{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T20:41:16Z","timestamp":1789159276867,"version":"build-2803163510"},"reference-count":160,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007051","name":"Uppsala University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007051","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/048a87296","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) emerged as one of the most promising next-generation immune checkpoint targets following the success of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. TIGIT suppresses antitumor immunity through interaction with cluster of differentiation 155 (CD155), inhibition of CD226-mediated co-stimulation, and promotion of immunosuppressive regulatory T-cell (Treg) activity within the tumor microenvironment (TME). Strong preclinical evidence demonstrated that TIGIT blockade, particularly in combination with PD-1\/PD-L1 inhibition, restored T-cell and natural killer (NK) cell function and produced durable antitumor responses in multiple tumor models, leading to rapid clinical development. Despite this compelling biological rationale, most late-stage clinical programs failed to reproduce early success. Although the phase II CITYSCAPE trial showed encouraging activity in PD-L1-high non-small cell lung cancer (NSCLC), subsequent phase III trials, including SKYSCRAPER-01, SKYSCRAPER-02, SKYSCRAPER-03, SKYSCRAPER-14, AdvanTIG-302, KEYVIBE, and STAR-221, failed to improve survival outcomes or meet primary endpoints. The notable exception was SKYSCRAPER-08 in esophageal squamous cell carcinoma, suggesting that TIGIT blockade may be effective only in selected biological contexts. This review critically examines the molecular biology of the TIGIT\u2013CD155\u2013CD226 axis, its role in immune regulation and tumor immune evasion, and the preclinical and clinical evidence supporting TIGIT-targeted therapy. Particular emphasis is placed on understanding the causes of clinical failure, including CD226 loss during T-cell exhaustion, checkpoint network redundancy, Fc-engineering uncertainty, immunosuppressive TMEs, inadequate biomarker-guided patient selection, and tumor-type-specific dependence on the TIGIT pathway. We also present original bioinformatics analyses demonstrating that broader checkpoint network signatures outperform TIGIT expression alone for patient stratification. Finally, we evaluate emerging solutions including biomarker-guided precision immunotherapy, Fc-optimized antibodies, bispecific checkpoint inhibitors, TIGIT-engineered chimeric antigen receptor T-cell (CAR-T) cells, radiotherapy combinations, and multi-checkpoint blockade. Collectively, current evidence suggests that the future of TIGIT-directed therapy lies not in universal checkpoint inhibition but in biologically informed, precision-guided immunotherapy strategies.<\/jats:p>","DOI":"10.3390\/pharmaceutics18080970","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T11:44:53Z","timestamp":1786103093000},"page":"970","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Right Key, the Wrong Lock: TIGIT Checkpoint Blockade and the Road to Precision Immunotherapy"],"prefix":"10.3390","volume":"18","author":[{"given":"Shukur Wasman","family":"Smail","sequence":"first","affiliation":[{"name":"College of Pharmacy, Cihan University-Erbil, Erbil 44001, Kurdistan Region, Iraq"},{"name":"Department of Biology, College of Science, Salahaddin University-Erbil, Erbil 44001, Kurdistan Region, Iraq"},{"name":"Department of Medical Science, Respiratory Medicine, and Allergology, Uppsala University and University Hospital, 75185 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6599-3213","authenticated-orcid":false,"given":"Hawro Taha","family":"Hamza","sequence":"additional","affiliation":[{"name":"Department of Oncology, Nanakali Teaching Hospital, Erbil 44001, Kurdistan Region, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0509-0625","authenticated-orcid":false,"given":"Mohammed Awat","family":"Ali","sequence":"additional","affiliation":[{"name":"Faculty of General Medicine, Koya University, Koya 44023, Kurdistan Region, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9886-9868","authenticated-orcid":false,"given":"Raya Kh.","family":"Yashooa","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Education for Pure Sciences, University of Al-Hamdaniya, Mosul 41002, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6853-4282","authenticated-orcid":false,"given":"Wissam Albeer","family":"Nooh","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Education for Pure Sciences, University of Al-Hamdaniya, Mosul 41002, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed Abdulrazzaq","family":"Bapir","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology, Erbil Health and Medical Technical College, Erbil Polytechnic University, Erbil 44001, Kurdistan Region, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dlzar B.","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Genetics Unit, Bio Diagnostic Center (BDC), Erbil 44001, Kurdistan Region, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0517-7545","authenticated-orcid":false,"given":"Mohammed O.","family":"Rahman","sequence":"additional","affiliation":[{"name":"Department of Genetics Unit, Bio Diagnostic Center (BDC), Erbil 44001, Kurdistan Region, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiba A.","family":"Haseeb","sequence":"additional","affiliation":[{"name":"Department of Genetics Unit, Bio Diagnostic Center (BDC), Erbil 44001, Kurdistan Region, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nivar B.","family":"Maaruf","sequence":"additional","affiliation":[{"name":"Department of Genetics Unit, Bio Diagnostic Center (BDC), Erbil 44001, Kurdistan Region, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shadyar O.","family":"Majeed","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, Salahaddin University-Erbil, Erbil 44001, Kurdistan Region, Iraq"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iman","family":"Ezzat","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE 68178, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5093-6980","authenticated-orcid":false,"given":"Christer","family":"Janson","sequence":"additional","affiliation":[{"name":"Department of Medical Science, Respiratory Medicine, and Allergology, Uppsala University and University Hospital, 75185 