Transient tumor exposure induces persistent functional defects in memory CD8 T cells.

Memory CD8 T cells generated during acute infections exhibit enhanced effector functions upon reactivation. However, persistent antigen exposure, such as in cancer, can impair their functionality. In this study, we compared memory CD8 T cells generated following tumor rejection (Tum-CD8) with those arising from an acute viral infection (Vir-CD8). Using vaccinia virus and EL4 tumor models expressing the same antigen, we found that Tum-CD8 cells displayed a distinct phenotype, including sustained expression of inhibitory receptors (PD-1, TIM-3), altered integrin expression, and reduced production of IFNγ and TNF. Despite retaining cytotoxic activity, their protective capacity was compromised, even after viral recall. Transcriptomic and functional analyses revealed that transient tumor exposure imprints a stable, exhaustion-like program on memory CD8 T cells. These findings highlight how suboptimal priming conditions during tumor challenge durably shape memory T cell responses.