Metabolic reprogramming and plasticity in breast Cancer: Mechanisms driving tumor progression, metastasis, and therapeutic resistance.

Abstract

Breast cancer remains the most frequently diagnosed malignancy and a leading cause of cancer-related mortality among women worldwide. Despite substantial advances in endocrine therapy, human epidermal growth factor receptor 2 (HER2)-targeted therapy, chemotherapy, and immunotherapy, therapeutic resistance and metastatic progression remain major clinical challenges. Accumulating evidence has established metabolic reprogramming as a fundamental hallmark of breast cancer, enabling tumor cells to adapt dynamically to nutrient limitation, hypoxia, oxidative stress, and therapeutic pressure. Beyond the classical Warburg effect, breast cancer cells exhibit remarkable metabolic plasticity through coordinated reprogramming of glycolysis, oxidative phosphorylation (OXPHOS), glutamine metabolism, lipid metabolism, and one‑carbon metabolism. These metabolic alterations not only sustain bioenergetic and biosynthetic demands but also reshape the tumor microenvironment (TME), promote immune evasion, maintain cancer stemness, and facilitate metastatic dissemination. Recent studies further reveal that metabolic heterogeneity varies substantially across molecular subtypes, metastatic niches, and treatment-resistant cell populations. In parallel, stromal cells, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and immune cells establish complex metabolic symbiotic relationships with tumor cells through metabolite exchange and immunometabolic regulation. Importantly, therapy-induced metabolic adaptation has emerged as a central mechanism underlying resistance to chemotherapy, endocrine therapy, HER2-targeted therapy, CDK4/6 inhibitors, and immune checkpoint blockade. In this review, we comprehensively summarize the molecular mechanisms governing metabolic reprogramming and metabolic plasticity in breast cancer, with particular emphasis on how they contribute to tumor progression, metastasis, immune escape, and therapeutic resistance. We further discuss emerging therapeutic strategies targeting glycolysis, mitochondrial metabolism, glutamine utilization, lipid metabolism, ferroptosis-associated pathways, and immunometabolic vulnerabilities. Finally, we highlight current challenges in clinical translation, including metabolic heterogeneity, compensatory pathway activation, and limited therapeutic selectivity, and outline future directions that integrate multi-omics profiling, spatial metabolomics, and precision metabolic targeting for individualized breast cancer therapy.