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1016\/j.cell.2023.03.006","article-title":"Immune checkpoint therapy-current perspectives and future directions","volume":"186","author":"Sharma","year":"2023","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e184846","DOI":"10.1172\/JCI184846","article-title":"Checkpoint therapy in cancer treatment: Progress, challenges, and future directions","volume":"134","author":"Bicak","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"144","DOI":"10.33696\/cancerimmunol.7.113","article-title":"Next-Generation Immune Checkpoint Inhibitors in Cancer: Mechanisms, Current Clinical Advances, and Future Directions","volume":"7","author":"Hussain","year":"2025","journal-title":"J. Cancer Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/ni.1674","article-title":"The surface protein TIGIT suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells","volume":"10","author":"Yu","year":"2009","journal-title":"Nat. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17858","DOI":"10.1073\/pnas.0903474106","article-title":"The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity","volume":"106","author":"Stanietsky","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.it.2016.10.002","article-title":"TIGIT: A Key Inhibitor of the Cancer Immunity Cycle","volume":"38","author":"Manieri","year":"2017","journal-title":"Trends Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1111\/cei.13407","article-title":"TIGIT as an emerging immune checkpoint","volume":"200","author":"Harjunpaa","year":"2020","journal-title":"Clin. Exp. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e000957","DOI":"10.1136\/jitc-2020-000957","article-title":"TIGIT in cancer immunotherapy","volume":"8","author":"Chauvin","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e004711","DOI":"10.1136\/jitc-2022-004711","article-title":"TIGIT-CD226-PVR axis: Advancing immune checkpoint blockade for cancer immunotherapy","volume":"10","author":"Chiang","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/imr.12518","article-title":"TIGIT and CD96: New checkpoint receptor targets for cancer immunotherapy","volume":"276","author":"Dougall","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/j.immuni.2016.05.001","article-title":"Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation","volume":"44","author":"Anderson","year":"2016","journal-title":"Immunity"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1172\/JCI80445","article-title":"TIGIT and PD-1 impair tumor antigen-specific CD8+ T cells in melanoma patients","volume":"125","author":"Chauvin","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s12943-023-01800-3","article-title":"Co-inhibition of TIGIT and PD-1\/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials","volume":"22","author":"Chu","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e124427","DOI":"10.1172\/jci.insight.124427","article-title":"TIGIT signaling restores suppressor function of Th1 Tregs","volume":"4","author":"Lucca","year":"2019","journal-title":"JCI Insight"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1111\/j.1365-2567.2006.02321.x","article-title":"Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: The role of T regulatory cells","volume":"117","author":"Taylor","year":"2006","journal-title":"Immunology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1016\/j.ccell.2014.10.018","article-title":"The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function","volume":"26","author":"Johnston","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhou, X.M., Li, W.Q., Wu, Y.H., Han, L., Cao, X.G., Yang, X.M., Wang, H.F., Zhao, W.S., Zhai, W.J., and Qi, Y.M. (2018). Intrinsic Expression of Immune Checkpoint Molecule TIGIT Could Help Tumor Growth in vivo by Suppressing the Function of NK and CD8+ T Cells. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02821"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2419838","DOI":"10.1080\/19420862.2024.2419838","article-title":"Insights into the mechanisms of serplulimab: A distinctive anti-PD-1 monoclonal antibody, in combination with a TIGIT or LAG3 inhibitor in preclinical tumor immunotherapy studies","volume":"16","author":"Zhang","year":"2024","journal-title":"mAbs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.immuni.2022.02.005","article-title":"Mechanistic convergence of the TIGIT and PD-1 inhibitory pathways necessitates co-blockade to optimize anti-tumor CD8+ T cell responses","volume":"55","author":"Banta","year":"2022","journal-title":"Immunity"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"101184","DOI":"10.1016\/j.esmoop.2023.101184","article-title":"Anti-TIGIT therapies for solid tumors: A systematic review","volume":"8","author":"Rousseau","year":"2023","journal-title":"ESMO Open"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"CT051","DOI":"10.1158\/1538-7445.AM2025-CT051","article-title":"Abstract CT051: SKYSCRAPER-01: A phase III, randomized trial of tiragolumab (tira) + atezolizumab (atezo) versus placebo (pbo) + atezo in patients (pts) with previously-untreated PD-L1-high, locally advanced unresectable\/metastatic NSCLC","volume":"85","author":"Peters","year":"2025","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1200\/JCO.23.01363","article-title":"SKYSCRAPER-02: Tiragolumab in Combination With Atezolizumab Plus Chemotherapy in Untreated Extensive-Stage Small-Cell Lung Cancer","volume":"42","author":"Rudin","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_23","first-page":"CD-NW2025-0078","article-title":"Anti-TIGIT Monotherapies Struggle to Deliver","volume":"15","author":"Gruber","year":"2025","journal-title":"Cancer Discov."},{"key":"ref_24","unstructured":"Taylor, P. (2026, June 06). BeiGene Abandons TIGIT Antibody After Lung Cancer Flop|Pharmaphorum [News Report]. Available online: https:\/\/pharmaphorum.com\/news\/beigene-abandons-tigit-antibody-after-lung-cancer-flop."},{"key":"ref_25","unstructured":"Armstrong, A. (2026, June 01). \u2018Au Revoir TIGIT\u2019: Gilead, Arcus Cut Gastro Cancer Drug After Late-Stage Failure [News Report]. Available online: https:\/\/www.biospace.com\/drug-development\/au-revoir-tigit-gilead-arcus-cut-gastro-cancer-drug-after-late-stage-failure."