美国石溪大学Luis A. Martinez研究团队近日取得一项新成果。经过不懈努力，他们发现p53突变（mtp53）通过抑制先天免疫信号传导促进肿瘤发生。相关论文于2021年2月4日在线发表在《癌细胞》杂志上。

研究人员揭示了mtp53抑制细胞自主和细胞非自主的信号传导，从而促进癌细胞存活和逃避肿瘤免疫监视的新机制。Mtp53会干扰细胞质DNA感应通路cGAS-STING-TBK1-IRF3的功能，后者会激活先天免疫反应。Mtp53而非野生型p53，与TANK结合蛋白激酶1（TBK1）结合，从而阻止TBK1、STING和IRF3形成三聚体复合物，而该复合体是IRF3激活、核转运和转录活性所必需的。

mtp53诱导的先天性免疫信号失活会改变细胞因子的产生，从而导致免疫逃逸。恢复TBK1信号足以绕过mtp53恢复免疫细胞的功能和癌细胞根除。该工作具有转化意义，因为恢复TBK1功能的治疗可能会重新激活免疫监视并消除mtp53肿瘤。

研究人员介绍，mtp53具有促进癌症功能获得的能力。

附：英文原文

Title: Mutant p53 suppresses innate immune signaling to promote tumorigenesis

Author: Monisankar Ghosh, Suchandrima Saha, Julie Bettke, Rachana Nagar, Alejandro Parrales, Tomoo Iwakuma, Adrianus W.M. van der Velden, Luis A. Martinez

Issue&Volume: 2021-02-04

Abstract: 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-autonomoussignaling 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 toTANK-binding protein kinase 1 (TBK1) and prevents the formation of a trimeric complexbetween TBK1, STING, and IRF3, which is required for activation, nuclear translocation,and transcriptional activity of IRF3. Inactivation of innate immune signaling by mtp53alters cytokine production, resulting in immune evasion. Restoring TBK1 signalingis sufficient to bypass mtp53 and lead to restored immune cell function and cancercell eradication. This work is of translational interest because therapeutic approachesthat restore TBK1 function could potentially reactivate immune surveillance and eliminatemtp53 tumors.

DOI: 10.1016/j.ccell.2021.01.003

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00041-6