An Immune‐Metabolic Signature Reveals Prognostic Stratification and Tumor Microenvironment Features in Breast Cancer

ABSTRACT

Breast cancer progression reflects coupled immune and metabolic reprogramming, but biomarkers that capture this interplay and provide additional prognostic information beyond routine clinicopathological assessment remain limited. We developed an 11‐gene immune–metabolic risk Score in TCGA‐BRCA ( n  = 1099) by integrating C7 immune signatures and KEGG metabolic pathways through Cox and LASSO‐Cox modeling. The fixed model was applied without retraining to three public cohorts and an independent institutional cohort of 146 patients from Harbin Medical University Cancer Hospital. The score consistently stratified overall survival across independent cohorts and provided additional prognostic information beyond conventional clinicopathological variables. Integrative analyses showed that high‐risk tumors were characterized by enhanced cell‐cycle and metabolic activation, reduced lymphocyte‐associated immune features, and monocytic‐lineage enrichment. At single‐cell resolution, high‐score cancer‐associated fibroblasts exhibited enhanced extracellular‐matrix remodeling, inflammatory iCAF activity, and TGF‐β‐associated immunosuppressive programs. In an exploratory pembrolizumab‐containing cohort, lower pretreatment scores were associated with pathological complete response and immune‐active transcriptional programs; however, these findings do not establish the score as a predictive biomarker for immunotherapy benefit. The 11‐gene immune–metabolic risk Score provides complementary prognostic stratification beyond conventional clinical variables and characterizes a stromal‐remodeled immune–metabolic state associated with adverse breast cancer outcomes.