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1200\/JCO.2024.42.3_suppl.245","article-title":"SKYSCRAPER-08: A phase III, randomized, double-blind, placebo-controlled study of first-line (1L) tiragolumab (tira) + atezolizumab (atezo) and chemotherapy (CT) in patients (pts) with esophageal squamous cell carcinoma (ESCC)","volume":"42","author":"Hsu","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1002\/eji.201041136","article-title":"Vstm3 is a member of the CD28 family and an important modulator of T-cell function","volume":"41","author":"Levin","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5399","DOI":"10.1073\/pnas.1120606109","article-title":"Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering","volume":"109","author":"Stengel","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ou, X., Yin, J., Shi, F., Zhao, Y., Zhou, Q., Yuan, K., Lyu, S., Wu, J., Li, Y., and Song, Q. (2025). CD155-TIGIT\/CD96\/CD226 immune checkpoint axis interacting with tumor-infiltrating lymphocytes to exhibit diverse prognostic effects on breast cancer: A cohort study. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1649078"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1084\/jem.20150785","article-title":"Identification of CD112R as a novel checkpoint for human T cells","volume":"213","author":"Zhu","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Liu, K., Liu, Y., Xiong, H., and Ning, Z. (2025). The Immune Regulatory Functions of CD226 and Its Implications in Immune-Mediated Diseases. Biomolecules, 15.","DOI":"10.3390\/biom15071007"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1186\/s13046-021-02053-y","article-title":"The CD112R\/CD112 axis: A breakthrough in cancer immunotherapy","volume":"40","author":"Zeng","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Jin, S., Zhang, Y., Zhou, F., Chen, X., Sheng, J., and Zhang, J. (2022). TIGIT: A promising target to overcome the barrier of immunotherapy in hematological malignancies. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1091782"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e000266","DOI":"10.1136\/jitc-2019-000266","article-title":"Nectin4 is a novel TIGIT ligand which combines checkpoint inhibition and tumor specificity","volume":"8","author":"Reches","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"354","DOI":"10.12688\/f1000research.22877.1","article-title":"Targeting the \u201cPVR-TIGIT axis\u201d with immune checkpoint therapies","volume":"9","author":"Gorvel","year":"2020","journal-title":"F1000Research"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/cdd.2012.141","article-title":"Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells","volume":"20","author":"Liu","year":"2013","journal-title":"Cell Death Differ."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e1036214","DOI":"10.1080\/2162402X.2015.1036214","article-title":"The checkpoint inhibitor TIGIT limits antitumor and antiviral CD8+ T cell responses","volume":"4","author":"Johnston","year":"2015","journal-title":"Oncoimmunology"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Jantz-Naeem, N., Bottcher-Loschinski, R., Borucki, K., Mitchell-Flack, M., Bottcher, M., Schraven, B., Mougiakakos, D., and Kahlfuss, S. (2023). TIGIT signaling and its influence on T cell metabolism and immune cell function in the tumor microenvironment. Front. Oncol., 13.","DOI":"10.3389\/fonc.2023.1060112"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.immuni.2014.02.012","article-title":"Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses","volume":"40","author":"Joller","year":"2014","journal-title":"Immunity"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/s41586-024-07121-9","article-title":"Anti-TIGIT antibody improves PD-L1 blockade through myeloid and T(reg) cells","volume":"627","author":"Guan","year":"2024","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1111\/1759-7714.14478","article-title":"TIGIT\/CD47 dual high expression predicts prognosis and is associated with immunotherapy response in lung squamous cell carcinoma","volume":"13","author":"Peng","year":"2022","journal-title":"Thorac. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2549","DOI":"10.1007\/s00262-022-03182-9","article-title":"Targeting PD-L1 and TIGIT could restore intratumoral CD8 T cell function in human colorectal cancer","volume":"71","author":"Thibaudin","year":"2022","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/s41392-023-01521-5","article-title":"Immunotherapy in hematologic malignancies: Achievements, challenges and future prospects","volume":"8","author":"Tang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1007\/s00277-025-06304-2","article-title":"TIGIT\/PVR axis regulates anti-tumor immunity in hematologic malignancies","volume":"104","author":"Meng","year":"2025","journal-title":"Ann. Hematol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s40364-023-00543-z","article-title":"Targeting TIGIT for cancer immunotherapy: Recent advances and future directions","volume":"12","author":"Zhang","year":"2024","journal-title":"Biomark. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e21110","DOI":"10.1200\/JCO.2023.41.16_suppl.e21110","article-title":"TIGIT expression and outcomes in pembrolizumab treated patients with NSCLC","volume":"41","author":"Senosain","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7526","DOI":"10.1158\/1538-7445.AM2024-7526","article-title":"Abstract 7526: Landscape of TIGIT and PD-L1 co-expression in solid tumors","volume":"84","author":"Pabla","year":"2024","journal-title":"Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5160565","DOI":"10.1155\/2019\/5160565","article-title":"Patterns of TIGIT Expression in Lymphatic Tissue, Inflammation, and Cancer","volume":"2019","author":"Blessin","year":"2019","journal-title":"Dis. Markers"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"22502","DOI":"10.1038\/s41598-021-01933-9","article-title":"A pan-cancer analysis revealing the role of TIGIT in tumor microenvironment","volume":"11","author":"Wen","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e14637","DOI":"10.1200\/JCO.2023.41.16_suppl.e14637","article-title":"TIGIT transcriptomic expression and high levels of multiple checkpoints across diverse cancers","volume":"41","author":"Adashek","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Murakami, D., Matsuda, K., Iwamoto, H., Mitani, Y., Mizumoto, Y., Nakamura, Y., Matsuzaki, I., Iwamoto, R., Takahashi, Y., and Kojima, F. (2022). Prognostic value of CD155\/TIGIT expression in patients with colorectal cancer. