Clinical implications of combining physical activity and immune checkpoint inhibitor therapy

Introduction

With growing momentum, there is an increasing focus on the positive effects of exercise on cancer. This is important, because, in the early 1980’s, patients with cancer were recommended to rest, but early studies in specifically breast cancer and later prostate cancer started changing this. Today, guidelines from organizations such as the American Cancer Society and American College of Sports Medicine advocate for all patients with cancer to be physically active during and after treatment. Importantly, the clinical effects of exercise have also shifted from improving patient-reported outcomes and therapy side effects, to demonstrating biological activity.

The field of exercise oncology can be divided into prevention, treatment, and follow-up. A large meta-analysis concluded that physical activity is associated with reduced risk of 13 different cancers (1-5). Early studies in patients with breast, colon and prostate cancer associated exercise training with better overall survival (OS) and decreased risk of recurrence (6-8). This has been deep-rooted by the global Challenge study, published last year in NEJM, including 889 patients with colon cancer, showing significant progression-free survival (PFS) (and tendencies of OS) benefits for patients following a structured exercise intervention for 3 years (9). These data support the notion that physical activity and structured exercise are key components in cancer prevention and reduce the risk of recurrence for colon cancer.

During the phase of active cancer treatment, it has been demonstrated that exercise has positive effects on quality of life (QoL), fitness, energy, anxiety and depression for patients (5,10,11). However, whether exercise can translate directly to a therapeutic effect is more complex and to understand the underlying mechanism, most studies are performed in preclinical models. Previous studies, including our own, have shown that exercise markedly suppresses tumor growth in mice (12). Thus, in mice exercise leads to increased infiltration of tumors by cytotoxic immune cells, including natural killer (NK) cells and T cells (13). Mechanistically, it has been shown that these cells were responsible for the antitumor effect of exercise training. Exercise thus lead to adrenaline-dependent mobilization of immune cells, and a subsequent greatly increased influx of immune cells to the tumor. These immune cells are then able to kill cancer cells and thus prevent or at least delay cancer cell growth (14).

The majority of clinical exercise oncology studies have been conducted in combination with chemotherapy, with comparatively fewer investigations focusing on newer treatment modalities such as immunotherapy. This imbalance highlights an important gap in the literature and underscores the need for further research exploring whether exercise in combination with immunotherapy may exert direct biological effects on tumor control.

Exercise oncology in the era of immunotherapy

The study by Parker et al. [2025] (15) raises an important focus on the potential of physical activity in the era of immunotherapy treatment. The most striking contribution of this study is its suggestion of a survival advantage for physically active individuals undergoing immune checkpoint inhibitor (ICI) therapy. Prior literature has emphasized the positive associations between physical activity and cancer outcomes in general, but empirical evidence is almost entirely restricted to patients undergoing chemotherapy treatment. Evidence specifically in ICI-treated populations is limited to absent. Biological plausibility is grounded in the ability of exercise to modulate immune function: The fact that the immune system is strongly modulated by acute exercise was initially discovered in 1992 (16). In short, exercise strongly mobilizes immune cells to the peripheral blood and modulates the serum proteome, and as previously mentioned, immune cell infiltration into tumors might be increased by exercise, which is shown in murine cancer models. In smaller clinical studies, exercise training enhances T cell activation, reduces immunosuppressive myeloid infiltration, and favorably alters the tumor microenvironment, potentially improving responsiveness to immunotherapy (17). While mechanistic studies support this immunomodulatory framework, the current analysis importantly extends these concepts into a real-world clinical setting.

Parker et al. [2025] (15) provides evidence linking physical activity prior to treatment with improved survival in cancer patients receiving ICI therapy. Using a retrospective cohort of 930 patients treated with immunotherapy, the authors found that higher levels of self-reported pre-treatment physical activity [measured in weekly metabolic equivalent of task (MET) minutes] were associated with significantly lower hazards of all-cause mortality, including in landmark analyses extending survival beyond 1 year. Patients in the upper quartiles of activity had up to approximately 28% reduced mortality risk compared to the least active group, after multivariable adjustment for key confounders including age, performance status, body mass index (BMI), smoking, comorbidities, tumor stage, and ICI treatment line.

