100 Section - Regulatory effects and mechanisms of different intensities of aerobic exercise on the chemotherapy efficacy in mouse models of breast cancer

Objectives : Chemotherapy is often limited by tumor metabolic dysregulation and immune evasion, with lactate playing a central regulatory role in breast cancer. Aerobic exercise is widely used in cancer rehabilitation, but the mechanisms by which different exercise intensities influence chemotherapy sensitivity remain unclear. This study aimed to investigate how varying aerobic exercise intensities affect chemotherapy efficacy in breast cancer and to explore metabolic and immune mechanisms underlying exercise-induced chemosensitization.

Design: 4T1 and AT3 breast cancer models were established in immunocompetent BALB/c and C57BL/6 mice. Mice were assigned to control, chemotherapy, light-, moderate-, or high-intensity exercise, and three exercise-chemotherapy combination groups. Tumor growth and body weight were monitored. At endpoint, tumor and serum were collected. Angiogenesis was assessed by CD31 immunofluorescence/immunohistochemistry; intratumoral carboplatin and docetaxel levels were measured by LC–MS. RNA-seq and targeted metabolomics analyzed transcriptional and metabolic changes. Flow cytometry quantified key immune cell subsets in tumors and spleens.

Results: Moderate-intensity exercise produced the strongest enhancement of chemotherapy, significantly suppressing tumor growth without affecting body weight. Exercise promoted vascular normalization by increasing functional CD31⁺ vessels and lumen openness but did not alter intratumoral drug concentrations. Transcriptomics showed marked upregulation of T cell activation, antigen presentation, chemokine signaling, and adaptive immune pathways. Flow cytometry demonstrated that exercise reversed chemotherapy-induced immunosuppression, increasing NK cells, CD4⁺/CD8⁺ T cells, and effector memory T cells. Metabolomics revealed reduced glycolysis-related metabolites—especially intratumoral lactate. Exogenous lactate supplementation abolished exercise-induced chemosensitization and reduced immune cell infiltration and IFN-γ expression, confirming lactate as a key mediator linking exercise, metabolism, and immunity.

Conclusion: Moderate-intensity aerobic exercise enhances chemotherapy efficacy by lowering intratumoral lactate, improving the immune microenvironment, and promoting T cell and NK cell infiltration. These findings support exercise as an effective metabolic-immune modulator in breast cancer treatment.