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0265908"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Li, S., Li, L., Pan, T., Li, X., Tong, Y., and Jin, Y. (2022). Prognostic value of TIGIT in East Asian patients with solid cancers: A systematic review, meta-analysis and pancancer analysis. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.977016"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e1674605","DOI":"10.1080\/2162402X.2019.1674605","article-title":"Targeting the TIGIT-PVR immune checkpoint axis as novel therapeutic option in breast cancer","volume":"8","author":"Stamm","year":"2019","journal-title":"Oncoimmunology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2638","DOI":"10.1158\/1078-0432.CCR-23-0258","article-title":"TIGIT Expression Delineates T-cell Populations with Distinct Functional and Prognostic Impact in Pancreatic Cancer","volume":"29","author":"Heiduk","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/s41587-020-0546-8","article-title":"Visualizing and interpreting cancer genomics data via the Xena platform","volume":"38","author":"Goldman","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.cell.2017.09.028","article-title":"Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab","volume":"171","author":"Riaz","year":"2017","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/nature25501","article-title":"TGFbeta attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells","volume":"554","author":"Mariathasan","year":"2018","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/S1470-2045(22)00226-1","article-title":"Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): Primary and follow-up analyses of a randomised, double-blind, phase 2 study","volume":"23","author":"Cho","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Ghasemi, K. (2025). Tiragolumab and TIGIT: Pioneering the next era of cancer immunotherapy. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1568664"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1001\/jamaoncol.2023.3867","article-title":"Anti-TIGIT Antibody Tiragolumab Alone or with Atezolizumab in Patients With Advanced Solid Tumors: A Phase 1a\/1b Nonrandomized Controlled Trial","volume":"9","author":"Kim","year":"2023","journal-title":"JAMA Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"S887","DOI":"10.1016\/j.annonc.2020.08.1714","article-title":"1400P Vibostolimab, an anti-TIGIT antibody, as monotherapy and in combination with pembrolizumab in anti-PD-1\/PD-L1-refractory NSCLC","volume":"31","author":"Ahn","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"S1010","DOI":"10.1016\/j.jtho.2021.08.331","article-title":"P14. 01 Phase 3 Study of First-Line Pembrolizumab\u00b1Vibostolimab (anti-TIGIT) in Patients With PD-L1\u2013Positive Metastatic NSCLC","volume":"16","author":"Hellmann","year":"2021","journal-title":"J. Thorac. Oncol."},{"key":"ref_63","unstructured":"Merck (2024, December 16). Merck Provides Update on KeyVibe and KEYFORM Clinical Development Programs Evaluating Investigational Vibostolimab and Favezelimab Fixed-Dose Combinations with Pembrolizumab. News Release. Available online: https:\/\/www.merck.com\/news\/merck-provides-update-on-keyvibe-and-keyform-clinical-development-programs-evaluating-investigational-vibostolimab-and-favezelimab-fixed-dose-combinations-with-pembrolizumab\/."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.annonc.2021.11.002","article-title":"First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer","volume":"33","author":"Niu","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Roussot, N., Kaderbhai, C., and Ghiringhelli, F. (2025). Targeting Immune Checkpoint Inhibitors for Non-Small-Cell Lung Cancer: Beyond PD-1\/PD-L1 Monoclonal Antibodies. Cancers, 17.","DOI":"10.3390\/cancers17050906"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e005829","DOI":"10.1136\/jitc-2022-005829","article-title":"AdvanTIG-105: A phase I dose escalation study of the anti-TIGIT monoclonal antibody ociperlimab in combination with tislelizumab in patients with advanced solid tumors","volume":"11","author":"Frentzas","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"5819","DOI":"10.1038\/s41467-025-60757-7","article-title":"Dual TIGIT and PD-1 blockade with domvanalimab plus zimberelimab in hepatocellular carcinoma refractory to anti-PD-1 therapies: The phase 2 LIVERTI trial","volume":"16","author":"Hsiehchen","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cllc.2023.12.010","article-title":"STAR-121: A Phase III Randomized Study of Domvanalimab and Zimberelimab in Combination With Chemotherapy Versus Pembrolizumab With Chemotherapy in Untreated Metastatic Non-Small Cell Lung Cancer With No Actionable Gene Alterations","volume":"25","author":"Gray","year":"2024","journal-title":"Clin. Lung Cancer"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"S621","DOI":"10.1016\/j.annonc.2023.09.2160","article-title":"1021MO Safety and efficacy of etigilimab (anti-TIGIT) with nivolumab (anti-PD1) in recurrent\/advanced solid tumors","volume":"34","author":"McKean","year":"2023","journal-title":"Ann. Oncol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1158\/1078-0432.CCR-21-2780","article-title":"A Phase 1a\/b Open-Label, Dose-Escalation Study of Etigilimab Alone or in Combination with Nivolumab in Patients with Locally Advanced or Metastatic Solid Tumors","volume":"28","author":"Mettu","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_71","unstructured":"Beaney, A. (2025). GSK and iTeos Drop Anti-TIGIT Drug Following Trial Failure\u2014Clinical Trials Arena, GlobalData."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Cuende, J., Nicolas, R., Valerie, R., Bart, C., Paola, T., Mercier, M., Wald, N., Vezzu, A., Preillon, J., and Aliz\u00e9e, C. (2025). a-TIGIT mAb belrestotug in combination with anti-PD1 induces an immunocompetent tumor microenvironment (TME). medRxiv.","DOI":"10.1101\/2025.07.25.25332187"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"510","DOI":"10.4049\/jimmunol.2101175","article-title":"LIGHT (TNFSF14) Costimulation Enhances Myeloid Cell Activation and Antitumor Immunity in the Setting of PD-1\/PD-L1 and TIGIT Checkpoint Blockade","volume":"209","author":"Kellsey","year":"2022","journal-title":"J. