T Cell Receptor-Engineered T Cell Therapy in Solid Tumors: Where We Stand and What's to Come.

T cell receptor-engineered T (TCR-T) cell therapy has emerged as a promising adoptive cellular therapy for solid tumors by enabling recognition of intracellular antigens presented via human leukocyte antigen (HLA) molecules. Unlike chimeric antigen receptor T cell therapy, TCR-T cell therapy targets a broader antigen repertoire, including cancer-testis antigens, neoantigens, and viral antigens. Recent clinical advances, highlighted by the approval of afamitresgene autoleucel in synovial sarcoma, demonstrate meaningful antitumor activity. However, several limitations remain, including HLA restriction, antigen heterogeneity, toxicity related to on-target/off-tumor effects, and mechanisms of resistance such as antigen loss and T cell exhaustion. Advances in antigen selection, gene editing, and synthetic biology are improving both safety and efficacy. Combination strategies and next-generation engineered constructs are expected to overcome current barriers. This review summarizes the biological rationale, clinical evidence, safety considerations, and resistance mechanisms of TCR-T cell therapy in solid tumors and discusses future directions to optimize their therapeutic potential.