Incorporating structured exercise into conventional oncology care may reprogram the tumor immune microenvironment (TME) and significantly optimize treatment efficacy for patients with cancer, according to Nathan Goodyear, MD.
In an interview with CancerNetwork®, Goodyear emphasized that physical decline accelerates immunosenescence, immune exhaustion, and immune evasion, leading to rapid disease progression that is often detected radiologically only after immunological collapse. Conversely, research demonstrates that exercise serves as a powerful, biologically interventional therapy capable of prolonging longevity; lowering recurrence risk; and enhancing the efficacy of chemotherapy, immunotherapy, and surgery.
Data from the phase 3 CHALLENGE trial (NCT00819208) in patients with stage II and III colorectal cancer highlighted a lower risk of death and reduced recurrence following a 3-year structured exercise program.1 Furthermore, the OPTIMUS trial (NCT02950324) demonstrated that a short-term exercise program preceding surgery or alongside chemotherapy increased CD8-positive T-cell infiltration and decreased immunosuppressive cells, effectively turning “cold” tumors “hot.”2 According to Goodyear, maximizing these benefits require integrative care specialists to precisely tailor physical activity to each patient’s specific disease stage, physical capabilities, and prior fitness levels while treating exercise as a precise, customizable prescription rather than a generalized recommendation.
Goodyear is an integrative medicine physician at the Williams Cancer Institute.
CancerNetwork: Can you elaborate upon this idea that declining fitness may be an early warning sign of cancer progression?
Goodyear: When you look at cancer progression, it’s [often] something that we see radiologically. It’s something we see on imaging where the tumors are bigger, or there are more tumors. What if there were signals that we could see before that collapse on a massive scale? What if we get insight into early dysfunction? In fact, exercise is a window into that ongoing collapse, particularly when you look at the immune system. We know that as a person’s activity declines, the immune system declines, and immune exhaustion increases. Basically, those 2 steps alone cause immunosenescence to increase. Aging accelerates, which is immunosenescence.
What you have here is that as activity declines, you’re getting a counter-upregulation of the processes that promote accelerated aging, immune dysfunction, immune senescence, immune exhaustion, and immune evasion. All of that is going to lead to rapid progression that we ultimately see in the radiologic images, but here, you see it immunologically. For example, you start to see interleukin-6 elevate, and it stays chronic. C-reactive protein elevates and stays chronic. These are subtle markers. Those 2 are markers that are available via any regular lab test, yet they’re almost never evaluated.
If you look at it as it relates to activity, an oncologist almost never asks about activity…. But what if science is showing that exercise is equal to many of the conventional cancer care therapies that have been celebrated? There has been research—human studies—[showing] that it can prolong longevity; reduce recurrence; reduce metastasis; and increase the efficacy of chemotherapy, immunotherapy, and surgery. That’s the reality of it.
What we have is the capacity to monitor that ecosystem; that’s what research is showing us right now. Within the [TME], it’s an ecosystem that is not confined there [but] transported throughout the body. We have the capacity not only to monitor it but to intervene with something as simple as exercise. It’s not just immunologic; it’s also metabolic and endocrinological––[I am] talking about the circadian rhythm and the sleep-wake cycles. All of these are huge adjuvants to the immune system. I believe that the immune system is the body’s major defense that we need to engage. The standards of therapy over the last 75 years or so have not been involving that immune system, but if we engage it, it’s going to make everything better.
How might exercise optimize treatment efficacy for patients with cancer?
There’s research that shows that it does, but then there’s research that shows how it does. 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.
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. [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 gave some healthy information and 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.
Another [study], called the OPTIMUS study from the NHS in the UK, was following these patients through a 12- or 16-week exercise program. It was a much smaller study related to [48] patients, whereas the CHALLENGE study was almost 900. What they did is they followed these patients in 2 segments––it was 8 weeks each time––one with chemotherapy, which improved results, and one preceding surgery. They surgically resected and looked at the tumors. Here’s where it gets into the “how”: they found CD8-positive T-cell infiltration and a reduction in immunosuppressing cells.
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. It is enabling the infiltration and the recruitment of immune cells within the TME, reprogramming it, and allowing the immune system to be engaged. Now, you’re going to take what tends to be a predominantly immune-excluded environment and turn it into one where the immune system can now be harnessed. That is next level.
