Spatial immune niches in gastric cancer immunotherapy resistance: mechanisms and translational implications

Abstract

Immune checkpoint inhibitors have changed the treatment landscape for gastric and gastroesophageal junction adenocarcinoma, yet durable benefit remains uneven across biomarker-defined groups. PD-L1 combined positive score, MSI/dMMR, tumor mutational burden, EBV status, HER2, and CLDN18.2 guide treatment eligibility, but they do not explain why effector immunity succeeds in one lesion and fails in another. This narrative review uses spatial immune niches as a framework for interpreting immunotherapy resistance in gastric cancer. These niches are tissue compartments in which malignant-cell states, effector-cell access, tertiary lymphoid structures, cancer-associated fibroblasts, tumor-associated macrophages, extracellular matrix, vascular function, and metastatic-site ecology jointly shape response. We synthesize evidence from clinical trials, single-cell and spatial multi-omics, multiplex immunohistochemistry and immunofluorescence, digital pathology, and translational biomarker studies. The review highlights clinically relevant niche states, including lymphoid-organized inflamed, inflamed-but-suppressed, stromal-excluded, myeloid-dominant, vascular/hypoxic, target-antigen-associated, and peritoneal metastatic niches. It further discusses how compact spatial assays could refine patient selection and support niche-matched combination strategies.