The central concept guiding this research is the tumor microenvironment, or TME, the scaffold of extracellular matrix within which tumor cells and host immune cells communicate and compete. Many cancers are described as immunologically cold, meaning they contain few functional cytotoxic immune cells and resist the effects of immune checkpoint inhibitors, the landmark therapies that block inhibitory receptors such as PD-1 and PD-L1 to unleash CD8-positive T cells. Checkpoint inhibitors have transformed survival for many patients since emerging in the 1990s, but their efficacy is throttled by features of the TME, including low T cell numbers, T cell exhaustion, oxygen-starved tissue, and dense populations of immunosuppressive cells. The review’s authors, led by Campbell M. Johnston and Hongji Zhang of the University of Virginia’s Department of Surgery, argue that exercise directly counters many of these barriers, effectively warming cold tumors and sensitizing them to drugs that were previously powerless against them.

One of the most detailed lines of evidence concerns tumor-associated macrophages, or TAMs, immune cells that are abundant within cold tumors and frequently promote malignancy. TAMs exist along a spectrum from the M1 phenotype, which fights tumors, to the M2 phenotype, which secretes immunosuppressive molecules such as interleukin-4, interleukin-10, PD-L1, and transforming growth factor-beta that blunt effector T cell function and empower regulatory T cells. Worse, TAMs can push CD8-positive T cells into a terminally exhausted state from which they cannot recover, and hypoxia accelerates this process. In mouse models of glioblastoma, depleting TAMs increased the proportion of stem-like progenitor-exhausted T cells and improved responsiveness to anti-PD-1 therapy, underscoring how central these cells are to treatment failure. Preclinical studies now show that aerobic exercise can tip the balance, repolarizing macrophages from the pro-tumor M2 state toward the anti-tumor M1 state and reducing total M2 numbers within tumors.

The macrophage data are remarkably consistent across exercise modalities. Breast cancer-bearing mice that ran on treadmills before and after tumor inoculation showed fewer M2 macrophages within their tumors, while medium-intensity treadmill running increased the M1-to-M2 ratio in similar models. In melanoma-inoculated mice, swimming prevented M2 polarization and reduced interleukin-6 production, inhibiting tumor glycolysis and lowering lactic acid accumulation. Exercise also increased the production of major histocompatibility complex class II molecules on macrophages, sharpening their ability to activate T cells. These findings matter clinically because pharmacological strategies targeting macrophage biology, including inhibitors of transforming growth factor-beta, have struggled in human trials, failing to show clear benefit or producing severe adverse events. Exercise, by contrast, achieves a similar biological reprogramming without toxicity, offering a route around a therapeutic bottleneck that has frustrated drug developers.

Myeloid-derived suppressor cells, or MDSCs, represent a second immunosuppressive population that exercise appears to tame. These cells promote immune evasion by impairing chemokine secretion, recruiting regulatory T cells, and increasing PD-1 expression on T cells. Multiple preclinical studies show that physical activity delays MDSC accumulation and reduces their numbers within tumors. Mice exercised before and after breast carcinoma inoculation had significantly lower intratumoral MDSC levels than sedentary controls, and treadmill running started after tumor inoculation reduced splenic MDSCs, slowed tumor progression, and increased immune cell infiltration in mammary carcinoma models, with an inverse relationship between MDSC abundance and CD8-positive T cell presence. Crucially, these findings extend to humans. In newly diagnosed breast cancer patients, a single session of acute exercise increased natural killer and CD8-positive T cell levels while reducing MDSCs. In esophageal cancer patients who exercised during neoadjuvant chemotherapy, CD8-positive T cell counts rose while inflammatory biomarkers associated with MDSCs and TAMs fell significantly.

Hypoxia and disordered blood vessel growth form a third pillar of the exercise-immunotherapy connection. Tumors grow so erratically that their vasculature becomes tangled and inefficient, starving tissue of oxygen and stabilizing hypoxia-inducible factors that drive further abnormal angiogenesis. The resulting hypoxic environment excludes natural killer and CD8-positive T cells, inhibits dendritic cells and antigen presentation, recruits immunosuppressive cells, and pushes macrophages toward the pro-tumor M2 phenotype through a CXCL8-interleukin-10 signaling axis, all of which correlate with poor prognosis and resistance to checkpoint blockade. Exercise directly counters this vicious cycle. Melanoma-bearing mice that swam at low or moderate intensity showed significantly reduced expression of hypoxia and glycolysis genes, along with greater CD8-positive T cell infiltration and cytotoxicity. Daily high-intensity exercise lowered intratumoral hypoxic fractions in breast carcinoma models, and in a landmark clinical observation, pancreatic cancer patients who exercised during preoperative therapy showed increased tumor vascularity, while exercised mice bearing patient-derived pancreatic tumors displayed vascular remodeling, accelerated regression, and delayed regrowth.

