TBK1-Zyxin signaling mitigates antitumor immunity by mechanical control of tumor-associated macrophage residency

Mechanical control of cell residency, such as tumor-associated macrophages (TAMs), is a fundamental cellular and tissue physiology process. While innate immune sensing pathways such as cGAS-STING signaling and RLR-MAVS signaling impact both the pathogenesis and therapeutics of malignant diseases, their effects on cell residency and motility remain incompletely understood. Here, we uncovered a novel biological function by which TBK1, activated by cGAS-STING or RLR-MAVS signaling, directly phosphorylates and mobilizes Zyxin, a key regulator of actin dynamics. Under pathological conditions, TBK1-mediated Zyxin phosphorylation at the S143 residue in STING or MAVS signalosomes facilitates rapid recruitment of phospho-Zyxin to focal adhesions, a process independent of IRF3 and leads to subsequent F-actin reorganization and macrophage tissue residency. Noticeably, intratumoral STING-TBK1-Zyxin signaling was evidently in TAMs and critical in antitumor immunity, while myeloid-specific or global intervention in this chemomechanical signaling significantly decreased CD11b+F4/80+ TAMs and promoted PD-1-mediated antitumor immunotherapy. Thus, our findings identify a new biological function downstream of TBK1 signaling that grants macrophage residency as a prominent aspect of innate immune sensing and provides unanticipated insights into context-dependent mitigation of antitumor immunity.