2025). Immune checkpoint inhibition in renal cell carcinoma: Mechanisms of resistance and emerging therapeutic strategies. Biomed. Pharmacother., 193.","DOI":"10.1016\/j.biopha.2025.118875"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1038\/s12276-020-00500-y","article-title":"Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity","volume":"52","author":"Lee","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Swamy, K. (2022). Vascular normalization and immunotherapy: Spawning a virtuous cycle. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1002957"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Zhang, H.-J., Han, L.-Z., Zhang, X., and Ge, Y.-L. (2026). Why CAR T cell therapy fails in renal cell carcinoma. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1828738"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Rosellini, M., Mollica, V., Marchetti, A., Coluccelli, S., Giunchi, F., Tassinari, E., Ricci, C., Fiorentino, M., Tallini, G., and De Biase, D. (2024). Chromosome 3p gene alterations as biomarkers for immunocombinations in metastatic renal cell carcinoma: A hypothesis-generating analysis. Pathol. Res. Pract., 254.","DOI":"10.1016\/j.prp.2024.155142"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/s41588-024-01662-5","article-title":"Multi-omic profiling of clear cell renal cell carcinoma identifies metabolic reprogramming associated with disease progression","volume":"56","author":"Hu","year":"2024","journal-title":"Nat. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Shi, W., Zhang, Z., Xu, X., Tian, Y., Feng, L., Huang, X., Du, Y., and Li, Z. (2025). Single-cell and spatial transcriptomics integration: New frontiers in tumor microenvironment and cellular communication. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1649468"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Mohammadi, M., Najafi, H., and Mohammadi, P. (2025). CAR T-cell therapy in renal cell carcinoma: Opportunities, challenges, and new strategies to overcome. Med. Oncol., 42.","DOI":"10.1007\/s12032-025-02735-z"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.ccell.2025.03.019","article-title":"CAR-T therapy in solid tumors","volume":"43","author":"Du","year":"2025","journal-title":"Cancer Cell"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Jansen, L., Wienke, J., Molkenbur, R., Rossig, C., and Meissner, R. (2025). B7-H3 in the tumor microenvironment: Implications for CAR T cell therapy in pediatric solid tumors. Cancer Metastasis Rev., 44.","DOI":"10.1007\/s10555-025-10294-y"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Emaldi, M., Rey-Iborra, E., Mar\u00edn, \u00c1., Mosteiro, L., Lecumberri, D., \u00d8yjord, T., Roncier, N., M\u00e6landsmo, G.M., Angulo, J.C., and Errarte, P. (2024). Impact of B7-H3 expression on metastasis, immune exhaustion and JAK\/STAT and PI3K\/AKT pathways in clear cell renal cell carcinoma. Oncoimmunology, 13.","DOI":"10.1080\/2162402X.2024.2419686"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.molimm.2024.10.006","article-title":"Preclinical assessment of the efficacy of B7-H3 CAR-T in renal cell carcinoma","volume":"176","author":"Li","year":"2024","journal-title":"Mol. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1007\/s12094-024-03792-y","article-title":"Development of B7-H3 targeted CAR-T cells for renal cell carcinoma therapy: In vitro and in vivo efficacy","volume":"27","author":"Deng","year":"2025","journal-title":"Clin. Transl. Oncol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Courcier, J., de la Taille, A., Nourieh, M., Leguerney, I., Lassau, N., and Ingels, A. (2020). Carbonic Anhydrase IX in Renal Cell Carcinoma, Implications for Disease Management. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197146"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Wang, Y., Buck, A., Piel, B., Zerefa, L., Murugan, N., Coherd, C.D., Miklosi, A.G., Johal, H., Bastos, R.N., and Huang, K. (2024). Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects. Mol. Cancer, 23.","DOI":"10.1186\/s12943-024-01952-w"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3038","DOI":"10.1039\/D5LC00062A","article-title":"Patient-derived organotypic tumor spheroids, tumoroids, and organoids: Advancing immunotherapy using state-of-the-art 3D tumor model systems","volume":"25","author":"Bozym","year":"2025","journal-title":"Lab. Chip"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.omto.2021.12.019","article-title":"Anti-CAIX BB\u03b6 CAR4\/8 T cells exhibit superior efficacy in a ccRCC mouse model","volume":"24","author":"Wang","year":"2022","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1097\/CJI.0000000000000301","article-title":"CAIX-specific CAR-T Cells and Sunitinib Show Synergistic Effects Against Metastatic Renal Cancer Models","volume":"43","author":"Li","year":"2020","journal-title":"J. Immunother."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Fang, L., Tian, W., Zhang, C., Wang, X., Li, W., Zhang, Q., Zhang, Y., and Zheng, J. (2023). Oncolytic adenovirus-mediated expression of CCL5 and IL12 facilitates CA9-targeting CAR-T therapy against renal cell carcinoma. Pharmacol. Res., 189.","DOI":"10.1016\/j.phrs.2023.106701"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Li, Q., Yang, L., Li, S., Zhao, W., Xue, Y., Lu, Z., Tang, J., Gao, X., Zheng, J., and Zhang, Q. (2024). Cabozantinib enhances CAIX specific CAR-T cells against renal cancer by improving effector functions and augmenting tumor immune microenvironment. Biochem. Biophys. Res. Commun., 734.","DOI":"10.1016\/j.bbrc.2024.150781"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Wang, Y., Cho, J.W., Kastrunes, G., Buck, A., Razimbaud, C., Culhane, A.C., Sun, J., Braun, D.A., Choueiri, T.K., and Wu, C.J. (2024). Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model. iScience, 27.","DOI":"10.1016\/j.isci.2024.108879"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"de Campos, N.S.P., de Oliveira Beserra, A., Pereira, P.H.B., Chaves, A.S., Fonseca, F.L.A., da Silva Medina, T., Dos Santos, T.G., Wang, Y., Marasco, W.A., and Suarez, E.R. (2022). Immune Checkpoint Blockade via PD-L1 Potentiates More CD28-Based than 4-1BB-Based Anti-Carbonic Anhydrase IX Chimeric Antigen Receptor T Cells. Int. J. Mol. Sci., 23.","DOI":"10.20944\/preprints202204.0308.v1"},{"key":"ref_80","first-page":"497","article-title":"Carbonic Anhydrase IX and Cyclooxygenase-2 Regulation in Renal Cell Carcinoma and Impact on Therapeutic Efficiency of Anti-CAIX CAR T cells","volume":"26","author":"Pivetta","year":"2025","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1097\/01.ju.0000158121.49085.ba","article-title":"CD70: A new tumor specific biomarker for renal cell carcinoma","volume":"173","author":"Junker","year":"2005","journal-title":"J. Urol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Zhang, X., Hong, B., Yu, W., Miao, Q., Wang, W., Wang, Y., Sun, Z., Bo, Y., Zhang, J., and Zhang, H. (2025). Comprehensive pan-cancer analysis reveals CD70 as a promising therapeutic target and biomarker in clear cell renal cell carcinoma. Int. J. Biol. Macromol., 307.","DOI":"10.1016\/j.ijbiomac.2025.142079"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Xiong, Q., Wang, H., Shen, Q., Wang, Y., Yuan, X., Lin, G., and Jiang, P. (2024). The development of chimeric antigen receptor T-cells against CD70 for renal cell carcinoma treatment. J. Transl. Med., 22.","DOI":"10.1186\/s12967-024-05101-1"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Kathuria-Prakash, N., Drolen, C., Hannigan, C.A., and Drakaki, A. (2021). Immunotherapy and Metastatic Renal Cell Carcinoma: A Review of New Treatment Approaches. Life, 12.","DOI":"10.3390\/life12010024"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2610","DOI":"10.1158\/0008-5472.CAN-21-2931","article-title":"Preclinical Development and Evaluation of Allogeneic CAR T Cells Targeting CD70 for the Treatment of Renal Cell Carcinoma","volume":"82","author":"Panowski","year":"2022","journal-title":"Cancer Res."