Exercise-induced Metabolic Stress Drives Apoptotic Adaptation In Melanoma Tumors

PURPOSE: Tumor reliance on glycolysis contributes to an acidic microenvironment which promotes an aggressive phenotype and therapy resistance. Aerobic exercise is a promising adjuvant strategy to enhance anti-cancer treatments, however, its direct effects on tumor metabolism remain unclear. We aimed to investigate exercise’s impact on tumor glucose metabolism and associated anti-tumor mechanisms. METHODS: C57BL/6 mice injected with YUMMER 1.7 melanoma cells were divided into control (No Ex, n = 5) and exercise (Ex, n = 5) groups once tumors reached ~100 mm3. Ex mice underwent treadmill running (12 m/min for 45 min/day) for 11 days. Tumor glucose uptake and pyruvate-to-lactate conversion were examined by real-time functional imaging modalities, 18F-FDG PET/CT and HP 13C MRI. After euthanasia, tumor metabolites were quantified by NMR spectroscopy, while glucose and lactate transporters were measured by Western blot. Mass spectrometry imaging (MSI) and multiplex immunofluorescence were used to assess metabolic and cellular changes in a tumor microarray. RESULTS: Exercise reduced tumor glucose uptake (1.4 vs. 1.0, p = .07) and significantly lowered GLUT1 expression and pyruvate-to-lactate conversion (p = .01), indicating reduced glycolysis. NMR confirmed lactate as the predominant tumor metabolite, yet total lactate levels remained unchanged despite suppressed glycolysis. Notably, Ex tumors exhibited higher MCT1 expression (p = .03), suggesting increased lactate uptake. MSI revealed significantly lower TCA cycle byproduct oxalic acid and ATP (-Log p = 1.97 and 1.40; Log2 FC: -0.28 and -0.58), while metabolic pathway enrichment analysis identified glutamate metabolism as the most increased pathway (-Log p = 4.25). Immunophenotyping demonstrated increased apoptosis and reduced proliferation in Ex tumors (p < .01). CONCLUSIONS: Aerobic exercise suppresses tumor glycolysis, inducing metabolic reprogramming for energy compensation and increasing apoptosis. Future studies will incorporate spatial metabolomics and proteomics to identify the tumor subpopulations most susceptible to metabolic stress and apoptosis. Given that metabolic stress may sensitize tumors, testing exercise in combination with metabolic targeted therapy could provide novel combination therapy for melanoma.