T cell-based therapies show promise but face barriers in solid tumors

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 “living drug” 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—integrating advanced genetic engineering, metabolic reprogramming, and TME-modulating agents like oncolytic viruses—to overcome the multifaceted defenses of solid tumors.