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Updated: Jun 12, 2025
In Vitro Assay to Study Tumor-macrophage Interaction
Published on: August 1, 2019
TBK1-Zyxin signaling controls tumor-associated macrophage recruitment to mitigate antitumor immunity
Ruyuan Zhou1,2,3, Mengqiu Wang1, Xiao Li1
1MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China.
Abstract:
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.
Insights
Innate immune sensing pathways regulate macrophage migration by activating TBK1 kinase, which phosphorylates Zyxin. This signaling impacts tumor-associated macrophage localization and antitumor immunity.
Area of Science:
- Immunology
- Cell Biology
- Cancer Research
Background:
- Mechanical cues are crucial for cell positioning in tissues, affecting tumor-associated macrophages (TAMs).
- Innate immune sensing pathways like cGAS-STING and RLR-MAVS influence cancer but their role in macrophage residency and motility is unclear.
Purpose of the Study:
- To investigate the role of TBK1 kinase, activated by cGAS-STING/RLR-MAVS, in regulating macrophage localization and migration.
- To explore the impact of this signaling pathway on TAMs and antitumor immunity.
Main Methods:
- Investigated TBK1 kinase activity in macrophages stimulated by cGAS-STING or RLR-MAVS.
- Analyzed Zyxin phosphorylation and its effect on focal adhesions and F-actin dynamics.
- Examined the role of STING-TBK1-Zyxin signaling in TAMs within tumors.
- Assessed the impact of disrupting this pathway on TAM populations and immunotherapy response.
Main Results:
- TBK1 kinase directly phosphorylates Zyxin at S143, promoting its recruitment to focal adhesions.
- This phosphorylation leads to F-actin reorganization and reduced macrophage migration.
- Intratumoral STING-TBK1-Zyxin signaling is present in TAMs and influences antitumor immunity.
- Disrupting this pathway reduced TAMs and enhanced PD-1 immunotherapy.
Conclusions:
- Identified a novel function for innate immune sensing pathways in controlling macrophage tissue localization.
- The STING-TBK1-Zyxin axis regulates TAM behavior and impacts the efficacy of antitumor immunotherapy.
- Findings offer insights into modulating macrophage localization for improved cancer treatment.
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