MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China.
Institute of Intelligent Medicine, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, 310058, China.
EMBO J. 2024 Nov;43(21):4984-5017. doi: 10.1038/s44318-024-00244-9. Epub 2024 Sep 20.
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.
机械控制对于组织内的细胞定位至关重要，包括肿瘤相关巨噬细胞（TAMs）。虽然先天免疫感应途径 cGAS-STING 和 RLR-MAVS 影响恶性疾病的发病机制和治疗，但它们对细胞居留和迁移的影响仍不完全清楚。在这里，我们发现 TBK1 激酶被巨噬细胞中的 cGAS-STING 或 RLR-MAVS 信号激活，可直接磷酸化并动员 Zyxin，这是肌动蛋白动力学的关键调节剂。在病理条件下以及在 STING 或 MAVS 信号小体中，TBK1 介导的 Zyxin 在 S143 处的磷酸化促进了磷酸化 Zyxin 快速募集到焦点黏附，导致随后的 F-肌动蛋白重排和巨噬细胞迁移减少。在 TAMs 中可以明显观察到肿瘤内的 STING-TBK1-Zyxin 信号，并且在抗肿瘤免疫中至关重要。此外，髓样细胞特异性或全身性破坏这种信号会减少 CD11b F4/80 TAMs 的数量，并促进 PD-1 介导的抗肿瘤免疫治疗。因此，我们的研究结果确定了先天免疫感应途径通过调节巨噬细胞组织定位的新生物学功能，从而为理解抗肿瘤免疫的上下文依赖性缓解提供了思路。