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1182\/blood-2021-152395","article-title":"TIG-007: Study of EOS884448\/GSK4428859A Alone, and in Combination with Iberdomide with or without Dexamethasone, in Participants with Relapsed or Refractory Multiple Myeloma","volume":"138","author":"Moreau","year":"2021","journal-title":"Blood"},{"key":"ref_75","first-page":"50","article-title":"COM902 (Anti-TIGIT antibody) monotherapy\u2013preliminary evaluation of safety, tolerability, pharmacokinetics and receptor occupancy in patients with advanced solid tumors (NCT04354246)","volume":"1000","author":"Dumbrava","year":"2021","journal-title":"Age"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e010584","DOI":"10.1136\/jitc-2024-010584","article-title":"TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: A first-in-human, phase 1, dose-escalation trial","volume":"13","author":"Naing","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_77","first-page":"A351","article-title":"The anti-TIGIT antibody M6223 induces significant anti-tumor efficacy and immune response via multiple mechanisms of action","volume":"9","author":"Xu","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_78","first-page":"A1","article-title":"483 Dual blockage of PD-1 and TIGIT with rilvegostomig inhibits tumor growth in various in vitro\/in vivo\/ex vivo tumor models through effector CD8 activation and immune modulation","volume":"12","author":"Chariou","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"S1903","DOI":"10.1016\/j.annonc.2025.10.301","article-title":"475TiP ARTEMIDE-HCC01: A phase III, randomised, open-label, sponsor-blinded, multicentre, global study of rilvegostomig in combination with bevacizumab with or without tremelimumab as first-line (1L) treatment for unresectable hepatocellular carcinoma (uHCC)","volume":"36","author":"Zhou","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"S821","DOI":"10.1016\/j.annonc.2023.09.2476","article-title":"1445P A randomized phase III trial on Pembrolizumab Alone versUs pembrolizumab-chemotherapy in first LInE NSCLC (PAULIEN), results of the interim analysis","volume":"34","author":"Houda","year":"2023","journal-title":"Ann. Oncol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"TPS8653","DOI":"10.1200\/JCO.2025.43.16_suppl.TPS8653","article-title":"ARTEMIDE-Lung03: A phase 3, randomized, double-blind, multicenter, global study of rilvegostomig or pembrolizumab in combination with platinum-based chemotherapy as first-line treatment for patients with metastatic non-squamous non-small-cell lung cancer whose tumors express PD-L1","volume":"43","author":"Mathias","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Karnik, I., Her, Z., Neo, S.H., Liu, W.N., and Chen, Q. (2023). Emerging preclinical applications of humanized mouse models in the discovery and validation of novel immunotherapeutics and their mechanisms of action for improved cancer treatment. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15061600"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1007\/s00262-025-04128-7","article-title":"Anti-TIGIT therapies: A review of preclinical and clinical efficacy and mechanisms","volume":"74","author":"Sundstrom","year":"2025","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1158\/1535-7163.MCT-20-0464","article-title":"Restoration of T-cell Effector Function, Depletion of Tregs, and Direct Killing of Tumor Cells: The Multiple Mechanisms of Action of a-TIGIT Antagonist Antibodies","volume":"20","author":"Preillon","year":"2021","journal-title":"Mol. Cancer Ther."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3584","DOI":"10.1002\/cam4.2976","article-title":"TIGIT enhances CD4(+) regulatory T-cell response and mediates immune suppression in a murine ovarian cancer model","volume":"9","author":"Chen","year":"2020","journal-title":"Cancer Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2588717","DOI":"10.1080\/07853890.2025.2588717","article-title":"Immunotherapeutic strategies targeting the PVR-TIGIT\/CD96\/CD226 signaling pathway in glioma treatment","volume":"57","author":"Qian","year":"2025","journal-title":"Ann. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.2174\/0929867330666230324152532","article-title":"CD155-TIGIT Axis as a Therapeutic Target for Cancer Immunotherapy","volume":"31","author":"Mu","year":"2024","journal-title":"Curr. Med. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.1158\/1538-7445.AM2017-2612","article-title":"Abstract 2612: Anti-Tigit induces T cell mediated anti-tumor immune response and combines with immune checkpoint inhibitors to enhance strong and long term anti-tumor immunity","volume":"77","author":"Srivastava","year":"2017","journal-title":"Cancer Res."},{"key":"ref_89","first-page":"14","article-title":"Abstract 5627: Anti-TIGIT biomarker study: Inhibition of TIGIT induces loss of Tregs from tumors and requires effector function for tumor growth inhibition","volume":"2018","author":"Argast","year":"2018","journal-title":"Clin. Res."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Xin, C., Xue, L., Xiao-Bao, D., Jing, Z., Lei, J., Shan, L., Hongjia, H., Bin, J., Liang, C., and Qing, Z. (2022). An Fc-Competent Anti-Human TIGIT Blocking Antibody Ociperlimab (BGB-A1217) Elicits Strong Immune Responses and Potent Anti-Tumor Efficacy in Pre-Clinical Models. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.828319"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.4049\/jimmunol.1901413","article-title":"A Cross-Species Reactive TIGIT-Blocking Antibody Fc Dependently Confers Potent Antitumor Effects","volume":"205","author":"Yang","year":"2020","journal-title":"J. Immunol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"4986","DOI":"10.1158\/1538-7445.AM2019-4986","article-title":"Abstract 4986: TIGIT directed human antibody modulates T-regulatory and effector cell function","volume":"79","author":"Smith","year":"2019","journal-title":"Cancer Res."},{"key":"ref_93","first-page":"3161","article-title":"Abstract 3161: Preparation of aclinical trial with a-TIGIT antagonist antibody EOS884448, which demonstrates potent preclinical activity and safe toxicology profile","volume":"80","author":"Nguyen","year":"2020","journal-title":"Clin. Res."