Dynamic Spatial Tumor–Immune Remodeling Drives Response and Resistance to ICI plus Chemotherapy in Metastatic Gastric Cancer
Year: 2026
Type: article
Study design: Observational Study
Abstract: Immune checkpoint inhibitors (ICIs) improve survival in advanced gastric cancer, but the tumor–immune ecosystems that determine response, primary resistance, and acquired resistance remain poorly understood. We established a prospective longitudinal cohort of patients with metastatic gastric cancer undergoing first-line ICI plus chemotherapy, collecting serial tumor biopsies and paired blood samples before treatment, during therapy, and at disease progression. We integrated single-nucleus RNA-seq, spatial transcriptomics, immune profiling, and spatial validation to map tumor–immune evolution during treatment. We find that clinical benefit was associated with both enrichment and spatial aggregation of lymphoid hubs and T/B-cell-enriched antitumor communities linked to CD8⁺ T cell-recruiting macrophages and circulating GZMK⁺/proliferating CD8⁺ T cell responses. By contrast, primary resistance featured spatial niches of SMAD3-high tumor, IL1B⁺/SPP1⁺ myeloid, and profibrotic stromal cells. The predictive value of lymphoid hub and SMAD3-high tumor signatures was validated using transcriptomic data from the phase 3 CheckMate-649 trial. Acquired resistance featured preserved lymphoid hub abundance but disrupted spatial cohesion, accompanied by infiltration of inflammatory myeloid–stromal niches and high CEACAM1 expression. These findings identify dynamic spatial remodeling of tumor–immune ecosystems as a determinant of both response and acquired resistance to ICI-based chemotherapy in gastric cancer.
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7208744625