Intratumoral Bacillus Calmette-Guérin as a dual immunometabolic therapy for triple-negative breast cancer: A comprehensive narrative review of mechanistic insights and translational potential

Abstract

Triple-negative breast cancer (TNBC) is an aggressive and metabolically distinct subtype of breast cancer characterized by immune evasion, a high reliance on glycolysis, and poor treatment outcomes. Given the limitations of conventional therapies, there is an urgent need for novel, targeted approaches that integrate immune stimulation with metabolic disruption. This review explores the potential of intratumoral Bacillus Calmette-Guérin (BCG) therapy as a dual-action strategy in TNBC, focusing on its ability to convert immunologically “cold” tumors into “hot” tumors when simultaneously targeting TNBC’s metabolic vulnerabilities. A comprehensive narrative review was conducted using PubMed, Scopus, and Web of Science, identifying 60 peer-reviewed studies published between 2000 and 2024. The selection criteria focused on BCG’s role in oncology, its immunological and metabolic effects, and its application in solid tumors. Studies were assessed for methodological rigor using the Scale for the Assessment of Narrative Review Articles checklist. BCG enhances antitumor immunity by engaging Toll-like receptors, triggering proinflammatory cytokine release (e.g., tumor necrosis factor alpha, interferon gamma, and interleukin-12), and promoting the infiltration of tumor-infiltrating lymphocytes, including cytotoxic T-cells and natural killer cells. This immune activation reprograms the tumor microenvironment, increasing susceptibility to immunotherapy. Simultaneously, BCG disrupts TNBC’s glycolytic dependence by downregulating hexokinase 2 and pyruvate kinase M2, forcing a metabolic shift toward oxidative phosphorylation. This metabolic stress induces mitochondrial dysfunction, reactive oxygen species accumulation, and tumor cell apoptosis. In addition, BCG-induced “trained immunity” epigenetically reprograms innate immune cells, enhancing long-term tumor surveillance and reducing recurrence risk. Intratumoral BCG presents a promising immunometabolic intervention for TNBC by simultaneously enhancing immune activation and disrupting tumor metabolism. Future studies should focus on optimizing its clinical application, developing sustained-release formulations, and exploring synergistic combinations with immune checkpoint inhibitors and metabolic inhibitors. By addressing TNBC’s dual vulnerabilities, this strategy may redefine treatment paradigms and improve patient outcomes.

Keywords

Triple-negative breast cancer / Bacillus Calmette-Guérin / Intratumoral injection / Warburg effect / Glycolysis inhibition / Immunotherapy / Trained immunity

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