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Ji, F., Zhang, F., Zhang, M., Long, K., Xia, M., Lu, F., Li, E., Chen, J., Li, J., and Chen, Z. (2021). Targeting the DNA damage response enhances CD70 CAR-T cell therapy for renal carcinoma by activating the cGAS-STING pathway. J. Hematol. Oncol., 14.","DOI":"10.1186\/s13045-021-01168-1"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Li, Z., Xu, H., Yu, L., Wang, J., Meng, Q., Mei, H., Cai, Z., Chen, W., and Huang, W. (2022). Patient-derived renal cell carcinoma organoids for personalized cancer therapy. Clin. Transl. Med., 12.","DOI":"10.1002\/ctm2.970"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1038\/s41416-022-02100-1","article-title":"Development of CAR-T cells specifically targeting cancer stem cell antigen DNAJB8 against solid tumours","volume":"128","author":"Watanabe","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Weber, J., Rade, M., Michael, J., Tony, L.T., Freitag, F., Spieler, P., M\u00fcller, C., Kalogirou, C., Mainz, L., and Lehmann, J. (2025). ROR2-specific CAR T cells are effective against hematologic and solid tumors and well tolerated in mice. Cell Rep. Med., 6.","DOI":"10.1016\/j.xcrm.2025.102400"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1111\/cas.14835","article-title":"Anti-tumor efficacy of human anti-c-met CAR-T cells against papillary renal cell carcinoma in an orthotopic model","volume":"112","author":"Mori","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1016\/j.ymthe.2024.05.006","article-title":"GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy","volume":"32","author":"Shi","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Yang, P., Chen, X., Yu, F., Wang, L., Li, M., Bai, Z., and Xu, H. (2024). CAR T cells secreting NGF-neutralizing scFv enhance efficacy in clear cell renal cell carcinoma by relieving immunosuppression through immunosympathectomy. J. Immunother. Cancer, 12.","DOI":"10.1136\/jitc-2024-009910"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Miller, C.P., Fung, M., Jaeger-Ruckstuhl, C.A., Xu, Y., Warren, E.H., Akilesh, S., and Tykodi, S.S. (2023). Therapeutic targeting of tumor spheroids in a 3D microphysiological renal cell carcinoma-on-a-chip system. Neoplasia, 46.","DOI":"10.1016\/j.neo.2023.100948"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1007\/s12185-021-03209-4","article-title":"Engineering the next generation of CAR-NK immunotherapies","volume":"114","author":"Rezvani","year":"2021","journal-title":"Int. J. Hematol."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"An, M., Yan, J., Liu, B., and Liu, Q. (2026). Harnessing the Power of CAR-NK Cells for Solid Tumors: Challenges, Innovations, and Future Frontiers in Immunotherapy. Cancer Commun., 46.","DOI":"10.34133\/cancomm.0023"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Sabbah, M., Jondreville, L., Lacan, C., Norol, F., Vieillard, V., Roos-Weil, D., and Nguyen, S. (2022). CAR-NK Cells: A Chimeric Hope or a Promising Therapy?. Cancers, 14.","DOI":"10.3390\/cancers14153839"},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"J\u00f8rgensen, L.V., Christensen, E.B., Barnkob, M.B., and Barington, T. (2025). The clinical landscape of CAR NK cells. Exp. Hematol. Oncol., 14.","DOI":"10.1186\/s40164-025-00633-8"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Zhou, Z., Zhao, K., Xiao, X., Yang, W., Miao, Y., Wu, T., Kong, X., Tao, Y., Wang, W., and Dong, Z. (2026). Natural killer and CAR-NK cell therapies in urological cancers: Progress, mechanistic lessons from CAR-T, and future directions. Crit. Rev. Oncol. Hematol., 221.","DOI":"10.1016\/j.critrevonc.2026.105208"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1080\/14712598.2024.2418321","article-title":"The future of cellular therapy for the treatment of renal cell carcinoma","volume":"24","author":"Chaoul","year":"2024","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/978-1-0716-4558-1_19","article-title":"Engineered CAR-NK Cells for Cancer Immunotherapy: Lentiviral-Based CAR Transduction of NK-92 Cells","volume":"2930","author":"Schmidt","year":"2025","journal-title":"Methods Mol. Biol."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Tian, K., Xu, J., Zhang, H., Li, L., Fu, Q., Chai, D., Li, H., and Zheng, J. (2017). Synergistic Effects of Cabozantinib and EGFR-Specific CAR-NK-92 Cells in Renal Cell Carcinoma. J. Immunol. Res., 2017.","DOI":"10.1155\/2017\/6915912"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Li, X., Zhang, Y., Ye, Y., Xiao, W., Liu, L., and Zhang, X. (2025). NK cells in renal cell carcinoma and its implications for CAR-NK therapy. Front. Cell Dev. Biol., 13.","DOI":"10.3389\/fcell.2025.1532491"},{"key":"ref_103","first-page":"3714","article-title":"Bortezomib improves adoptive carbonic anhydrase