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The CSF1+ tumor cell-SPP1+ macrophage axis drives gastric cancer progression and immunotherapy resistance
Heng Zhang1, Yundong You1, Jinhao Peng1
1Department of Gastrointestinal Surgery, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China.
Background:
Gastric cancer (GC) remains a leading cause of global cancer mortality, characterized by profound heterogeneity. While immune checkpoint blockade (ICB) has emerged as a promising strategy, pervasive resistance frequently limits its clinical efficacy. Elucidating the mechanisms driving this resistance and identifying predictive biomarkers remain critical challenges for achieving precision oncology in GC.
Methods:
We constructed a spatial multi-omic atlas by integrating scRNA-seq from GC patients with public spatial transcriptomics (ST) data. Computational deconvolution of independent immunotherapy cohorts was performed to pinpoint specific macrophage and fibroblast subsets linked to ICB efficacy. Intercellular immunosuppressive signaling and spatial proximity were characterized via cell-cell communication and ST analysis. We validated the biological significance of this crosstalk using non-contact co-culture systems and mIHC analysis of an independent clinical cohort.
Results:
We constructed a spatially resolved multi-omic atlas by integrating scRNA-seq from 131,027 cells with spatial transcriptomics. Deconvolution of immunotherapy cohorts identified the synchronous enrichment of SPP1+macrophages and MFAP5+fibroblasts in tumors with 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 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.
Conclusions:
Our study identifies a spatially organized niche involving CSF1+malignant cells and SPP1+ macrophages as a key driver of ICB resistance in GC. By defining the CSF1-mediated crosstalk between these two cell types, these findings highlight promising therapeutic targets to enhance the efficacy of immunotherapy.
Insights
A spatial niche of malignant cells and SPP1+ macrophages drives gastric cancer resistance to immune checkpoint blockade (ICB). Targeting CSF1-mediated crosstalk offers a new strategy to improve ICB efficacy in gastric cancer patients.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Gastric cancer (GC) exhibits significant heterogeneity, leading to frequent resistance to immune checkpoint blockade (ICB).
- Identifying resistance mechanisms and predictive biomarkers is crucial for advancing precision oncology in GC.
Purpose of the Study:
- To construct a spatial multi-omic atlas of GC.
- To identify cellular players and signaling pathways contributing to ICB resistance.
- To validate therapeutic targets for enhancing ICB efficacy.
Main Methods:
- Integrated single-cell RNA sequencing (scRNA-seq) with spatial transcriptomics (ST) data.
- Performed computational deconvolution of immunotherapy cohorts.
- Analyzed cell-cell communication and spatial proximity.
- Validated findings using co-culture systems and multiplex immunohistochemistry (mIHC).
Main Results:
- Identified synchronous enrichment of SPP1+ macrophages and MFAP5+ fibroblasts in tumors resistant to ICB.
- Quantified co-localization of CSF1-producing malignant cells and SPP1+ macrophages.
- Demonstrated that malignant cell-derived CSF1 induces SPP1+ macrophage polarization, upregulating IL-10 and TGF-β1.
- Confirmed that this crosstalk enhances GC cell invasion and validated in situ co-localization.
Conclusions:
- A spatially organized niche of CSF1+ malignant cells and SPP1+ macrophages drives ICB resistance in GC.
- CSF1-mediated crosstalk between these cells is a key mechanism of resistance.
- Targeting this crosstalk presents a promising strategy to improve immunotherapy efficacy in gastric cancer.
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