TBK1-Zyxin signaling controls tumor-associated macrophage recruitment to mitigate antitumor immunity
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<sup>+</sup> F4/80<sup>+</sup> 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.
Authors
- Tingbo Liang (ORCID: https://orcid.org/0000-0003-3262-2587)
- Qi Zhang (ORCID: https://orcid.org/0000-0003-1754-4058)
- Jian-zhong Shao (ORCID: https://orcid.org/0000-0003-3483-1817)
- Qirou Wu (ORCID: https://orcid.org/0009-0001-5659-2186)
- Pinglong Xu (ORCID: https://orcid.org/0000-0001-7726-5443)
- Bing Xia (ORCID: https://orcid.org/0000-0002-1637-7908)
- Xin‐Hua Feng (ORCID: https://orcid.org/0000-0002-4418-0811)
- Dante Neculai (ORCID: https://orcid.org/0000-0001-8887-9168)
- Ruyuan Zhou (ORCID: https://orcid.org/0000-0003-4321-9718)
- Qian Zhang (ORCID: https://orcid.org/0000-0001-9924-6024)
- Chen Chen (ORCID: https://orcid.org/0000-0003-2104-534X)
- Xiaojian Wang (ORCID: https://orcid.org/0000-0001-8232-0558)
- Yutong Liu (ORCID: https://orcid.org/0000-0003-2236-6962)
- Xiao Li (ORCID: https://orcid.org/0000-0002-2255-4499)
- Jian Zou (ORCID: https://orcid.org/0000-0002-8884-9978)
- Mengqiu Wang (ORCID: https://orcid.org/0009-0002-6923-7615)
- Yihan Yao (ORCID: https://orcid.org/0000-0002-7247-0314)
- Ailian Wang
Institutions
- Zhejiang Cancer Hospital (CN)
- Zhejiang Lab (CN)
- Second Affiliated Hospital of Zhejiang University (CN)
- Hangzhou Cancer Hospital (CN)
- First Affiliated Hospital Zhejiang University (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-09-20
- DOI
- https://doi.org/10.1038/s44318-024-00244-9
- Citations
- 6
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 1.44
Funders
- National Natural Science Foundation of China
- Key Programme