CSF1+ tumor cells and SPP1+ macrophages form axis driving gastric cancer progression and immunotherapy resistance

Gastric cancer (GC) remains a leading cause of global cancer mortality, characterized by significant heterogeneity. While immune checkpoint blockade (ICB) offers promise, widespread resistance frequently limits its clinical efficacy. A critical gap exists in understanding the mechanisms driving this resistance and identifying predictive biomarkers for precision oncology. This study investigates how specific cellular interactions within the tumor microenvironment contribute to GC progression and ICB resistance, focusing on macrophage and fibroblast subsets.

Researchers constructed a spatial multi-omic atlas by integrating scRNA-seq data from GC patients with public spatial transcriptomics (ST) data. Computational deconvolution of independent immunotherapy cohorts identified specific macrophage and fibroblast subsets linked to ICB efficacy. Intercellular immunosuppressive signaling and spatial proximity were characterized via cell-cell communication and ST analysis. The biological significance of this crosstalk was validated using non-contact co-culture systems and mIHC analysis of an independent clinical cohort, focusing on the interaction between CSF1-producing malignant cells and SPP1+ macrophages.

A spatially resolved multi-omic atlas was constructed from 131,027 cells, integrating scRNA-seq and spatial transcriptomics. Deconvolution of immunotherapy cohorts identified the synchronous enrichment of SPP1+macrophages and MFAP5+fibroblasts in tumors exhibiting poor ICB efficacy. Spatial analysis quantified a significant co-localization between CSF1-producing malignant cells and SPP1+ macrophages. Experimentally, malignant cell-derived CSF1 induced SPP1+ macrophage polarization, triggering the synergistic upregulation of IL-10 and TGF-β1. This specific crosstalk significantly enhanced GC cell colony formation and invasive potential, as confirmed by secretome profiling and functional assays. Finally, mIHC staining validated the co-localization of CSF1+malignant cells and SPP1+macrophages in situ within clinical tumor tissues.

The CSF1+ malignant cell-SPP1+ macrophage axis was identified as a key driver of ICB resistance in gastric cancer, promoting tumor progression via IL-10 and TGF-β1 upregulation.