Future perspective of clinical usefulness of metabolic and mitochondrial heterogeneity in triple-negative breast cancers.

Triple-negative breast cancer (TNBC) is best characterized by high aggressiveness and significant biological heterogeneity. Although the current TNBC clinical trials include genomic biomarkers to stratify treatment arms, they are still limited by metabolic heterogeneity within TNBC subtypes. The metabolic reprogramming, a cancer hallmark, in TNBC involves adaptive regulation of glycolysis, lipid metabolism, and oxidative phosphorylation (OXPHOS), with distinct metabolic phenotypes significantly influencing tumor sensitivity to treatment. Mitochondrial heterogeneity exacerbates the metabolic diversity of TNBC, with its dynamic functional regulation closely linked to cellular energy metabolism and signaling pathway adaptation. Interplay between OXPHOS, metabolites, and immune activity creates a self-reinforcing mechanism where metabolic adaptations in TNBC cells not only support their energy demands but also actively construct an immune-privileged niche that shields tumors from immune surveillance and limits the efficacy of treatments. These mechanisms and mitochondrial diversity could be heterogeneous and specific to TNBC subtypes. Thus, metabolic phenotyping of TNBC subtypes could reveal previously unidentified patient subgroups, potentially explaining divergent survival outcomes and offering metabolism-targeted therapeutic strategies that might improve outcomes for patients who currently lack effective treatment alternatives.