Nathaniel Zhang

Background:  Cutaneous melanoma is the most aggressive form of skin cancer, characterized by its swift progression and high risk of metastasis, and its incidence has risen much faster than other cancers, with around 30 new cases per 100,000 people in the US¹. Primary treatment usually involves surgical resection, but medication is administered if surgery is nonviable³. Recently, newer methods of treatment such as immune checkpoint inhibitor (ICI) therapy have been favored in nonsurgical treatment^2,3. ICI therapy targets immune checkpoints, which are cell surface proteins expressed to regulate immune activity, particularly in lymphocytes³. Common target proteins such as PD-1, LAG3, and CTLA4 are bound by monoclonal antibodies to prevent downregulation of antitumor response⁴. Although ICI therapy has helped improve the five-year survival rate of melanoma patients from under 5% to over 50%, a high proportion of patients on both anti-PD-1 and anti-CTLA4 medications show medication resistance in their tumor cells, and the treatment can cause immune-related adverse events (irAEs) that affect multiple organs and are potentially fatal^2,4. This narrative review describes the potential for exercise to improve the efficacy of ICI therapy. Physical activity has been shown to reduce cancer risk, and recent research points toward exercise-induced metabolic and immunological changes that may directly influence tumor progression^5,6.

Objective: In this narrative review, we explored the mechanisms through which exercise affects the body’s immune response to cutaneous melanoma in conjunction with ICI treatments.

Search Method: An online search in the PubMed database was conducted for sources from 2019-2026 with the following keywords: “checkpoint inhibitors”, ” melanoma”, “exercise”, and “physical activity”.

Results: Studies indicate that exercise increases the number of circulating lymphocytes with preference for natural killer (NK) cells and cytotoxic (CD8+) T-lymphocytes⁷. Lymphocytes isolated after exercise improved survival rates and decreased tumor progression after transfusion⁷. Transcriptomic analyses of CD8+ showed specific enrichment of gene sets encoding for cytotoxic granule compounds such as granzyme B, perforin, and NKG7⁷. Exercise also modulates tumor microenvironment to reduce hypoxia through improved blood flow and vasculature, increasing the lymphocyte infiltration into the tumor tissue⁸. Lactate released from skeletal muscle activity can serve as an energy source for lymphocytes, increasing their activity with a dependency on the CD8+ cell population⁹. CD8+ activity also increased as a result of formate production by the gut microbiota in response to exercise, which exhibited compounded effects of reduced tumor growth when administered with anti-PD-1 therapy⁵. A clinical study tracking physical activity in patients on ICI therapy, 61% of whom were diagnosed with melanoma, found that higher quantity and intensity of physical activity improved patient survival rates and reduced incidence of irAEs⁴.

Conclusions: Studies found that exercise improves immune response against melanoma tumors through increasing lymphocyte number, boosting cytotoxicity via cellular metabolism and gene expression, and modulating tumor microenvironment to improve immune cell infiltration. These changes enhance CD8+ cells as the end effectors of ICI treatment, and this research has potential impact for indicating a low-cost, active intervention to improve melanoma treatment. Some future foci for research to expand on the utility of these findings would be to test specific exercise regimens, interaction of exercise with other lifestyle factors, and administration of isolated exercise metabolites for patients that may not be able to engage in regular exercise.

Works Cited:

1. Long GV, Swetter SM, Menzies AM, Gershenwald JE, Scolyer RA. Cutaneous melanoma. The Lancet. 2023;402(10400):485-502. doi:10.1016/S0140-6736(23)00821-8
2. Jalil A, Donate MM, Mattei J. Exploring resistance to immune checkpoint inhibitors and targeted therapies in melanoma. Cancer Drug Resist. 2024;7:42. doi:10.20517/cdr.2024.54
3. Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. The Lancet. 2021;398(10304):1002-1014. doi:10.1016/S0140-6736(21)01206-X
4. Verheijden RJ, Cabané Ballester A, Smit KC, et al. Physical activity and checkpoint inhibition: association with toxicity and survival. JNCI: Journal of the National Cancer Institute. 2024;116(4):573-579. doi:10.1093/jnci/djad245
5. Phelps CM, Willis NB, Duan T, et al. Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy. Cell. 2025;188(20):5680-5700.e28. doi:10.1016/j.cell.2025.06.018
6. Rundqvist H, Veliça P, Barbieri L, et al. Cytotoxic T-cells mediate exercise-induced reductions in tumor growth. eLife. 2020;9:e59996. doi:10.7554/eLife.59996
7. Batatinha H, Diak DM, Niemiro GM, et al. Human lymphocytes mobilized with exercise have an anti-tumor transcriptomic profile and exert enhanced graft-versus-leukemia effects in xenogeneic mice. Front Immunol. 2023;14:1067369. doi:10.3389/fimmu.2023.1067369
8. Yan H, Jiang A, Huang Y, et al. Exercise sensitizes PD-1/PD-L1 immunotherapy as a hypoxia modulator in the tumor microenvironment of melanoma. Front Immunol. 2023;14:1265914. doi:10.3389/fimmu.2023.1265914
9. Rundqvist H, Veliça P, Barbieri L, et al. Cytotoxic T-cells mediate exercise-induced reductions in tumor growth. eLife. 2020;9:e59996. doi:10.7554/eLife.59996