Co-stimulatory signal deficiency impairs cytotoxic T lymphocyte function in tumor immune evasion: molecular mechanisms and therapeutic implications.

The generation and maintenance of effective tumor-specific CTL responses require more than antigen recognition. In most settings, TCR engagement must be accompanied by co-stimulatory input, with the B7-1/B7-2-CD28 axis being one of the best-characterized examples. When this second signal is weak or absent, tumor-reactive CD8+ T cells may recognize tumor antigens but fail to expand, survive, or acquire and sustain cytotoxic activity. Tumors take advantage of this vulnerability by reducing co-stimulatory ligand availability, increasing inhibitory checkpoint signaling, and remodeling the tumor microenvironment in ways that further restrict T-cell activation. Depending on the stage and context of dysfunction, this shift may favor anergy-like dysfunction, impaired persistence and apoptotic attrition, or, under persistent antigen exposure and sustained inhibitory signaling, exhaustion-associated dysfunction, thereby promoting immune escape. This review examines how reduced or functionally restricted B7-CD28 co-stimulation impairs CTL activation, intratumoral reactivation, and persistence, and how checkpoint signaling, suppressive immune cells, metabolic stress, and stromal barriers compound this defect within tumors. We also evaluate strategies intended to restore or bypass inadequate co-stimulatory input, distinguishing established checkpoint-based interventions from co-stimulatory agonists, engineered T-cell therapies, multispecific antibodies, and gene-based approaches that remain preclinical or early translational in many settings. We propose that mechanism-matched therapy should be guided by the phase at which the dominant barrier arises-tumor-reactive CD8+ T-cell priming, intratumoral CTL reactivation, or long-term CTL persistence.