{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T00:03:22Z","timestamp":1793664202552,"version":"4.5.1"},"reference-count":140,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016694","name":"Science and Technology Development Plan of Shandong Province","doi-asserted-by":"publisher","award":["ZR2022QH372"],"award-info":[{"award-number":["ZR2022QH372"]}],"id":[{"id":"10.13039\/100016694","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The advent of cancer immunotherapy has fundamentally restructured the oncological paradigm, moving away from agents that directly target tumor cell kinetics toward strategies that empower the host immune system to recognize and eliminate malignancy. Central to this revolution is the cytotoxic T lymphocyte (CTL), now harnessed as a potent \u201cliving drug\u201d through engineered and naturally selected modalities. This review provides a critical, in-depth examination of the three dominant pillars of T cell-driven therapies: Chimeric Antigen Receptor T-cell (CAR-T) therapy, Tumor-Infiltrating Lymphocyte (TIL) therapy, and T Cell Engagers (TCEs). We dismantle the molecular mechanisms defining each approach, contrasting the synthetic, major histocompatibility complex (MHC)-independent signaling of CAR-T cells with the diverse, MHC-restricted TCR repertoire of TILs, and the transient, pharmacologic bridging provided by bispecific TCEs. While CAR-T therapy has achieved historic success in hematologic malignancies, its translation to solid tumors is severely compromised by the hostile tumor microenvironment (TME), characterized by metabolic insulation, physical exclusion, and profound immunosuppression. Conversely, TIL therapy offers a polyclonal strategy tailored for solid tumors but is hindered by complex biomanufacturing logistics and variable tumor immunogenicity. TCEs promise off-the-shelf accessibility but face challenges regarding persistence and on-target\/off-tumor toxicity. Beyond clinical outcomes, we explore the pathophysiological underpinnings of resistance, including antigen escape mechanisms and T cell exhaustion programs. Finally, we posit that the future of curative regimens lies in rational combinatorial strategies\u2014integrating advanced genetic engineering, metabolic reprogramming, and TME-modulating agents like oncolytic viruses\u2014to overcome the multifaceted defenses of solid tumors.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1847986","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T05:29:59Z","timestamp":1780291799000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["The trinity of T cell engagement: navigating the molecular and clinical landscape of CAR-T, TILs, and TCEs in the war against cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Qiang","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, Lanzhou University Second Hospital","place":["Lanzhou, Gansu, 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