IX-specific chimeric antigen receptor-modified NK92 cell therapy in mouse models of human renal cell carcinoma","volume":"40","author":"Zhang","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s00262-017-2055-2","article-title":"Clinical grade manufacturing of genetically modified, CAR-expressing NK-92 cells for the treatment of ErbB2-positive malignancies","volume":"67","author":"Nowakowska","year":"2018","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/mt.2014.219","article-title":"Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2\/HER2-specific chimeric antigen receptor","volume":"23","author":"Sahm","year":"2015","journal-title":"Mol. Ther."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"5137","DOI":"10.1158\/1078-0432.CCR-25-0197","article-title":"Facts and Hopes of Chimeric Antigen Receptor-Redirected NK T Cells","volume":"31","author":"Courtney","year":"2025","journal-title":"Clin. Cancer Res."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Li, Y.R., and Yang, L. (2026). Protocol to generate human stem cell-derived CD70-directed allogeneic CAR-NKT cells for treating renal cell carcinoma. STAR Protoc., 7.","DOI":"10.1016\/j.xpro.2025.104340"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.jtct.2025.09.044","article-title":"Under the Hood: Evidence-Based Review of Allogeneic Chimeric Antigen Receptor T Cells for Hematologic Malignancies","volume":"32","author":"Cheema","year":"2026","journal-title":"Transplant. Cell. Ther."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Liu, Y., Duan, Y., Du, Z., Lu, B., Liu, S., Li, L., Tian, M., Li, L., Yao, R., and Ouyang, C. (2025). Current challenges and emerging opportunities of chimeric antigen receptor-engineered cell immunotherapy. Exp. Hematol. Oncol., 14.","DOI":"10.1186\/s40164-025-00683-y"},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Tang, X., and Xiao, Q. (2026). CAR-macrophages: A new chapter in cancer immunotherapy. Acta Biochim. Biophys. Sin., 58.","DOI":"10.3724\/abbs.2026017"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/s43018-025-00950-1","article-title":"An in situ engineered chimeric IL-2 receptor potentiates the tumoricidal activity of proinflammatory CAR macrophages in renal cell carcinoma","volume":"6","author":"Jing","year":"2025","journal-title":"Nat. Cancer"},{"key":"ref_112","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_113","first-page":"67","article-title":"Human and mouse iNKT cell expansion and engineering with viral vectors","volume":"196","author":"Delfanti","year":"2025","journal-title":"Methods Cell Biol."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Liu, Y., Dang, Y., Zhang, C., Liu, L., Cai, W., Li, L., Fang, L., Wang, M., Xu, S., and Wang, G. (2024). IL-21-armored B7H3 CAR-iNKT cells exert potent antitumor effects. iScience, 27.","DOI":"10.1016\/j.isci.2023.108597"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Khawar, M.B., and Sun, H. (2021). CAR-NK Cells: From Natural Basis to Design for Kill. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.707542"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"8874","DOI":"10.1073\/pnas.1033098100","article-title":"CD1d-restricted T cells regulate dendritic cell function and antitumor immunity in a granulocyte-macrophage colony-stimulating factor-dependent fashion","volume":"100","author":"Gillessen","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Li, Y.R., Hu, J., Li, Z., Zhu, E., Chen, Y., Halladay, T., Shen, X., Fang, Y., Zhu, Y., and Lyu, Z. (2025). Multimodal targeting of metastatic renal cell carcinoma via CD70-directed allogeneic CAR-NKT cells. Cell Rep. Med., 6.","DOI":"10.1016\/j.xcrm.2025.102321"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Li, Y.R., Shen, X., Zhu, Y., Li, Z., Hon, R., Tian, Y., Huang, J., Zhao, A.S., Ma, N.Y., and Zhang, C. (2025). Targeting triple-negative breast cancer using cord-blood CD34+ HSPC-derived mesothelin-specific CAR-NKT cells with potent antitumor activity. J. Hematol. Oncol., 18.","DOI":"10.1186\/s13045-025-01736-9"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Pan, K., Farrukh, H., Chittepu, V., Xu, H., Pan, C.X., and Zhu, Z. (2022). CAR race to cancer immunotherapy: From CAR T, CAR NK to CAR macrophage therapy. J. Exp. Clin. Cancer Res., 