Metformin as an immunometabolic modulator in breast cancer: integrating NK and NKT cell responses

Breast cancer progression is increasingly recognized as an immunometabolic disorder in which tumor-intrinsic metabolic reprogramming and microenvironmental stress converge to impair innate immune surveillance. Beyond its established role in glycemic control, metformin has emerged as a promising immunometabolic modulator with anticancer potential. Accumulating evidence indicates that metformin suppresses breast tumor growth by targeting key metabolic vulnerabilities, including dysregulated glycolysis, lipid metabolism, and mitochondrial energetics, while simultaneously restoring the functional competence of innate immune effectors, particularly natural killer (NK) and natural killer T (NKT) cells. At the molecular level, metformin engages AMP-activated protein kinase (AMPK)-centered signaling and mitochondrial complex I-associated energetic stress, leading to downstream modulation of mTOR activity, redox balance, autophagy, and RNA-mediated regulatory networks. These coordinated effects reduce tumor cell plasticity and enhance immune permissiveness. Within the tumor microenvironment, metformin attenuates hormone-dependent stromal support, disrupts immunosuppressive myeloid networks, normalizes chemokine and cytokine profiles, and promotes antigen presentation and innate immune cell recruitment. Preclinical studies consistently demonstrate delayed tumor onset, suppression of aggressive breast cancer subtypes, impairment of cancer stem cell maintenance, and reinforcement of NK/NKT-mediated antitumor surveillance following metformin treatment. However, emerging clinical and translational evidence suggests that therapeutic efficacy is context dependent, influenced by tumor molecular subtype, host metabolic status, immune composition, and pathway-specific biomarker engagement. This review critically synthesizes mechanistic, preclinical, and clinical findings to position metformin as a host-directed immunometabolic adjuvant in breast cancer. Integrating insights from metabolism, innate immunology, pharmacology, and biotechnology, this work highlights opportunities for biomarker-guided stratification and rational combination strategies aimed at enhancing NK/NKT-cell-driven antitumor immunity in breast cancer therapy.