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

Ziqiang Ling1, Renzhe Tang2, Botao Yuan1

  • 1The First Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China.

Frontiers in Immunology
|August 18, 2026
PubMed

Insights

Spatial immune niches explain immunotherapy resistance in gastric cancer, guiding better patient selection. Understanding these niches can improve treatment strategies for better outcomes in this disease.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Biology

Background:

  • Immune checkpoint inhibitors (ICIs) have transformed gastric cancer treatment, but responses vary significantly.
  • Current biomarkers (e.g., PD-L1, MSI) predict eligibility but not treatment success or failure.
  • Understanding resistance mechanisms is crucial for optimizing immunotherapy in gastric and gastroesophageal junction adenocarcinoma.

Purpose of the Study:

  • To review the role of spatial immune niches in immunotherapy resistance in gastric cancer.
  • To explore how different niche components influence treatment response.
  • To identify clinically relevant niche states and their implications for patient selection and combination therapies.

Main Methods:

  • Narrative review synthesizing evidence from clinical trials and multi-omics studies.
  • Analysis of single-cell and spatial multi-omics, multiplex immunohistochemistry/immunofluorescence, and digital pathology data.
  • Integration of translational biomarker studies to understand resistance.

Main Results:

  • Spatial immune niches are defined by interactions between malignant cells, immune cells, stromal components, and the tumor microenvironment.
  • Clinically relevant niche states include lymphoid-organized inflamed, inflamed-but-suppressed, stromal-excluded, myeloid-dominant, vascular/hypoxic, target-antigen-associated, and peritoneal metastatic niches.
  • These niches collectively shape effector immunity and immunotherapy response.

Conclusions:

  • Spatial immune niches provide a framework for understanding immunotherapy resistance in gastric cancer.
  • Identifying specific niche states can refine patient selection for ICIs.
  • Compact spatial assays and niche-matched combination strategies hold promise for improving durable benefit in gastric cancer patients.
Keywords:
cancer-associated fibroblastsgastric cancerimmunotherapy resistancepredictive biomarkersspatial transcriptomicstertiary lymphoid structurestumor microenvironmenttumor-associated macrophages

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