Understanding the factors that regulate T cell infiltration and functional states in solid
tumors is crucial for advancing
cancer immunotherapies. Here, we discovered that the expression of
interferon regulatory factor 4 (IRF4) was a critical T cell intrinsic requirement for effective anti-
tumor immunity. Mice with T-cell-specific ablation of IRF4 showed significantly reduced T cell
tumor infiltration and function, resulting in accelerated growth of subcutaneous syngeneic
tumors and allowing the growth of allogeneic
tumors. Additionally, engineered overexpression of IRF4 in anti-
tumor CD8+ T cells that were adoptively transferred significantly promoted their
tumor infiltration and transition from a naive/memory-like cell state into effector T cell states. As a result, IRF4-engineered anti-
tumor T cells exhibited significantly improved anti-
tumor efficacy, and inhibited
tumor growth either alone or in combination with PD-L1 blockade. These findings identify IRF4 as a crucial cell-intrinsic driver of T cell infiltration and function in
tumors, emphasizing the potential of IRF4-engineering as an immunotherapeutic approach.