},{"key":"ref_94","first-page":"9650","article-title":"Anti-TIGIT antibodies promote immune activation relevant to targeting stem-like and tumor-specific T cells in combination with anti-PD-1","volume":"208","author":"Gauthier","year":"2022","journal-title":"J. Immunol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"5614","DOI":"10.1158\/1538-7445.AM2020-5614","article-title":"Abstract 5614: Combination of anti-TIGIT and anti-PD-1 antibodies enhance antitumor response in a PD-1\/TIGIT double HuGEMM\u2122 model engrafted with mouse syngeneic tumors","volume":"80","author":"He","year":"2020","journal-title":"Cancer Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1038\/s41590-018-0132-0","article-title":"Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity","volume":"19","author":"Zhang","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2124666","DOI":"10.1080\/2162402X.2022.2124666","article-title":"Immune targeting of three independent suppressive pathways (TIGIT, PD-L1, TGFbeta) provides significant antitumor efficacy in immune checkpoint resistant models","volume":"11","author":"Franks","year":"2022","journal-title":"Oncoimmunology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"110932","DOI":"10.1016\/j.radonc.2025.110932","article-title":"TIGIT blockade increases efficacy of PD-1 blockade combined with radiation therapy in triple-negative breast cancer model","volume":"208","author":"Kim","year":"2025","journal-title":"Radiother. Oncol."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Zhu, X., Cui, X., Yu, H., Xu, J., Chen, X., Ren, X., Wei, X., Chen, S., Wang, Y., and Fei, L. (2026). Enhancing anti-tumor immunity through co-blocking PD-L1 and TIGIT by facilitating tumor-directed responses and additional VEGF inhibition. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1746155"},{"key":"ref_100","first-page":"A1687","article-title":"579-B\u2005TIGIT and PD-L1 co-blockade promotes clonal expansion of non-exhausted anti-tumour CD8+T cells by facilitating costimulation","volume":"11","author":"Katherine","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"e007502","DOI":"10.1136\/jitc-2023-007502","article-title":"Knockout of the inhibitory receptor TIGIT enhances the antitumor response of ex vivo expanded NK cells and prevents fratricide with therapeutic Fc-active TIGIT antibodies","volume":"11","author":"Hasan","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"15114","DOI":"10.1002\/anie.202002783","article-title":"A Novel D Peptide Identified by Mirror-image Phage Display Blocks TIGIT\/PVR for Cancer Immunotherapy","volume":"59","author":"Zhou","year":"2020","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"116162","DOI":"10.1016\/j.bcp.2024.116162","article-title":"Dual targeting of TIGIT and PD-1 with a novel small molecule for cancer immunotherapy","volume":"223","author":"Li","year":"2024","journal-title":"Biochem. Pharmacol."},{"key":"ref_104","first-page":"A1","article-title":"198\u2005Combination intratumoral treatment with INTASYL\u2122 self-delivering RNAi targeting TIGIT and PD-1\/PD-L1 improves tumor control compared to monotherapy in a CT26 model of murine colorectal cancer","volume":"8","author":"Cuiffo","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1007\/s11030-025-11172-z","article-title":"Computational screening for natural compounds as potential immune checkpoint inhibitors against TIGIT, a new avenue in cancer immunotherapy","volume":"30","author":"Chakraborty","year":"2025","journal-title":"Mol. Divers."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"4274","DOI":"10.1038\/s41591-025-04022-w","article-title":"Domvanalimab and zimberelimab in advanced gastric, gastroesophageal junction or esophageal cancer: A phase 2 trial","volume":"31","author":"Janjigian","year":"2025","journal-title":"Nat. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1007\/s11912-022-01281-5","article-title":"Clinical Development of Anti-TIGIT Antibodies for Immunotherapy of Cancer","volume":"24","author":"Florou","year":"2022","journal-title":"Curr. Oncol. Rep."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"ltad009","DOI":"10.1093\/immadv\/ltad009","article-title":"TIGIT-based immunotherapeutics in lung cancer","volume":"3","author":"Patel","year":"2023","journal-title":"Immunother. Adv."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Rotte, A., Sahasranaman, S., and Budha, N. (2021). Targeting TIGIT for Immunotherapy of Cancer: Update on Clinical Development. Biomedicines, 9.","DOI":"10.3390\/biomedicines9091277"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/s13045-023-01499-1","article-title":"Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy","volume":"16","author":"Cai","year":"2023","journal-title":"J. Hematol. Oncol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"155202","DOI":"10.1016\/j.prp.2024.155202","article-title":"TIGIT: A potential immunotherapy target for gynecological cancers","volume":"255","author":"Jiang","year":"2024","journal-title":"Pathol. Res. Pract."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Piekarz, J., Picheta, N., Szklener, K., and Mandziuk, S. (2025). TIGIT Expression and Its Implications in Non-Small-Cell Lung Cancer Progression and Therapy: A Systematic Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26199307"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"109316","DOI":"10.1016\/j.lungcan.2026.109316","article-title":"Domvanalimab combined with zimberelimab as first-line treatment in patients with PD-L1-high, advanced non-small cell lung cancer: Results from the randomized phase 2 ARC-10 study, Part1","volume":"215","author":"Naidoo","year":"2026","journal-title":"Lung Cancer"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/S1470-2045(25)00709-0","article-title":"Vibostolimab coformulated with pembrolizumab versus pembrolizumab alone as adjuvant therapy for high-risk stage IIB-IV melanoma (KEYVIBE-010): A randomised, double-blind, phase 3 study","volume":"27","author":"Dummer","year":"2026","journal-title":"Lancet Oncol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"e012457","DOI":"10.1136\/jitc-2025-012457","article-title":"Why has immune \u201ccheckpoint\u201d therapy failed in most clinical trials?","volume":"13","author":"Yang","year":"2025","journal-title":"J. Immunother. Cancer"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"e121157","DOI":"10.1172\/jci.insight.121157","article-title":"CD226 opposes TIGIT to disrupt Tregs in melanoma","volume":"3","author":"Fourcade","year":"2018","journal-title":"JCI Insight"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Annese, T., Tamma, R., and Ribatti, D. (2022). Update in TIGIT Immune-Checkpoint Role in Cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.871085"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Cui, H., and Elkord, E. (2024). Turning Cancer Immunotherapy to the Emerging Immune Checkpoint TIGIT: Will This Break Through the Limitations of the Legacy Approach?. Vaccines, 12.","DOI":"10.3390\/vaccines12121306"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"110358","DOI":"10.1016\/j.intimp.2023.110358","article-title":"TIGIT: An emerging immune checkpoint target for immunotherapy in autoimmune disease and cancer","volume":"120","author":"Zhao","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1038\/s43018-025-00986-3","article-title":"The tumor microenvironment\u2019s role in the response to immune checkpoint blockade","volume":"6","author":"Aliazis","year":"2025","journal-title":"Nat. Cancer"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.medj.2024.02.001","article-title":"Rethinking strategies in SCLC: Lessons learned from tiragolumab in the SKYSCRAPER-02 study","volume":"5","author":"Laura","year":"2024","journal-title":"Med"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"S1594","DOI":"10.1016\/j.annonc.2025.09.062","article-title":"LBA50 IMbrave152\/SKYSCRAPER-14: A phase III study of first-line tiragolumab (tira) + atezolizumab (atezo) + bevacizumab (bev) vs placebo (pbo) + atezo + bev for patients (pts) with untreated locally advanced or metastatic hepatocellular carcinoma (HCC)","volume":"36","author":"Finn","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"S1610","DOI":"10.1016\/j.annonc.2025.09.081","article-title":"LBA69 SKYSCRAPER-03: Phase III, open-label, randomised study of atezolizumab (atezo) + tiragolumab (tira) vs durvalumab (durva) in locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC) after platinum-based concurrent chemoradiation (cCRT)","volume":"36","author":"Dziadziuszko","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"A024","DOI":"10.1158\/2326-6074.IO2026-A024","article-title":"Abstract A024: TIGIT blockade enhances the effect of anti-PD-1 against CD155hi expressing tumors in mouse and human models","volume":"14","author":"Meibers","year":"2026","journal-title":"Cancer Immunol. Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"101831","DOI":"10.1016\/j.xcrm.2024.101831","article-title":"Analysis of PD1, LAG3, TIGIT, and TIM3 expression in human lung adenocarcinoma reveals a 25-gene signature predicting immunotherapy response","volume":"5","author":"Guegan","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"CT053","DOI":"10.1158\/1538-7445.AM2024-CT053","article-title":"Abstract CT053: Exploration of potential biomarkers correlated with efficacy of ociperlimab (anti-TIGIT) plus tislelizumab (anti-PD-1) in 1L PD-L1+ non-small cell lung cancer (NSCLC)","volume":"84","author":"Kim","year":"2024","journal-title":"Cancer Res."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"100937","DOI":"10.1016\/j.medj.2025.100937","article-title":"Beyond TIGIT: Lessons from a failed immune checkpoint for rational target discovery","volume":"6","author":"Ding","year":"2025","journal-title":"Med"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2908","DOI":"10.1158\/1538-7445.AM2023-2908","article-title":"Abstract 2908: TIGIT knockout enhances anti-tumor response of Natural Killer cells and prevents fratricide when combined with therapeutic ADCC-competent TIGIT antibodies","volume":"83","author":"Hasan","year":"2023","journal-title":"Cancer Res."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1158\/0008-5472.CAN-23-2455","article-title":"Fc-silent anti-TIGIT antibodies potentiate anti-tumor immunity without depleting regulatory T cells","volume":"84","author":"Piovesan","year":"2024","journal-title":"Cancer Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.immuni.2020.09.010","article-title":"CD155 on Tumor Cells Drives Resistance to Immunotherapy by Inducing the Degradation of the Activating Receptor CD226 in CD8+ T Cells","volume":"53","author":"Braun","year":"2020","journal-title":"Immunity"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1158\/2326-6066.CIR-19-0877","article-title":"CD226(hi)CD8+ T Cells Are a Prerequisite for Anti-TIGIT Immunotherapy","volume":"8","author":"Jin","year":"2020","journal-title":"Cancer Immunol. Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"IA02","DOI":"10.1158\/1538-7445.MEL2019-IA02","article-title":"Abstract IA02: Next targets for immune checkpoint blockade in melanoma","volume":"80","author":"Chauvin","year":"2020","journal-title":"Cancer Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"14597","DOI":"10.1007\/s00432-023-05268-y","article-title":"Integrated single-cell and bulk sequencing analyses with experimental validation identify the prognostic and immunological implications of CD226 in pan-cancer","volume":"149","author":"Ma","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1007\/s00262-018-2246-5","article-title":"TIGIT: A novel immunotherapy target moving from bench to bedside","volume":"67","author":"Solomon","year":"2018","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"e70098","DOI":"10.1002\/ctd2.70098","article-title":"Reprogramming the tumour microenvironment: Emerging strategies to overcome immunotherapy resistance","volume":"5","author":"Essa","year":"2025","journal-title":"Clin. Transl. Discov."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"e013636","DOI":"10.1136\/jitc-2025-013636","article-title":"Specific depletion of TIGIT(high) CD226(-) clonally expanded intratumoral Tregs defines safe and effective TIGIT targeting","volume":"14","author":"Zhou","year":"2026","journal-title":"J. Immunother. Cancer"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"3074","DOI":"10.1200\/JCO.2017.35.15_suppl.3074","article-title":"Discovery of COM701, a therapeutic antibody targeting the novel immune checkpoint PVRIG, for the treatment of cancer","volume":"35","author":"Liang","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"e003134","DOI":"10.1136\/jitc-2021-003134","article-title":"TIGIT\/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment","volume":"9","author":"Kawashima","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"119","DOI":"10.54097\/8wmxvg77","article-title":"Pan-Cancer Analysis of TIGIT and Its Association with the Tumor Immune Microenvironment and Potential in Cold Tumor Therapy","volume":"13","author":"Cai","year":"2026","journal-title":"Int. J. Biol. Life Sci."