Exon-6 truncated p53 suppresses innate immune responses to facilitate immune evasion in bladder cancer
Previous studies have reported that truncated p53 exhibits pro-tumorigenic properties; however, whether it contributes to immune evasion by influencing the immune microenvironment remains unclear. Overall design: Here, we report that E6-trunc p53 isoforms  (E6-trunc p53) inhibit type I interferon (IFN-I) signaling, thereby supporting tumor cell survival and enabling immune evasion. Ectopic expression of E6-trunc p53 reduces T-cell infiltration into tumors and markedly promotes in vivo tumor growth in an immune-dependent manner. Mechanistically, E6-trunc p53 exhibit high-affinity binding to TBK1, thereby preventing cell-intrinsic activation of innate immune pathways and suppressing IFN-I–mediated antitumor immunity. Additionally, silencing E6-trunc p53 leads to robust upregulation of IFN-I signaling and induces tumor cell death. Deletion of TBK1 or IFN-ß completely abolishes the cell death triggered by knockdown of E6-trunc p53. Notably, TP53 truncating mutations correlate inversely with the extent of T-cell infiltration and predict poor responsiveness to immunotherapy in patients with bladder cancer. Collectively, our findings reveal a novel oncogenic role of E6-trunc p53 in modulating IFN-I signaling and driving tumor malignancy and immune evasion.