CD147 regulates CD8(+) T cell cytotoxic activity by facilitating phosphorylation and subsequent recruitment of proximal TCR signaling kinases.

CD8(+) T cells are the primary cytotoxic cells within the tumor microenvironment, where T cell receptor (TCR) signaling drives their activation and effector functions. However, aberrant TCR activation in this setting often leads to T cell dysfunction. Previous studies suggest that CD147 modulates T cell activation, effector function, and exhaustion. However, the underlying mechanisms remain unclear. Using a CD8(+) T cell-specific CD147 knockout model, we showed that CD147 loss significantly enhanced T cell cytotoxicity and reduced exhaustion. Mechanistically, CD147 promoted T cell exhaustion by disrupting proximal TCR kinase signaling through direct interactions with CD3ε, CD3ζ, and LCK, thereby promoting immune escape. Pharmacological inhibition with dasatinib attenuated CD147-driven overactivation and exhaustion. Furthermore, embedding the CD147 intracellular domain into CAR-T constructs significantly enhanced their cytotoxic efficacy while reducing exhaustion. These findings advance our understanding of T cell exhaustion in tumors and may inform strategies to optimize CAR-T therapy.