Mutant p53 (mtp53) proteins can exert cancer-promoting gain-of-function activities. We report a mechanism by which mtp53 suppresses both cell-autonomous and non-cell-autonomous signaling to promote cancer cell survival and evasion of tumor immune surveillance. Mtp53 interferes with the function of the cytoplasmic DNA sensing machinery, cGAS-STING-TBK1-IRF3, that activates the innate immune response. Mtp53, but not wild-type p53, binds to TANK-binding protein kinase 1 (TBK1) and prevents the formation of a trimeric complex between TBK1, STING, and IRF3, which is required for activation, nuclear translocation, and transcriptional activity of IRF3. Inactivation of innate immune signaling by mtp53 alters cytokine production, resulting in immune evasion. Restoring TBK1 signaling is sufficient to bypass mtp53 and lead to restored immune cell function and cancer cell eradication. This work is of translational interest because therapeutic approaches that restore TBK1 function could potentially reactivate immune surveillance and eliminate mtp53 tumors.

突变的 p53 (mtp53) 蛋白可以发挥促进癌症的功能获得活性。我们报告了 mtp53 抑制细胞自主和非细胞自主信号以促进癌细胞存活和逃避肿瘤免疫监视的机制。Mtp53 干扰激活先天免疫反应的细胞质 DNA 传感机制 cGAS-STING-TBK1-IRF3 的功能。Mtp53，但不是野生型 p53，与 TANK 结合蛋白激酶 1 (TBK1) 结合并阻止 TBK1、STING 和 IRF3 之间形成三聚体复合物，这是 IRF3 的激活、核易位和转录活性所必需的. mtp53 对先天免疫信号的失活会改变细胞因子的产生，从而导致免疫逃避。恢复 TBK1 信号足以绕过 mtp53 并导致恢复免疫细胞功能和消灭癌细胞。这项工作具有转化意义，因为恢复 TBK1 功能的治疗方法可能会重新激活免疫监视并消除 mtp53 肿瘤。