{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T17:56:29Z","timestamp":1788198989684,"version":"build-2803163510"},"reference-count":136,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"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>T-cell receptor-engineered T-cell (TCR-T) therapy has emerged as a promising strategy for solid tumors because it enables recognition of intracellular antigens presented by human leukocyte antigen (HLA) molecules, thereby extending targetability beyond cell-surface proteins. However, its clinical activity remains inconsistent because of HLA restriction, heterogeneous antigen expression, unstable antigen presentation, and an immunosuppressive tumor microenvironment. In this review, we summarize the biological basis of TCR-T therapy in solid tumors, including peptide\u2013HLA recognition, target selection, antigen-presentation barriers, and mechanisms of tumor-cell killing. We then review current clinical progress across major solid tumor types, highlighting meaningful responses in selected biomarker-defined settings while noting that efficacy in many epithelial cancers remains limited. Current evidence further indicates that target recognition alone is insufficient for durable tumor control; sustained benefit also depends on preserved antigen presentation, effective tumor trafficking, resistance to suppressive signals, and maintenance of T-cell fitness. We also discuss emerging strategies to improve therapeutic performance, including precision receptor engineering, multi-HLA target development, microenvironment-focused armoring, and manufacturing optimization. Overall, TCR-T therapy provides a compelling framework for solid-tumor treatment, but broader and more durable benefit will require integrated advances in target selection, safety design, and cellular engineering.<\/jats:p>","DOI":"10.3389\/fonc.2026.1810903","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:47:39Z","timestamp":1778129259000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting solid tumors with TCR-T cells: mechanisms, progress, and challenges"],"prefix":"10.3389","volume":"16","author":[{"given":"Wenfang","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital","place":["Zhengzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medical 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