Can Structured Exercise Reprogram the Tumor Microenvironment in Oncology?

In an exploration of the impact of exercise on oncologic outcomes, Nathan Goodyear, MD, MDH, emphasized examining both the “what” and the “how” to encourage widespread clinical adoption in an interview with CancerNetwork®. He highlighted 2 sentinel trials demonstrating that structured exercise can supplement conventional treatments.

The phase 3 CHALLENGE trial (NCT00819208) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meetingrevealed that a structured, 3-year exercise program at 2 days a week significantly reduced recurrence, the development of new cancers, and mortality risks in stage II/III colorectal cancer compared with general lifestyle advice.¹

Furthermore, Goodyear identified the NHS-led OPTIMUS trial (NCT02950324), which demonstrated that exercise may actively reprogram the tumor microenvironment (TME).² By inducing CD8-positive T-cell infiltration and reducing immunosuppressive cells, exercise could help turn “cold” tumors “hot.”

Additionally, he argued against a reductionist approach to oncology, advocating instead for a “stacking therapy” model. By integrating structured exercise alongside chemotherapy, immunotherapy, and surgery, clinicians can synergistically optimize patient outcomes and redefine standard cancer care.

Goodyear is an integrative medicine physician at the Williams Cancer Institute.

Transcript:

It’s not just one thing to show the “what,” but the “how.” Now, it becomes something strong and solid, and that’s also the way that we grow the number of practitioners who will incorporate exercise into their strategy.

Let me say this first: when you look at exercise, if a patient was diagnosed with cancer, they go to their doctor, and their doctor just said, “Hey, kill more cancer cells,” they go, “Okay, great, how?” “Just go do it.” It’s not going to be successful. So, if a patient goes to a doctor and the doctor says, “Hey, just exercise more; be more active,” and the patient goes, “How?” “Just go do it.” It’s not going to be successful.

There are a couple of sentinel articles that show the “what.” One was presented at the [2025 American Society of Clinical Oncology (ASCO) Annual Meeting]called the CHALLENGE study. They looked at stage III and stage II colorectal cancer, but the profound impact there was the reduction in recurrence, in new cancers, and the lower risk of death. Is that not what cancer is about—increasing survival and reducing recurrence and metastasis? [Investigators] compared one arm with a 3-year structured exercise program for 2 days a week––we’re not talking about an Ironman [Triathlon]––and in the second arm, they said, “Here’s some healthy information; just live a healthy lifestyle via exercise.” That had a profound impact.

In fact, when you look at those statistics, they’re comparable to some of the celebrated conventional cancer treatments. Now, that doesn’t mean we replace them; it means that when cancer is present, [we are not] following this reductionist approach going from A to B to C to D. We must start bringing this kind of stacking therapy approach together. If we can add something like exercise with chemotherapy [plus] immunotherapy preceding surgery, the results will be better.

In another [study], called the OPTIMUS study from the NHS in the UK…they found CD8-positive T-cell infiltration and a reduction in immunosuppressing cells. Now, you have to step back and say, “Oh my goodness.” This study, without saying it, showed that exercise is reprogramming the [TME]. Now, they didn’t say this, and it needs [further validation], but you could frame it as exercise turning cold tumors hot.

References

1. Courneya KS, Vardy JL, O’Callaghan CJ, et al. Structured exercise after adjuvant chemotherapy for colon cancer. N Engl J Med. 2025;393(1):13-25. doi:10.1056/NEJMoa2502760
2. Rayner CJ, Bartlett DB, Allen SK, et al. Prehabilitation during neoadjuvant chemotherapy results in an enhanced immune response in esophageal adenocarcinoma tumors: A randomized controlled trial. J Sport Health Sci. 2025;14:101063. doi:10.1016/j.jshs.2025.101063