Interpreting the observational associations between physical activity and ICI responses

While the findings by Parker et al. are an important foundation for the field of exercise oncology in patients receiving ICI treatment, several methodological considerations warrant careful interpretation. First, the reliance on retrospective self-reported physical activity introduces potential recall and misclassification bias, as acknowledged by the authors. The MET values reported in the upper quartile may appear very high for patients with a cancer diagnosis and thus raise the possibility that activity levels were overestimated. This limitation has been previously observed with physical activity questionnaire-based assessments, even for validated tools such as the International Physical Activity Questionnaire (IPAQ). Objective quantification of physical activity using wearable sensors, cardiopulmonary fitness measures such as cardiopulmonary exercise testing to assess VO₂max (which itself is an independent predictor of mortality in patients with cancer), or simple functional assessments such as grip strength may provide more reliable exposure measurements in future studies. To this end, VO₂max has been shown as a reliable exercise test for patients’ receiving ICI treatment (18).

Second, residual confounding remains an important concern. Individuals who are physically active prior to or around the time of diagnosis may differ systematically from those who are not, in ways that are difficult to fully capture in observational data. Factors such as functional status, symptom burden, and access to supportive care services may influence both physical activity levels and outcomes. Although Parker et al. adjusted for performance status and comorbidities, these variables incompletely capture physiological reserve. Patients with more aggressive disease and more severe clinical symptoms might have reduced activity levels before the therapy and thus partially explain this observed survival difference. These considerations highlight the need to interpret the findings in the context of the still limited data available in patients’ receiving immunotherapy and underscore the importance of prospective studies in this population.

Third, tumor-specific characteristics which can to a certain degree predict immunotherapy response were not reported in detail. Tumor PD-L1 expression, tumor mutational burden, immune cells infiltration and immune-related adverse events could interact with physical activity-associated immune modulation, and thus be associated with response to ICI treatment. Future studies will benefit from integrating these variables to independently assess the effect size of exercise.

The analysis by Parker et al. highlights an intriguing association between pre-treatment physical activity and outcomes in patients receiving ICI, but also underscores the methodological challenges of interpreting exercise behavior in observational cancer cohorts. An important contribution of studies like this (15) is the potential to form study design of future prospective randomized controlled studies (17). To this end, several priorities can be formulated for future research derived from the discussed limitations. These include objective quantification of physical activity, for example through wearable activity monitoring or cardiopulmonary fitness assessments, while simultaneously controlling for other lifestyle factors that may influence treatment outcomes, including nutritional status, body composition and cardiovascular profile (18). Beyond host-related factors, future study designs should account for differences between tumor types but also for molecular determinants of immunotherapy response.

From epidemiologic associations to immunologic mechanisms

Future studies will need to move beyond epidemiologic associations and directly interrogate whether exercise can modulate antitumor immunity in patients receiving ICIs. Now is the time to push for mechanism awareness in exercise oncology. Although increased exercise-induced immune cell infiltration into tumors has been described in preclinical models (14), there is currently no direct clinical evidence demonstrating that exercise improves ICI efficacy through defined immunologic mechanisms such as increased trafficking of cytotoxic lymphocytes, modulation of the tumor microenvironment, or alterations in systemic inflammatory signaling. Addressing this gap will require prospective trials integrating structured exercise interventions with longitudinal immune monitoring, including assessment of circulating immune cell dynamics, tumor immune infiltration, and biomarkers of treatment response. Importantly, such studies should account for both host parameters and tumor immunobiology, recognizing that exercise responses and immunotherapy sensitivity are likely heterogeneous across patients and tumor types. As the field advances, closer collaboration between multiple professional areas, such as epidemiology, oncologists/hematologists, sports scientists and physiotherapists, but also basic researchers, will be essential. Such interdisciplinary efforts can help move structured exercise training from a broadly recommended behavior to a targeted, evidence-based component of cancer care.

In conclusion, this population-based study strengthens the epidemiologic evidence linking physical activity to improved cancer outcomes for patients receiving ICI treatment. The task ahead is to translate these insights into effective structured exercise strategies that improve outcomes for patients with cancer and to identify the underlying biological mechanisms.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Cancer Epidemiology. The article has undergone external peer review.

