CEACAM5/6+ Tumor Cells and IL-1β+ Macrophages Drive Resistance to Chemo-immunotherapy in Gastric Cancer
Chen, J.; Zhang, L.; Luo, Y.; Han, X.; Kang, M.; Chen, J.; Liu, W.; Xun, Z.; Chen, G.; Chen, K.; Xu, S.; Zhang, C.; Wu, Z.; Wu, W.; Hao, Z.; Han, Y.; Lin, Q.; Xu, Y.; Wang, L.; Liang, H.
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Chemo-immunotherapy is a first-line treatment for advanced gastric cancer, yet response rates remain limited and resistance mechanisms are poorly defined. Here we generate a single-cell atlas of 542,121 cells from 35 patients treated with anti-PD-1 plus chemotherapy, profiling pre- and post-treatment tumors linked to clinical response. Integrating spatial transcriptomics, immunohistochemistry, and bulk RNA sequencing, we identify two temporally distinct resistance programs. Intrinsic resistance in pre-treatment non-responders is marked by enrichment of CEACAM5/6 tumor cells that form immune-excluded spatial niches characterized by macrophage recruitment and CD8 T-cell exhaustion. Acquired resistance in post-treatment non-responders is driven by expansion of IL-1{beta} macrophages, which induces coordinated NF-{kappa}B activation across tumor and stromal compartments, promoting PD-L1 upregulation, epithelial-mesenchymal transition, and chronic inflammation. These findings delineate an evolutionary trajectory of resistance and nominate CEACAM5/6 and IL-1{beta} as predictive biomarkers and therapeutic targets to improve anti-PD-1-based combination strategies.
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