Integrated Proteogenomic Characterization Identifies Breast Cancer Immune Subgroups and Subtype-Specific Therapeutic Strategies

Breast cancer remains the most common malignancy in women worldwide, and its marked heterogeneity continues to impede effective treatment. Immunotherapy has reshaped the therapeutic landscape, yet only a subset of patients achieves durable benefit, in large part because of immune and metabolic diversity within the tumor microenvironment. Posttranslational modifications are key regulators that couple cellular signaling to metabolic and immune homeostasis. Here, we generated a multiomics immune-metabolic atlas of breast cancer by integrating genomics, transcriptomics, proteomics, lactylomics, and phosphoproteomics from 115 tumor and 99 matched adjacent tissue samples. Using immune infiltration profiling, we defined 3 immune-related breast cancer subtypes with distinct metabolic states, posttranslational modifications cross-talk, and mutational landscapes. Integrated analyses revealed that the interplay between protein lactylation and phosphorylation orchestrates glycolytic reprogramming and immune modulation. Furthermore, we identified subtype-specific histone lactylation patterns and signaling rewiring associated with therapeutic response. This atlas provides a comprehensive framework for dissecting immune-metabolic regulation in breast cancer and yields molecular insights to guide subtype-specific precision immunotherapeutic strategies.