Cancer-associated fibroblast-derived POSTN as a metabolic “switch” shapes lipid-stressed macrophage polarization in gastric cancer

Abstract

Background Cancer-associated fibroblasts (CAFs) foster an immunosuppressive tumor microenvironment (TME) and confer resistance to immune checkpoint blockade (ICB) in gastric cancer (GC). However, the mechanisms by which specific CAF subsets regulate metabolic crosstalk and immune evasion remain poorly defined. Methods We integrated bulk and single-cell RNA-sequencing data, spatial transcriptomics, and clinical cohorts of GC patients treated with immunotherapy. Functional validation was performed using in vitro co-culture systems, multiple murine models, and lipid nanoparticle (LNP)-encapsulated siRNA targeting Postn. Results We identified POSTN + CAFs as a key subset enriched in ICB non-responders and associated with poor prognosis. Mechanistically, POSTN secreted by CAFs engaged integrin β1 (ITGB1) on tumor cells and macrophages, activating the PI3K/AKT/mTOR signaling axis and upregulating PPARγ. This signaling cascade drove lipid metabolic reprogramming, characterized by increased lipid accumulation and oxidative stress, and promoted the polarization of macrophages toward an immunosuppressive, lipid-stressed M2 phenotype. Targeting POSTN signaling with LNP-formulated siPostn attenuated tumor growth, suppressed lipid metabolism, and reduced M2 macrophage infiltration in the TME. Conclusion This work reveals that POSTN + CAFs establish an immunosuppressive TME and are associated with ICB non-response in GC by remodeling lipid metabolism through the ITGB1-PI3K/AKT/mTOR-PPARγ axis, a finding that underscores the therapeutic value of intervening in this specific CAF-macrophage metabolic crosstalk.