Immunotyping the Tumor Microenvironment Reveals Molecular Heterogeneity for Personalized Immunotherapy in Cancer

Abstract The tumor microenvironment (TME) significantly influences cancer prognosis and therapeutic outcomes, yet its composition remains highly heterogeneous, and currently, no highly accessible, high‐throughput method exists to define it. To address this complexity, the TMEclassifier, a machine‐learning tool that classifies cancers into three distinct subtypes: immune Exclusive (IE), immune Suppressive (IS), and immune Activated (IA), is developed. Bulk RNA sequencing categorizes patient samples by TME subtype, and in vivo mouse model validates TME subtype differences and differential responses to immunotherapy. The IE subtype is marked by high stromal cell abundance, associated with aggressive cancer phenotypes. The IS subtype features myeloid‐derived suppressor cell infiltration, intensifying immunosuppression. In contrast, the IA subtype, often linked to EBV/MSI, exhibits robust T‐cell presence and improved immunotherapy response. Single‐cell RNA sequencing is applied to explore TME cellular heterogeneity, and in vivo experiments demonstrate that targeting IL‐1 counteracts immunosuppression of IS subtype and markedly improves its responsiveness to immunotherapy. TMEclassifier predictions are validated in this prospective gastric cancer cohort (TIMES‐001) and other diverse cohorts. This classifier could effectively stratify patients, guiding personalized immunotherapeutic strategies to enhance precision and overcome resistance.