Natural killer cells, the innate immune system’s front-line tumor killers, emerge as perhaps the cells most responsive to exercise. NK cells mobilize more readily into tumors in exercised animals, and work by Cho and colleagues showed that NK cells from exercised individuals kill target cells more efficiently, with their cytotoxicity actually enhanced under hypoxic conditions, a striking advantage given the oxygen-poor nature of tumors. This resilience stems from exercise-induced metabolic reprogramming that reduces mitochondrial oxidative stress and, through interleukin-15 signaling, lessens sensitivity to reactive oxygen species such as hydrogen peroxide within the tumor microenvironment. Clinical translation is already visible: men with localized prostate cancer who adhered strictly to high-intensity interval training showed significantly increased NK cell infiltration into their tumors. Perhaps most dramatic, Pedersen and colleagues found that voluntary wheel running reduced tumor volume by 66 percent in mice lacking functional T cells, an effect abolished when NK cell production was blocked, proving that NK cells alone can mediate exercise-driven tumor suppression.

CD8-positive T cells, the primary targets of checkpoint inhibitors, are recruited into exercised tumors through well-defined molecular routes. The chemokine receptor CXCR3, which binds CXCL9, CXCL10, and CXCL11, guides these cells into tumor tissue, and CXCR3 knockout mice show reduced T cell infiltration and blunted responses to PD-1 blockade. Recent work demonstrated that four weeks of preoperative treadmill running increased CXCL9 release and CXCR3-positive T cell recruitment in colorectal liver metastases, an effect lost in CXCL9-deficient mice. Exercise also suppresses CCL5, a chemokine that recruits regulatory T cells, TAMs, and MDSCs and correlates with poor prognosis, while boosting interleukin-15, a cytokine essential for T cell survival that appears to actively shift CD8-positive cells from circulation into tumors rather than merely raising their blood counts.

The combination studies provide the most compelling case. Melanoma-bearing mice treated with exercise plus anti-PD-1 therapy developed smaller tumors with more apoptotic cells, more cytotoxic T cells, and fewer regulatory T cells than mice receiving the drug alone. Similar synergy appeared in triple-negative breast cancer, where treadmill running improved therapeutic response, boosted T cell and NK cell activation, and cut MDSC numbers alongside anti-PD-1 treatment. In transgenic breast cancer models, adding running to anti-PD-1 therapy delayed tumor growth and improved control, even when both interventions began only after tumors reached a clinically relevant size. Pancreatic ductal adenocarcinoma, notoriously resistant to checkpoint inhibitors, responded to low-intensity treadmill running combined with anti-PD-1 when neither approach worked alone, an especially promising result for patients too ill for vigorous activity. Clinically, hepatocellular carcinoma patients who exercised regularly had significantly better overall and progression-free survival on combined lenvatinib and anti-PD-1 therapy, with matching results in mouse models. Randomized trials such as HI AIM and ERICA are now testing supervised exercise before and during immunotherapy infusions in lung cancer patients.

The authors are careful to note that clinical evidence remains limited and that major questions persist regarding optimal exercise modality, intensity, frequency, timing, and patient selection across cancer types, ages, sexes, disease stages, and body mass indices. Yet the biological coherence of the evidence is difficult to dismiss: exercise relieves hypoxia, normalizes vasculature, repolarizes macrophages, suppresses MDSCs and regulatory T cells, mobilizes NK cells, and drives cytotoxic T cells into tumors through defined chemokine axes, collectively converting cold tumors into inflamed, drug-responsive ones. If ongoing adequately powered trials with longitudinal immune profiling confirm these mechanisms in patients, structured physical activity could become one of the first universally accessible adjuncts to cancer immunotherapy, a prescription written not on a pharmacy pad but into the daily routines of patients fighting some of medicine’s most treatment-resistant cancers.

Subject of Research: How physical exercise modulates the tumor microenvironment to enhance cancer immunotherapy efficacy

Article Title: Physical Exercise in Immunotherapy

Article References: Johnston, C. M., Kim, S. J., Zhang, Y., Tsung, C., Kent, E., May, A., & Zhang, H. (2026). Physical Exercise in Immunotherapy. Sports Medicine – Open, 12(1), Article 130. https://doi.org/10.1186/s40798-026-01101-1

Image Credits: AI Generated

DOI: 10.1186/s40798-026-01101-1

Keywords: physical exercise, cancer immunotherapy, immune checkpoint inhibitors, tumor microenvironment, tumor-associated macrophages, myeloid-derived suppressor cells, natural killer cells, CD8 T cells, PD-1, tumor hypoxia, interleukin-15, cold tumors