Candidate Spatial Niches Associated with Gastric Cancer Metastasis and Treatment Resistance: Functional...

Gastric cancer metastasis and poor treatment responses are spatially heterogeneous; however, single-marker positivity, cellular enrichment, or simple colocalization alone is insufficient to establish a functionally meaningful spatial niche. Within this framework, "treatment resistance" encompasses primary nonresponse, reduced treatment sensitivity, insufficient local drug delivery, post-treatment residual survival, acquired resistance, and interlesional differences in therapeutic efficacy. We propose a minimum criteria chain for candidate spatial niches comprising four elements: a specified spatial context; neighborhoods characterized using prespecified and transparently reported spatial rules; local functional programs concordant with these neighborhoods; and associations with malignant phenotypes or clinical outcomes. Based on the principle of linking dominant spatial contexts with their predominant malignant functional outputs, we summarize four candidate niches within primary tumors-the invasive front-tumor-stroma interface, immune exclusion-immune evasion, hypoxia-metabolic adaptation, and perivascular supportive niches-as well as an organ-context-dependent adaptive niche-forming process at metastatic sites. The level of evidence supporting these categories varies substantially. Immune-exclusion-related spatial states currently have relatively stronger links to treatment-response cohorts; however, rigorous gastric-cancer-specific in situ validation remains limited, and no candidate niche has yet achieved full clinical validation. Invasive-front and hypoxic niches are supported primarily by pathological or mechanistic evidence, whereas evidence for perivascular niches remains limited despite emerging longitudinal treatment-response observations, and metastatic niches outside the peritoneum require stronger longitudinal, local functional, and spatial-perturbation validation. This framework aims to standardize spatial-niche terminology and evidence interpretation and guide future quantification, validation, and potential clinical translation in gastric cancer.