Abstract
Both tumor-associated macrophage (TAM) and tumor stiffness may support immunosuppression and limit immunotherapy response, particularly in non-small cell lung cancer (NSCLC). TAMs influence extracellular matrix (ECM) remodeling, but whether they also affect tumor stiffness, or are regulated by mechanical signals in turn, remains to be investigated. Here, we use single-cell transcriptomics of primary NSCLC samples to show that TAMs are associated with an immunosuppressive niche and are also a major source of the ECM component fibronectin (FN1). Mechanistically, macrophage-specific FN1 deficiency induces pro-inflammatory macrophages in a subcutaneous tumor mouse model, reduces ECM stiffness, increases lymphocyte infiltration into tumors, strengthens antitumor immunity, and enhances immune checkpoint blockade efficacy. Within TAMs, FN1-mediated cytoskeleton assembly and autophagy induction impair macrophage glycolysis by inhibiting the RAC1-mTOR axis, thereby limiting the antitumor activity of macrophages. Collectively, these findings highlight macrophage-derived FN1 as a mechanical cue for aggravating immunosuppression and as an intervention target to supplement immunotherapy in NSCLC.
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This work was supported by grants from the State’s Key Project of Research and Development Plan (grant number 2021YFE0110600 (Li. Y.)), National Natural Science Foundation of China (grant number 82573155 (Li. Y.), 82350121 (Li. Y.), U24A20734 (Y. Z.)), Central Plains Science and Technology Innovation Leading Talent (grant number 264200510035 (Li. Y.)), Outstanding Young Talents Project from Henan Province (grant number 2523004210210 (Li. Y.)), Young and middle-aged Health Science and Technology Innovation Talents in Henan Province (grant number LJRC2024012 (Li. Y.)), Science and Technology Innovation Team Support Plan from Henan Province (grant number 25IRTSTHN039 (Li. Y.)), Top Talent Plan from Zhengzhou University (Li. Y.), and Funding for Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University (grant number ZYCXTD2023013 (Li. Y.)).
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Xin Xie, Haiqing Bai and Yu-Chieh Yuan are employed with their own equity at Xellar Inc., a company that has developed a 3D Organ Chip Culture for drug discovery. The authors declare no other competing interests.
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Li, A., Wang, Y., Bai, H. et al. Macrophage-derived fibronectin suppresses antitumor immunity via tissue stiffening and immunosuppressive cell induction in cancer mouse models. Nat Commun (2026). https://doi.org/10.1038/s41467-026-73287-7
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DOI: https://doi.org/10.1038/s41467-026-73287-7
