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.; 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.

doi:10.64898/2026.03.05.708917

bioRxiv · 10.64898/2026.03.05.708917

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.·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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Abstract

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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Chen, J., Zhang, L., Luo, Y., Han, X., Kang, M., 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.. 2026-03-08. CEACAM5/6+ Tumor Cells and IL-1β+ Macrophages Drive Resistance to Chemo-immunotherapy in Gastric Cancer. https://doi.org/10.64898/2026.03.05.708917

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