CARD11 signaling regulates CD8⁺ T cell tumoricidal function

Chronic stimulation in the tumor microenvironment can induce exhausted CD8⁺ T (T_ex) cells that have limited tumoricidal activity. Here, we show an inverse correlation between signal strength and T_ex cell differentiation by using patient-derived mutations in the T cell receptor (TCR)-signaling protein CARD11. Strong TCR signaling of the E134G mutant inhibits T_ex cell differentiation and increases tumor growth. Conversely, reduced TCR signaling by the K215M mutant promotes T_ex cell differentiation with better tumor control. These effects are a result of a restrained tumor-specific TCR clonal repertoire of T_ex cells that reduces immunopathology but compromises tumoricidal activity. Mechanistically, CARD11 is a TCR signal-strength sensor, controlling the TCR repertoire of T_ex cells by regulating the trafficking and homeostasis of the TCR complex. Expanding the TCR repertoire during T_ex cell differentiation by fine-tuning the CARD11-mediated TCR signal strength reinvigorated antitumor function and indicates a strategy for improving cancer immunotherapy.