| First Author | Zhou R | Year | 2024 |
| Journal | EMBO J | Volume | 43 |
| Issue | 21 | Pages | 4984-5017 |
| PubMed ID | 39304793 | Mgi Jnum | J:358061 |
| Mgi Id | MGI:7779528 | Doi | 10.1038/s44318-024-00244-9 |
| Citation | Zhou R, et al. (2024) TBK1-Zyxin signaling controls tumor-associated macrophage recruitment to mitigate antitumor immunity. EMBO J 43(21):4984-5017 |
| abstractText | 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. |
