{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T15:55:02Z","timestamp":1792166102617,"version":"4.4.0"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated significant efficacy in the treatment of hematological malignancies; however, its application in the solid tumor setting remains challenging. Given that solid tumors account for the vast majority of clinically diagnosed cancers, there is an urgent and significant clinical need to develop effective CAR-T therapy. This review focuses on the latest clinical trials of CAR-T therapy in major solid tumors, including glioma, colorectal, pancreatic, prostate, and lung cancers. It systematically evaluates the results of studies targeting key tumor-associated antigens, such as EGFR, IL13R\u03b12, GD2, B7-H3, CEA, MSLN, PSCA\/PSMA, and ROR1. The results indicate that locally delivered, dual-targeted CAR-T cells and engineered CAR-T cells show potential in reducing antigenic escape and enhancing cellular function. Significant survival benefit and tumor remission were observed in some studies. However, antigen heterogeneity-driven escape, tumor immunosuppressive microenvironment, insufficient persistence of CAR-T cells <jats:italic>in vivo<\/jats:italic>, and treatment-related toxicity still limit their efficacy and clinical application. To address these challenges, we further discuss various optimization strategies, including target selection, combination of immune checkpoint inhibitors or tumor microenvironment modulators, and optimization of CAR structural design and delivery methods. In the future, through the exploration of multi-dimensional optimization design and combination therapeutic regimen, it is expected to facilitate the broader application and clinical translation of CAR-T therapy in solid tumor treatment.<\/jats:p>","DOI":"10.3389\/fonc.2025.1652329","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T04:14:28Z","timestamp":1756872868000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Challenges and breakthroughs: current landscape and future prospects of CAR-T cell therapy clinical trials for solid tumors"],"prefix":"10.3389","volume":"15","author":[{"given":"Jing","family":"Guo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhe","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiyan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/d41573-024-00094-4","article-title":"The changing landscape of cancer cell therapies: clinical trials and real-world data","volume":"23","author":"Saez-Iba\u00f1ez","year":"2024","journal-title":"Nat Rev Drug Discov"},{"key":"B2","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1186\/s13045-024-01639-1","article-title":"Advances in CAR-T cell therapy for hematologic and solid Malignancies: latest updates from 2024 ESMO Congress","volume":"17","author":"Huang","year":"2024","journal-title":"J Hematol Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709866","article-title":"Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia","volume":"378","author":"Maude","year":"2018","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s40291-025-00771-z","article-title":"Obecabtagene autoleucel: first approval","volume":"29","author":"Lee","year":"2025","journal-title":"Mol Diagn Ther"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1707447","article-title":"Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma","volume":"377","author":"Neelapu","year":"2017","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)31366-0","article-title":"Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study","volume":"396","author":"Abramson","year":"2020","journal-title":"Lancet"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1914347","article-title":"KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma","volume":"382","author":"Wang","year":"2020","journal-title":"N Engl J Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2024850","article-title":"Idecabtagene vicleucel in relapsed and refractory multiple myeloma","volume":"384","author":"Munshi","year":"2021","journal-title":"N Engl J Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-24-0378","article-title":"FDA approval summary: ciltacabtagene autoleucel for relapsed or refractory multiple myeloma","volume":"30","author":"Natrajan","year":"2024","journal-title":"Clin Cancer Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2024.4879","article-title":"Equecabtagene autoleucel in patients with relapsed or refractory multiple myeloma: the FUMANBA - 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