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

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. Synopsis: Although the role of innate immune sensing pathways is well-studied in the pathogenesis of malignancies, whether they influence immune cell migration is not known. This study shows that innate immune signaling via cGAS-STING or RLR-MAVS regulates tumor-associated macrophage tissue residency through activation of the TBK1-Zyxin axis. STING signalosomes recruit and directly phosphorylate Zyxin, thus promoting its localization to focal adhesions. TBK1-Zyxin-mediated chemo-mechanical signaling enhances macrophage adhesion in response to cGAS-STING or RLR-MAVS signaling. STING-TBK1-Zyxin signaling activation in mouse intratumoral tumor-associated macrophages detains TAMs in the tumor and reduces antitumor immunity responses. Myeloid-specific or global inhibition of cGAS-STING-TBK1-Zyxin signaling facilitates antitumor immunotherapy. Innate immune sensing pathways activate the TBK1 kinase for phosphorylation of the actin dynamics regulator Zyxin to trap macrophages in the tumor. [ABSTRACT FROM AUTHOR]