Targeting Metabolic Pathways Improves TNBC Therapy

Abstract

Breast cancer (BC) accounts for a significant proportion of female tumor cases globally. Triple-negative breast cancer (TNBC) is its most difficult variant, which is defined by the absence of the estrogen receptor, progesterone receptor, and HER2 expression. Aerobic glycolysis (Warburg effect) plays a pivotal role in TNBC, influencing both tumor microenvironment and immune responses. TNBC cells undergo metabolic reprogramming, favoring glycolysis over oxidative phosphorylation for energy production, leading to lactate accumulation and extracellular acidification in the tumor milieu, which exacerbates tumor proliferation, metastasis, and immunosuppression. This review delves into key glycolytic enzymes and regulators, including hexokinase, phosphofructokinase, pyruvate kinase M2, lactate dehydrogenase, and monocarboxylate transporters, as potential therapeutic targets. Highlighting promising preclinical evidence and clinical studies utilizing glycolytic pathway modulators, the review underscores their potential to reduce TNBC cell viability, curb growth, inhibit metastasis, and enhance chemosensitivity. Chemotherapy is still the most commonly used systemic treatment for TNBC, although immunotherapy, especially employing PD-1 and PD-L1 inhibitors, has advanced despite obstacles in the metastatic setting due to TNBC heterogeneity and changed immunogenicity. This review underscores the urgent need for tailored, effective therapies for TNBC patients, especially those with metastatic disease, shedding light on strategies to harness glycolysis for improving treatment outcomes.