41.","DOI":"10.1186\/s13046-022-02327-z"},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Meng, L., Collier, K.A., Wang, P., Li, Z., Monk, P., Mortazavi, A., Hu, Z., Spakowicz, D., Zheng, L., and Yang, Y. (2023). Emerging Immunotherapy Approaches for Advanced Clear Cell Renal Cell Carcinoma. Cells, 13.","DOI":"10.3390\/cells13010034"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Ziane-Chaouche, L., Raffo-Romero, A., Hajjaji, N., Kobeissy, F., Pinheiro, D., Aboulouard, S., Cozzani, A., Mitra, S., Fournier, I., and Cizkova, D. (2024). Inhibition of furin in CAR macrophages directs them toward a proinflammatory phenotype and enhances their antitumor activities. Cell Death Dis., 15.","DOI":"10.1038\/s41419-024-07267-4"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.molimm.2026.02.011","article-title":"Navigating the frontier of CAR-T cell resistance: From underlying mechanisms to innovative therapeutic solutions","volume":"192","author":"Lan","year":"2026","journal-title":"Mol. Immunol."},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Zhang, W., Ren, W., Guo, S., Han, H., Cai, W., Bai, H., Li, L., Jiang, X., Zheng, X., and Zhang, T. (2025). ULBP2 CAR-T cells enhance gastric cancer immunotherapy by inhibiting CAF activation. Cell Death Dis., 16.","DOI":"10.1038\/s41419-025-07905-5"},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Deller, T.D., Alzubi, J., Mosti, L., Peschers, M., Gratzke, C., Wolf, P., and Cathomen, T. (2025). Engineering of Humanized PSMA-Directed CAR T Cells for Potent and Specific Elimination of Prostate Cancer Cells. Cells, 14.","DOI":"10.3390\/cells14171333"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1080\/1744666X.2024.2349738","article-title":"Overcoming the challenges of primary resistance and relapse after CAR-T cell therapy","volume":"20","author":"Dreyzin","year":"2024","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Wang, K., Ou, K., Zeng, Y., Yue, C., Zhuo, Y., Wang, L., Chen, H., and Tu, S. (2025). Epigenetic landscapes drive CAR-T cell kinetics and fate decisions: Bridging persistence and resistance. Crit. Rev. Oncol. Hematol., 211.","DOI":"10.1016\/j.critrevonc.2025.104729"},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Struckmeier, A.K., Gosau, M., and Smeets, R. (2025). Immunotherapeutic strategies beyond the PD-1\/PD-L1 pathway in head and neck squamous cell carcinoma\u2014A scoping review on current developments in agents targeting TIM-3, TIGIT, LAG-3, and VISTA. Oral Oncol., 161.","DOI":"10.1016\/j.oraloncology.2024.107145"},{"key":"ref_128","doi-asserted-by":"crossref","unstructured":"Ponzo, M., Drufuca, L., Buracchi, C., Sindoni, M.M., Nucera, S., Bugarin, C., Bason, R., Rossetti, G., Bonnal, R., and Meli, C. (2025). Acquisition of an immunosuppressive microenvironment after anti-CD19 CAR T-cell therapy is associated with T-cell dysfunction and resistance. J. Immunother. Cancer, 13.","DOI":"10.1136\/jitc-2025-011768"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.1200\/JCO.2006.05.9964","article-title":"Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: First clinical experience","volume":"24","author":"Lamers","year":"2006","journal-title":"J. Clin. Oncol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/mt.2013.17","article-title":"Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: Clinical evaluation and management of on-target toxicity","volume":"21","author":"Lamers","year":"2013","journal-title":"Mol. Ther."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1182\/blood-2010-07-294520","article-title":"Immune responses to transgene and retroviral vector in patients treated with ex vivo-engineered T cells","volume":"117","author":"Lamers","year":"2011","journal-title":"Blood"},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Wu, R., Chen, J., Wang, G., and Han, L. (2025). CD70 as a target in cancer immunotherapy: Advances, challenges, and future directions. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1609840"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"4124","DOI":"10.1182\/bloodadvances.2022009397","article-title":"CAR NK-92 cell-mediated depletion of residual TCR+ cells for ultrapure allogeneic TCR-deleted CAR T-cell products","volume":"7","author":"Kath","year":"2023","journal-title":"Blood Adv."