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/s41419-025-07984-4","article-title":"TIGIT in cancer: From mechanism of action to promising immunotherapeutic strategies","volume":"16","author":"Cui","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/S1470-2045(24)00679-X","article-title":"Tiragolumab in combination with atezolizumab and bevacizumab in patients with unresectable, locally advanced or metastatic hepatocellular carcinoma (MORPHEUS-Liver): A randomised, open-label, phase 1b-2, study","volume":"26","author":"Finn","year":"2025","journal-title":"Lancet Oncol."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1200\/JCO.2017.77.6385","article-title":"Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline","volume":"36","author":"Brahmer","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"110714","DOI":"10.1016\/j.clim.2026.110714","article-title":"Fc-enhanced anti-TIGIT antibody 30,278-IgG1 RMD amplifies antitumor immunity through effector cell activation and synergizes with PD-1 blockade","volume":"286","author":"Yang","year":"2026","journal-title":"Clin. Immunol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1080\/14796694.2024.2355863","article-title":"IMbrave152\/SKYSCRAPER-14: A Phase III study of atezolizumab, bevacizumab and tiragolumab in advanced hepatocellular carcinoma","volume":"20","author":"Badhrinarayanan","year":"2024","journal-title":"Future Oncol."},{"key":"ref_145","first-page":"1","article-title":"Tiragolumab (Anti-TIGIT) in SCLC: Skyscraper-02, a Towering Inferno","volume":"14","author":"Brazel","year":"2023","journal-title":"Lung Cancer"},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Ge, Z., Peppelenbosch, M.P., Sprengers, D., and Kwekkeboom, J. (2021). TIGIT, the Next Step Towards Successful Combination Immune Checkpoint Therapy in Cancer. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.699895"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s13046-025-03314-w","article-title":"A combination of PD-1 and TIGIT immune checkpoint inhibitors elicits a strong anti-tumour response in mesothelioma","volume":"44","author":"Shi","year":"2025","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"18011","DOI":"10.1038\/s41598-022-22975-7","article-title":"Development of a bispecific antibody targeting PD-L1 and TIGIT with optimal cytotoxicity","volume":"12","author":"Zhong","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_149","unstructured":"Cui, X., Zhu, X., Yu, H., Xu, J., Wei, X., Chen, S., Wang, Y., Chen, X., Feng, Y., and Ren, X. (2023). Co-engagement of TIGIT+ immune cells to PD-L1+ tumours by a bispecific antibody potentiates T-cell response and tumour control. bioRxiv."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"2358","DOI":"10.1158\/1538-7445.AM2024-2358","article-title":"Abstract 2358: YH41723 (IMC-202), a Novel TIGITxPD-L1 bispecific antibody, leads to potent anti-tumor immunity through T cell engaging and T\/NK cell activation","volume":"84","author":"Jee","year":"2024","journal-title":"Cancer Res."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"5303","DOI":"10.1158\/1538-7445.AM2024-5303","article-title":"Abstract 5303: A novel TIGIT and 4-1BB bispecific antibody, ABL112, exhibits potent in vitro and in vivo antitumor activity through dual immune modulation","volume":"84","author":"Son","year":"2024","journal-title":"Cancer Res."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"115653","DOI":"10.1016\/j.intimp.2025.115653","article-title":"Enhancing anti-tumor immunity through TIGIT blockade and tumor-directed targeting in pancreatic cancer","volume":"167","author":"Um","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1038\/s41419-025-08203-w","article-title":"Preclinical evaluation of TIGIT as a target to enhance efficacy and mitigate T cell exhaustion in multiple myeloma following BCMA-CAR-T therapy","volume":"16","author":"Xia","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.ymthe.2021.10.004","article-title":"PD-1 and TIGIT downregulation distinctly affect the effector and early memory phenotypes of CD19-targeting CAR T cells","volume":"30","author":"Lee","year":"2021","journal-title":"Mol. Ther."},{"key":"ref_155","doi-asserted-by":"crossref","unstructured":"Yang, F., Zhang, F., Ji, F., Chen, J., Li, J., Chen, Z., Hu, Z., and Guo, Z. (2023). Self-delivery of TIGIT-blocking scFv enhances CAR-T immunotherapy in solid tumors. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1175920"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"e14574","DOI":"10.1200\/JCO.2024.42.16_suppl.e14574","article-title":"A novel co-receptor with mutated TIGIT to enhance PSCA CAR-T therapy for bladder cancer","volume":"42","author":"Shen","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"115715","DOI":"10.1016\/j.intimp.2025.115715","article-title":"The synapse revisited: Molecular networks of CD4 T cell-DC interactions","volume":"167","author":"Bonilha","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"S589","DOI":"10.1016\/j.annonc.2022.07.143","article-title":"111P Interim biomarker analysis of a phase Ib\/II study of anti-TIGIT etigilimab (MPH313) and nivolumab in subjects with select locally advanced or metastatic solid tumors (ACTIVATE)","volume":"33","author":"Sarikonda","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"e001631","DOI":"10.1136\/jitc-2020-001631","article-title":"PD-1 and TIGIT coexpression identifies a circulating CD8 T cell subset predictive of response to anti-PD-1 therapy","volume":"8","author":"Simon","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"S822","DOI":"10.1016\/j.annonc.2023.09.2477","article-title":"1446P Preliminary efficacy and safety of rilvegostomig (AZD2936), a bispecific antibody targeting PD-1 and TIGIT, in checkpoint inhibitor (CPI)-pretreated advanced\/metastatic non-small-cell lung cancer (NSCLC): ARTEMIDE-01","volume":"34","author":"Hiltermann","year":"2023","journal-title":"Ann. Oncol."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/970\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T04:23:59Z","timestamp":1786249439000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/8\/970"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,7]]},"references-count":160,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["pharmaceutics18080970"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18080970","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,7]]}}}