TBK1-Zyxin signaling controls tumor-associated macrophage recruitment to mitigate antitumor immunity

作者：Ruyuan Zhou, Mengqiu Wang, Xiao Li, Yutong Liu, Yihan Yao, Ailian Wang, Chen Chen, Qian Zhang, Qirou Wu, Qi Zhang, Dante Neculai, Bing Xia, Jian-zhong Shao, Xin‐Hua Feng, Tingbo Liang, Jian Zou, Xiaojian Wang, Pinglong Xu · 发表于：The EMBO Journal · 年份：2024 · DOI：10.1038/s44318-024-00244-9 · 被引用次数：11 · 研究领域：interferon and immune responses、Ubiquitin and proteasome pathways、Immune cells in cancer

Abstract Mechanical control is fundamental for cellular localization within a tissue, including for tumor-associated macrophages (TAMs). While the innate immune sensing pathways cGAS-STING and RLR-MAVS impact the pathogenesis and therapeutics of malignant diseases, their effects on cell residency and motility remain incompletely understood. Here, we uncovered that TBK1 kinase, activated by cGAS-STING or RLR-MAVS signaling in macrophages, directly phosphorylates and mobilizes Zyxin, a key regulator of actin dynamics. Under pathological conditions and in STING or MAVS signalosomes, TBK1-mediated Zyxin phosphorylation at S143 facilitates rapid recruitment of phospho-Zyxin to focal adhesions, leading to subsequent F-actin reorganization and reduced macrophage migration. Intratumoral STING-TBK1-Zyxin signaling was evident in TAMs and critical in antitumor immunity. Furthermore, myeloid-specific or global disruption of this signaling decreased the population of CD11b + F4/80 + TAMs and promoted PD-1-mediated antitumor immunotherapy. Thus, our findings identify a new biological function of innate immune sensing pathways by regulating macrophage tissue localization, thus providing insights into context-dependent mitigation of antitumor immunity.