It gets even better. I had a patient the other day who had recurrent stage IV cancer. I often say that—and this applies to all doctors—we say stupid things, and patients never forget them. We are trying with intent to say something, and the words [sometimes] just don’t come out right…. [Another] doctor said [to a patient], “Your immune system is broken.” The patient [says to me], “How can you help me? My immune system’s broken.” I said, “It’s not broken. The problem is your immune system is not engaged; it doesn’t know [how to attack malignant cells].”
Exercise will decrease myeloid-derived suppressor cells and regulatory T cells. These are key immunosuppressive cells that help to create immune suppression barriers in and around the tumor. That disengages the immune system. The immune system may see the tumor, but along [they] come––there may be M2 macrophages, these myeloid-derived suppressor cells, and then the regulatory T cells––they’re rebuffing the immune system that’s alerted but kept out. Now, it’s not that the immune system’s broken; it’s that the immune system is not allowed to be engaged because of the tumor.
How can integrative care specialists best tailor exercise to ensure patients are best positioned to experience the most benefit?
That’s where the precise nature of oncology is: [finding] the right treatment for the right patient, and the right combination at the right place and right time. If you have a patient come to you, and they’re dealing with sarcopenia, cachexia, advanced stage IV cancer, and chemotherapy-induced peripheral neuropathy, you’re not going to say, “Let’s get you doing some weights about 3 or 4 times a week. Let’s go out and jog.” No. You must say, “Okay, you know what? Let’s get you moving.”
First, [give a] proper assessment. What is the patient’s activity like? [They may say,]
“I’m in a wheelchair all day,” or “I’m in bed.” Let’s start building a strategy of saying, “Well, let’s have you, if you’re capable…Walk to the kitchen. Let’s have you do a series of particular events during the day that get you mobile.” Now, what we have is the ability to remove somebody from a sedentary life to actually moving. There are going to be natural remedies from [moving]: myokines, cytokines, and modulation of the immune system.
That’s acute, not chronic; that’s one of the areas where we get mixed up. Exercise will acutely increase interleukin-6, not chronically. Human studies [show] if you block interleukin-6 and epinephrine with exercise, you block the ability of natural killer cells to infiltrate and lead to tumor necrosis. Acute vs chronic is very different as it relates to immune signaling.
There, in that patient instance, you go, “Let’s just get you mobile now. Let’s build a strategy from that.” If somebody comes in and says, “I’ve never exercised,” and they are 350 pounds, it’s kind of the same concept. Let’s just get [them] walking. Then, once you get that pattern set in place, you say, “Hey, let’s get you doing some 1-pound dumbbells as you’re walking 1 day a week.” [You must] build it because acute and chronic are different, and resistance and cardio are different as they relate to the immune system.
But let’s say an athlete comes in. We had a patient who said, “I was a professional rower competing in the Olympics.” It’s not going to take much to tell them, “All right, let’s get you doing cardio 3 days a week. Let’s get you doing resistance training twice a week.” The [opposite] is the problem here; I’ve got to tone them back. I say, “Look, you’re not training for the Olympics; we’re training for your immune system, which is very different.”
We have to look at disease stage; that plays a big role in this, too. For stage IV or III [disease], I’m going to approach it differently. For stage I or II [disease], I approach it differently. We have to look at each person and see where they are. What are they capable of doing? Let’s be honest; there are many of us who are athletes, and there are many who are not. Some people have that innate athletic ability, so in that aspect, you say, “Let’s build in free-weight resistance training because I know you can do this.” But don’t just say “do it,” say, “Here’s what I want you to do.”
What does that mean? “I’m going to go out there and be Arnold Schwarzenegger, and put 300 pounds on the bench press?” No. I want you, if you haven’t lifted in a while, to take 10-pound dumbbells. I want it to be so embarrassingly low weight that you’re embarrassed to be in the gym, and I want you to do high-rep, low-weight [lifting]. I want you to do 3 sets. I want you to do 45 seconds of rest in between. Then, we’re going to build on that with biceps, triceps, and lat lifts. Then, we’re going to say, “Let’s focus on the lower body muscle groups: glutes, hamstrings, and [gastrocnemius].”
What you do now is start to instruct. Just as we would say, “Here’s what we’re going to do from a surgical perspective to remove the tumor, and here’s what we’re going to do from an oncological perspective.” We need to do the same thing with exercise because research is now [about] showing the what and the how. Exercise is not a replaceable therapy; it is a biologically interventional therapy that stands on its own. But in conjunction with other therapies, it becomes an amazing stacking or sequential use of therapies that will help patients not just overcome their cancer but have better outcomes and live longer. That’s a concept I can dive into.
References
- 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
- 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
