Authors
Xiaoyu Wang, Yu Li, Kaixi Yang
Published in
OncoTargets and therapy. Volume 19. Pages 645997. Epub Sep 29, 2026.
Abstract
Recent advances in immune checkpoint blockade, chemotherapy, anti-angiogenic therapy, and molecularly targeted therapies have expanded therapeutic options for gastric cancer. However, primary and acquired resistance remain major barriers to achieving durable clinical benefit. Tumor cell-intrinsic molecular features, including HER2 status, PD-L1 expression, MSI/MMR status, claudin 18 isoform 2 (CLDN18.2), and fibroblast growth factor receptor 2b (FGFR2b) alterations, do not fully account for the substantial heterogeneity in treatment response, highlighting the need to consider the spatial organization of the tumor microenvironment. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) are key components of this microenvironment. Evidence from single-cell sequencing, spatial transcriptomics, multiplex imaging, clinicopathological cohorts, and functional experiments indicates that CAFs and TAMs can form spatially organized niches through chemokine-mediated monocyte recruitment, macrophage-state reprogramming, extracellular matrix remodeling, complement signaling, cytokine networks, and immunometabolic regulation. Our synthesis identifies recurrent gastric cancer-associated niche archetypes, including CCL2⁺ fibroblast-STAT3-activated macrophage, GREM1⁺ fibroblast-SPP1⁺ macrophage, FAP⁺ fibroblast-SPP1⁺ macrophage, and THBS2⁺ matrix CAF-SPP1⁺ TAM niches. Among these, the THBS2⁺ matrix CAF-SPP1⁺ TAM niche in peritoneal metastasis has particularly strong spatial and functional support, including experimental evidence that CAF-derived C3 promotes C3AR1-dependent accumulation of SPP1⁺ TAMs and resistance to immune checkpoint blockade. Other proposed interactions are supported to varying degrees by spatial colocalization, ligand-receptor inference, clinicopathological association, or experimental perturbation, but their causal and clinical relevance remains incompletely established. Collectively, the available evidence suggests that selected CAF-TAM niches may promote CD8⁺ T-cell exclusion, vascular dysfunction, impaired therapeutic delivery, and persistence of treatment-resistant tumor cells. Actionable pathways include CCL2-CCR2, CSF1-CSF1R, IL-6-JAK-STAT3, CXCL12-CXCR4, SPP1-integrin, FAP, TGF-β, LOX, and C3-C3AR1. Future strategies should move beyond non-selective depletion of CAFs or macrophages and instead integrate molecular subtype, metastatic site, treatment context, and spatial biomarker patterns to identify and selectively disrupt dominant pathogenic niches.
PMID:
42829718
Bibliographic data and abstract were imported from PubMed on 04 Oct 2026.
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