Integrative Multi‐Omics Analysis Uncovers Immunological Phenotypes Predictive of Combinatorial Immunotherapy Response in Gastric Cancer

Abstract Current understanding of immune characteristics in gastric cancer remains limited for guiding clinical practice, particularly immunotherapy. This study aims to elucidate the multidimensional landscape of tumor microenvironment in gastric cancer, identify predictive biomarkers potentially associated with favorable immunotherapy response, and propose a precision stratification framework to inform therapeutic strategies. This study introduces a novel immune classification system tumor immune microenvironment (TIME)‐inflamed, TIME‐desert, and TIME‐excluded), and characterize the cellular and molecular characteristics of each subtype. TIME‐inflamed tumors exhibit significantly higher infiltration of immune cells in tumor regions, as well as increased expression of inflamed‐genes. TIME‐desert tumors display minimal immune cell infiltration and feature abnormal microvasculature. TIME‐excluded subtype is defined by immune cell accumulation outside the tumor with ineffective intratumoral infiltration, prominent fibroblast activity, and collagen deposition. Application of this immune classification system to stratify gastric cancer within the SPACE cohort successfully demonstrates potential for predicting favorable outcomes of a subset of “cold tumor” patients upon receiving combined immunotherapy and chemotherapy. The findings contribute to advancing the classification of gastric cancer from traditional histopathological subtyping to functional immunological subtyping, providing a valuable scientific foundation for precise patient stratification and the development of individualized immunotherapy strategies in clinical practice.