Peer Review File: Available at https://ace.amegroups.com/article/view/10.21037/ace-2026-1-0012/prf

Funding: This work was supported by Danmarks Frie Forskningsfond (FSS) (grant No. 2096-00089B) and the Danish Cancer Society (grant No. KC25-01435).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ace.amegroups.com/article/view/10.21037/ace-2026-1-0012/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Guthold R, Stevens GA, Riley LM, et al. Worldwide trends in insufficient physical activity from 2001 to 2016: a pooled analysis of 358 population-based surveys with 1·9 million participants. Lancet Glob Heal 2018;6:e1077-86. [Crossref] [PubMed]
2. Wolin KY, Yan Y, Colditz GA, et al. Physical activity and colon cancer prevention: a meta-analysis. Br J Cancer 2009;100:611-6. [Crossref] [PubMed]
3. Howard RA, Leitzmann MF, Linet MS, et al. Physical activity and breast cancer risk among pre- and postmenopausal women in the U.S. Radiologic Technologists cohort. Cancer Causes Control 2009;20:323-33. [Crossref] [PubMed]
4. Steindorf K, Ritte R, Eomois PP, et al. Physical activity and risk of breast cancer overall and by hormone receptor status: the European prospective investigation into cancer and nutrition. Int J Cancer 2013;132:1667-78. [Crossref] [PubMed]
5. Moore SC, Lee IM, Weiderpass E, et al. Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults. JAMA Intern Med 2016;176:816-25. [Crossref] [PubMed]
6. Holmes MD, Chen WY, Feskanich D, et al. Physical activity and survival after breast cancer diagnosis. JAMA 2005;293:2479-86. [Crossref] [PubMed]
7. Irwin ML, Smith AW, McTiernan A, et al. Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study. J Clin Oncol 2008;26:3958-64. [Crossref] [PubMed]
8. Kenfield SA, Stampfer MJ, Giovannucci E, et al. Physical activity and survival after prostate cancer diagnosis in the health professionals follow-up study. J Clin Oncol 2011;29:726-32. [Crossref] [PubMed]
9. Courneya KS, Vardy JL, O’Callaghan CJ, et al. Structured Exercise after Adjuvant Chemotherapy for Colon Cancer. N Engl J Med 2025;393:13-25. [Crossref] [PubMed]
10. Gerritsen JKW, Vincent AJPE. Exercise improves quality of life in patients with cancer: a systematic review and meta-analysis of randomised controlled trials. Br J Sports Med 2016;50:796-803. [Crossref] [PubMed]
11. Buffart LM, Kalter J, Sweegers MG, et al. Effects and moderators of exercise on quality of life and physical function in patients with cancer: An individual patient data meta-analysis of 34 RCTs. Cancer Treat Rev 2016;52:91-104. [Crossref] [PubMed]
12. Fiuza-Luces C, Valenzuela PL, Gálvez BG, et al. The effect of physical exercise on anticancer immunity. Nat Rev Immunol 2024;24:282-93. [Crossref] [PubMed]
13. Rundqvist H, Veliça P, Barbieri L, et al. Cytotoxic T-cells mediate exercise-induced reductions in tumor growth. Elife 2020;9:e59996. [Crossref] [PubMed]
14. Pedersen L, Idorn M, Olofsson GH, et al. Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution. Cell Metab 2016;23:554-62. [Crossref] [PubMed]
15. Parker NH, Ramos JD, Tarhini AA, et al. A Retrospective Cohort Study of Physical Activity and Survival in Patients Treated with Immune Checkpoint Inhibitors. Cancer Epidemiol Biomarkers Prev 2025;34:2219-27. [Crossref] [PubMed]
16. Gabriel H, Schwarz L, Born P, et al. Differential mobilization of leucocyte and lymphocyte subpopulations into the circulation during endurance exercise. Eur J Appl Physiol Occup Physiol 1992;65:529-34. [Crossref] [PubMed]
17. Leuchte K, Trommer M, Holmen Olofsson G, et al. The cancer-immunity cycle in motion: The effects of exercise on antitumor immunity. Immunol Lett 2025;277:107101. [Crossref] [PubMed]
18. Zubac D, Niels T, Baumann FT. Reliability and applicability of the VO2 and heart rate kinetics during moderate-intensity cycling in immunotherapy patients and healthy controls. Eur J Appl Physiol 2025;125:3233-45. [Crossref] [PubMed]