},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Chen, X., Zhao, X., Mou, X., Zhao, J., Zhang, Z., Zhang, X., Huang, J., Liu, Y., Wang, F., and Zhang, M. (2024). PD-1-CD28-enhanced receptor and CD19 CAR-modified tumor-infiltrating T lymphocytes produce potential anti-tumor ability in solid tumors. Biomed. Pharmacother., 175.","DOI":"10.1016\/j.biopha.2024.116800"},{"key":"ref_135","doi-asserted-by":"crossref","unstructured":"Kagirova, E., Enikeeva, K., Mukhamadeev, R., Asadullina, D., Sharifyanova, Y., Shmelkova, P., Gainullina, D., Trifonova, D., Gattinger, P., and Docena, G. (2026). Discovery of tumor antigens in renal cell carcinoma and prospects for clinical application. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1771006"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1146\/annurev-med-070623-045906","article-title":"CD70: An Emerging Anticancer Target in Renal Cell Carcinoma and Beyond","volume":"76","author":"Zang","year":"2025","journal-title":"Annu. Rev. Med."},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Sj\u00f6berg, E. (2024). Molecular mechanisms and clinical relevance of endothelial cell cross-talk in clear cell renal cell carcinoma. Ups. J. Med. Sci., 129.","DOI":"10.48101\/ujms.v129.10632"},{"key":"ref_138","first-page":"95","article-title":"Armored CAR T-Cells: The Next Chapter in T-Cell Cancer Immunotherapy","volume":"15","author":"Hawkins","year":"2021","journal-title":"Biologics"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1158\/2159-8290.CD-18-0442","article-title":"Tumor Antigen Escape from CAR T-cell Therapy","volume":"8","author":"Majzner","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Li, W., Zhao, D., Chen, M., and Yan, X. (2025). Emerging advances in CAR-T therapy for solid tumors: Latest clinical trial updates from 2025 ASCO annual meeting. J. Hematol. Oncol., 18.","DOI":"10.1186\/s13045-025-01760-9"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1002\/cncr.31912","article-title":"A phase 1 trial of SGN-CD70A in patients with CD70-positive, metastatic renal cell carcinoma","volume":"125","author":"Pal","year":"2019","journal-title":"Cancer"},{"key":"ref_142","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_143","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_144","doi-asserted-by":"crossref","unstructured":"Itzhaki, O., Jacoby, E., Nissani, A., Levi, M., Nagler, A., Kubi, A., Brezinger, K., Brayer, H., Zeltzer, L.A., and Rozenbaum, M. (2020). Head-to-head comparison of in-house produced CD19 CAR-T cell in ALL and NHL patients. J. Immunother. Cancer, 8.","DOI":"10.1136\/jitc-2019-000148"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1158\/1078-0432.CCR-20-1457","article-title":"CD19-specific CAR T Cells that Express a PD-1\/CD28 Chimeric Switch-Receptor are Effective in Patients with PD-L1-positive B-Cell Lymphoma","volume":"27","author":"Liu","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Van der Vreken, A., Vanderkerken, K., De Bruyne, E., De Veirman, K., Breckpot, K., and Menu, E. (2024). Fueling CARs: Metabolic strategies to enhance CAR T-cell therapy. Exp. Hematol. Oncol., 13.","DOI":"10.1186\/s40164-024-00535-1"},{"key":"ref_147","doi-asserted-by":"crossref","unstructured":"Zhou, M., Xu, L., Hu, J., Chen, W., Hong, J., Wang, M., and Guo, Z. (2025). Metabolic reprogramming through PIM3 inhibition reverses hypoxia-induced CAR-T cell dysfunction in solid tumors. J. Transl. Med., 23.","DOI":"10.1186\/s12967-025-07278-5"},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Zhang, S., Sun, H., and Xu, L. (2025). The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma. Cell Death Discov., 11.","DOI":"10.1038\/s41420-025-02479-9"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"5426","DOI":"10.3390\/curroncol29080429","article-title":"Next Wave of Targets in the Treatment of Advanced Renal Cell Carcinoma","volume":"29","author":"Cardenas","year":"2022","journal-title":"Curr. Oncol."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"4231","DOI":"10.7150\/ijbs.110406","article-title":"Enhancing CAR-T Cell Metabolic Fitness and Memory Phenotype for Improved Efficacy against Hepatocellular Carcinoma","volume":"21","author":"You","year":"2025","journal-title":"Int. J. Biol. Sci."