Abstract / Summary
Cancer cells exhibit metabolic reprogramming, including increased aerobic glycolysis, glutaminolysis, and altered lipid metabolism, which supports tumor growth and contributes to immune evasion. A growing but heterogeneous body of literature has investigated whether targeting these metabolic dependencies alongside standard oncologic treatment may provide therapeutic benefit. This review critically examines clinically investigated metabolically directed approaches, including metronomic chemotherapy, hyperthermia, high-dose intravenous vitamin C, hyperbaric oxygen therapy, fasting-related nutritional strategies, ketogenic diets, and insulin-based approaches, while distinguishing them from established targeted therapies, monoclonal antibodies, and immune checkpoint inhibitors. Emerging immunometabolic and microenvironmental targets are also discussed, including lactate transport, ferroptosis, autophagy and amino acid metabolism, cancer-associated fibroblasts, tumor-associated macrophages, abnormal vasculature, and immunosuppressive cytokine signaling. In addition, drug-delivery strategies are considered by distinguishing the established pharmaceutical role of dimethyl sulfoxide (DMSO) as a solvent or excipient from nanoparticle-, exosome-, and peptide-based targeting platforms. Available evidence is characterized according to clinical maturity, ranging from established phase III-supported therapies and randomized clinical evidence to early-phase, preclinical, or currently unproven approaches. Although several metabolically directed interventions have biological rationale and varying degrees of clinical support, no comprehensive multicomponent metabolic regimen has been validated in controlled clinical trials. Future development should prioritize stepwise, biomarker-informed prospective studies evaluating individual interventions and biologically justified combinations alongside standard-of-care therapy. Metabolically directed strategies should therefore be interpreted according to the evidence supporting each component rather than as a single established therapeutic regimen.