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.

中文翻译：

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TBK1-Zyxin 信号转导控制肿瘤相关巨噬细胞募集以减轻抗肿瘤免疫。


机械控制是组织内细胞定位的基础，包括肿瘤相关巨噬细胞 （TAM）。虽然先天免疫感应通路 cGAS-STING 和 RLR-MAVS 影响恶性疾病的发病机制和治疗，但它们对细胞驻留和运动的影响仍不完全清楚。在这里，我们发现 TBK1 激酶在巨噬细胞中被 cGAS-STING 或 RLR-MAVS 信号转导激活，直接磷酸化并动员肌动蛋白动力学的关键调节因子 Zyxin。在病理条件下以及在 STING 或 MAVS 信号体中，TBK1 介导的 Zyxin 在 S143 位点磷酸化有助于磷酸化 Zyxin 快速募集到黏着斑，导致随后的 F-肌动蛋白重组和巨噬细胞迁移减少。瘤内 STING-TBK1-Zyxin 信号在 TAMs 中很明显，在抗肿瘤免疫中至关重要。此外，该信号传导的髓系特异性或整体破坏减少了 CD11b+ F4/80+ TAMs 的数量，并促进了 PD-1 介导的抗肿瘤免疫治疗。因此，我们的研究结果通过调节巨噬细胞组织定位确定了先天免疫感应通路的新生物学功能，从而为抗肿瘤免疫的环境依赖性缓解提供了见解。