The case for timing cancer treatments to daily circadian rhythms
NEWS | 17 March 2026
A growing field of research suggests that some medical treatments, such as cancer therapy or vaccines, might be more effective when given at certain times of the day Could your body’s biological clock determine how receptive you’ll be to treatments and therapies? Some evidence suggests yes. A string of recent animal studies and early clinical trials have shown that certain medical interventions, from vaccines to immunotherapies, might be more effective when they are timed to a person’s circadian rhythm, the body’s internal clock that drives essential biological functions such as sleep, eating, metabolism—and immune activity. And scientists are trying to tap the interconnection between circadian rhythms and the immune system through an approach called chronotherapy. “Anything you look at is probably oscillating to one degree or another in your body, and almost every drug you can think of probably would benefit from some time-of-day analysis,” says Zachary Buchwald, a radiation oncologist and physician-scientist at Emory University. Buchwald is currently leading a trial on timed immunotherapy for people with skin cancer called the TIME trial. He and others are trying to understand if there’s solid biological evidence to make the case for personalizing therapies based on an individual’s unique circadian rhythm—or finding ways to alter their internal clock to ensure the treatment works effectively. Scientific American spoke with Buchwald about how circadian rhythms are linked to the immune system, what ongoing clinical trials are investigating and what potential limitations the field must consider if timed therapies become the norm. On supporting science journalism If you're enjoying this article, consider supporting our award-winning journalism by subscribing. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today. [An edited transcript of the interview follows.] Tell me a bit about the history of chronotherapy. A lot of this research was conducted by many other investigators who have been working on this for decades. The paper I came across that got me particularly interested in this topic was from a colleague of mine named Christoph Scheiermann in Geneva. He showed, in mice, that there is oscillation throughout the day in where immune cells are located. If you think of the immune parts of the body as different compartments—the blood and the lymph nodes—at one time of the day, there are more white blood cells, or T cells, in the lymph nodes. And then, 12 hours later, there are more immune cells in the blood. So it oscillates in a 24-hour circadian cycle. This finding has been corroborated by others and shown, to a certain, extent in humans. To confirm it in humans, you would have to take out lymph nodes serially over a 24-hour cycle, which we’re not doing for obvious ethical reasons. But you can take blood many times over a 24-hour cycle, and there are changes that are associated with the time of day: data show that the frequencies of different T cell subsets in the blood oscillate throughout the 24-hour cycle. How did you personally become interested investigating these timing-related effects for cancer therapies? I had been studying lymph nodes fairly extensively in the lab, and we’ve known the lymph node that drains the tumor is very important for response to immunotherapy and cancer. And lymph nodes are super important for the response to anti-PD-1, which is a widely used antibody that helps stimulate the immune response to cancer. In Scheiermann’s mouse study, he also showed that if you synchronize the timing of a vaccine with circadian-induced peak of T cells in the lymph node, that leads to a more robust immune response. I was fascinated by that. Given those findings, I hypothesized that something similar might be happening with antibody administration for treating cancer. To test that idea, we did a very simple retrospective analysis asking the question: If patients get more of their antibody infusions at a specific time of day, do they live longer? We published that first study in the Lancet Oncology in 2021. It showed that if patients get more of their infusions very late in the day, they live a shorter period of time. “I would not be surprised if there are many other areas of research and contexts where circadian rhythm could have significant implications.” —Zachary Buchwald, oncologist, Emory University What is the basis of the TIME trial you’re currently running? It is a phase 2 randomized study for patients with advanced melanoma who are getting an immunotherapy called ipi-nivo, or ipilimumab plus nivolumab—two drugs that are standard of care for patients with that diagnosis. The participants are randomized to one of three blocks of time throughout the day, which dictates when the drug is infused into their arm. The three blocks of time are 8 A.M. to 11 A.M., 11 A.M. to 2 P.M. and 2 P.M. to 5 P.M. I don’t have any data to report yet, but I would say patients seem very open to the question being asked. So if people receive the therapy later in the day, how might it affect them? What about people who have circadian rhythms that favor a nighttime cycle? The short answer to that question is: I don’t know. But the longer answer is this: in the initial retrospective studies, we included all 299 participants. And even taking a broad population of people—without any data on their circadian rhythm or sleep habits—we still saw a sizable effect. That suggests that person-to-person variability may be important, but the effect is still large enough to overcome person-to-person differences, at least in the earlier retrospective analysis. In our randomized trial, we are collecting individual circadian data on all patients enrolled, so hopefully we can get more answers. How does circadian rhythm factor into other kinds of diseases? Because I am an oncologist, most of the stuff that comes into my brain is in oncology. There are patients who get what’s called cell therapy, which is an infusion of immune cells to help fight cancer. In another paper from [Scheiermann and his colleagues], they showed, in mice, that the time of day that they infuse the immune cells seems to make a difference in terms of how well the cells get into the tumor. There have also been very nice papers published on bone marrow transplants and the importance of time of day. John Hogenesch [a chronobiologist at Cincinnati Children’s Hospital] is very famous in this space for trying to implement circadian discoveries in clinical scenarios. Specifically, he’s been working on altering the lighting in [hospital settings] to more appropriately align with a patient’s underlying circadian rhythm. I’m not involved in this work, but the goal is, ultimately, to align medical care, generally, with the intrinsic circadian rhythm we all have, and that can include the environment that a patient is exposed to but also the medications the patient receives. I would not be surprised if there are many other areas of research and contexts where circadian rhythm could have significant implications. What are some of the limitations of the research that scientists still need to address? I think there’s a healthy amount of skepticism about whether this phenomenon is real—whether timing antibody administration with your own circadian clock can influence responses to the drug. And I think that skepticism is based on solid assumptions and ideas about how the antibody works. For example, if the antibody has a really long half-life [time in the body], why does it matter when you infuse it if it’s going to be floating around for multiple circadian cycles? But that idea, while valid in one context, doesn’t fully address how the antibody might be interacting with the T cells within a 24-hour cycle. If the data shows that there is no effect, then there’s no effect. But if there is, I think it’s an area that hopefully others will be interested in pursuing. What might chronotherapy look like in hospitals and clinics? What considerations do clinicians still need to make? We and others in different countries at different institutions demonstrably show that earlier infusion is associated with better outcomes for patients with different types of cancer. If that’s the case, then I would imagine there will be a broader push by at least some clinicians and, most likely, patients to get infused earlier in the day. This is going to create a significant logistical problem for infusion centers around our country and, potentially, around the world. It could also exacerbate socioeconomic differences, because folks of lesser means might not have as much flexibility to come at a specific time of day—or could only come later in the day. The broader, longer-term goal, in my mind, is not just to find an optimal time of day to infuse drugs but to be able to actually find a way to drug the circadian rhythm itself so that a patient could come at any time of day.
Author: Tanya Lewis. Lauren J. Young.
Source