T cell-specific loss of IRF1 results in defective CD8 T cell activation and antitumor immunity

ABSTRACT Interferon regulatory factor 1 (IRF1) has long been recognized as a tumor suppressor; however, recent studies have revealed context-specific and sometimes opposing roles in cancer progression. Here, we describe a T cell–specific mechanism underlying the antitumor activity of IRF1. Unlike germline Irf1 -deficient mice, T cell–specific loss of IRF1 does not lead to a deficiency in cytotoxic CD8⁺ T cells. Nevertheless, tumor burden remains elevated in these mice, associated with reduced CD8⁺ T cell infiltration driven by impaired activation and proliferation in the absence of IRF1. Transcriptomic analysis of activated Irf1 -deficient T cells identified NFATc1 as a key gene significantly downregulated upon IRF1 loss. Analysis of human melanoma datasets further corroborated this finding, highlighting a previously unappreciated role for IRF1 in regulating T cell activation and antitumor immunity.