},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Zhu, M., Han, Y., Gu, T., Wang, R., Si, X., Kong, D., Zhao, P., Wang, X., Li, J., and Zhai, X. (2024). Class I HDAC inhibitors enhance antitumor efficacy and persistence of CAR-T cells by activation of the Wnt pathway. Cell Rep., 43.","DOI":"10.1016\/j.celrep.2024.114065"},{"key":"ref_152","doi-asserted-by":"crossref","unstructured":"Zhang, J., and Siller-Farf\u00e1n, J.A. (2022). Current and future perspectives of chimeric antigen receptors against glioblastoma. Immunother. Adv., 2.","DOI":"10.1093\/immadv\/ltac014"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1158\/2159-8290.CD-19-0945","article-title":"Tuning the Antigen Density Requirement for CAR T-cell Activity","volume":"10","author":"Majzner","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"Nolan-Stevaux, O., and Smith, R. (2024). Logic-gated and contextual control of immunotherapy for solid tumors: Contrasting multi-specific T cell engagers and CAR-T cell therapies. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1490911"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/s41586-023-05707-3","article-title":"CAR immune cells: Design principles, resistance and the next generation","volume":"614","author":"Labanieh","year":"2023","journal-title":"Nature"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/s41573-019-0041-4","article-title":"Next-generation regulatory T cell therapy","volume":"18","author":"Ferreira","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_157","doi-asserted-by":"crossref","unstructured":"Samadani, A.A., Keymoradzdeh, A., Shams, S., Soleymanpour, A., Rashidy-Pour, A., Hashemian, H., Vahidi, S., and Norollahi, S.E. (2021). CAR T-cells profiling in carcinogenesis and tumorigenesis: An overview of CAR T-cells cancer therapy. Int. Immunopharmacol., 90.","DOI":"10.1016\/j.intimp.2020.107201"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"3413","DOI":"10.1038\/s41388-020-1234-3","article-title":"Modeling clear cell renal cell carcinoma and therapeutic implications","volume":"39","author":"Wolf","year":"2020","journal-title":"Oncogene"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.urolonc.2019.12.003","article-title":"Transcriptomics in RCC","volume":"38","author":"Syed","year":"2020","journal-title":"Urol. Oncol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1002\/ajh.26506","article-title":"Safety and efficacy of a humanized CD19 chimeric antigen receptor T cells for relapsed\/refractory acute lymphoblastic leukemia","volume":"97","author":"Shi","year":"2022","journal-title":"Am. J. Hematol."},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Golkaram, M., Kuo, F., Gupta, S., Carlo, M.I., Salmans, M.L., Vijayaraghavan, R., Tang, C., Makarov, V., Rappold, P., and Blum, K.A. (2022). Spatiotemporal evolution of the clear cell renal cell carcinoma microenvironment links intra-tumoral heterogeneity to immune escape. Genome Med., 14.","DOI":"10.1186\/s13073-022-01146-3"},{"key":"ref_162","doi-asserted-by":"crossref","unstructured":"Cole, E.B., Lamcaj, S., Sydenstricker, A.V., Voss, A.G., Hiner, C.R., Hur, H.B., Kandpal, M., Valderrama Pena, N., Zheng, J.H., and Xiong, Y. (2026). IL-7\/IL-15\/IL-21 cytokine-fusion scaffold generates highly functional CAR T cells enriched in long-lived T memory stem cells. Sci. Adv., 12.","DOI":"10.1126\/sciadv.aec2632"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1038\/s41423-021-00655-2","article-title":"Enhancing CAR-T cell efficacy in solid tumors by targeting the tumor microenvironment","volume":"18","author":"Liu","year":"2021","journal-title":"Cell Mol. Immunol."},{"key":"ref_164","doi-asserted-by":"crossref","unstructured":"Albarr\u00e1n, V., San Rom\u00e1n, M., Pozas, J., Chamorro, J., Rosero, D.I., Guerrero, P., Calvo, J.C., Gonz\u00e1lez, C., Garc\u00eda de Quevedo, C., and P\u00e9rez de Aguado, P. (2024). Adoptive T cell therapy for solid tumors: Current landscape and future challenges. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1352805"},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Berz, A.M., Dromain, C., Vietti-Violi, N., Boughdad, S., and Duran, R. (2022). Tumor response assessment on imaging following immunotherapy. Front. 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