Cancer shots are more effective in the morning, while new vaccines work better when given late in the afternoon. That is because cells closely tied to cancer or immune responses move in sync with a 24-hour body clock. Phenomena observed while treating patients have been confirmed as causal through clinical trials. As research advances, simply adjusting the timing of drug administration is expected to further boost treatment effects.
A team led by Professor Yongchang Zhang at Central South University's medical school in China said in Nature Medicine on the 3rd that "in a phase 3 clinical trial, patients with Non-small cell lung cancer (NSCLC) who received immune checkpoint inhibitors before 3 p.m. saw their disease progress more slowly than those treated later." The study was conducted jointly by researchers in China, Hong Kong and France.
◇ Extended survival in cancer patients by nearly 70%
Lung cancer is classified into small cell lung cancer and larger non-small cell lung cancer by cancer cell size, and non-small cell lung cancer accounts for about 80% of all lung cancers. The researchers randomly assigned 210 patients with advanced non-small cell lung cancer to receive the immune checkpoint inhibitors Keytruda (ingredient pembrolizumab) or Tyvyt (sintilimab) before 3 p.m. or after, every three weeks for four cycles. Both drugs are PD-1 class immune checkpoint inhibitors.
Immune checkpoints are a way of marking so that T cells do not attack normal cells. When the PD-1 protein on T cells binds to PD-L1 on normal cells, T cells pass by. The problem is that cancer cells also produce PD-L1 to disguise themselves as normal cells. The anticancer drugs administered here use antibody proteins that first bind to PD-1 on T cells, preventing them from mistaking cancer cells for normal cells.
The team followed patients for 29 months after the first treatment. In the clinical trial, those treated before 3 p.m. survived a median of 28 months, while those who received anticancer drugs later survived 17 months. Francis Lévi of Paris-Saclay University, a co-corresponding author of the paper, said it was "a remarkable result with survival nearly doubled."
Progression-free survival, when the disease does not get worse, was 11.3 months in the early-treatment group and 5.7 months in the delayed-treatment group. The risk of disease worsening fell by 60%. Patients who received the anticancer shot early had more cytotoxic T cells in the blood that attack cancer cells, and their activity was higher.
Dozens of studies have reported that giving immune checkpoint inhibitors, a type of anticancer drug, earlier in the day significantly cuts the risk of death for cancer patients. But all had been post hoc analyses of treatment outcomes. This is the first time a real clinical trial randomly assigned patients and varied the timing of drug administration.
◇ Treatment strategy tailored to morning-type immune cells
The team explained that the stronger efficacy in the early-administration group was because the targeted T cells gather around the tumor in the morning. T cells gradually move into circulation over time. Administering anticancer drugs early means T cells can attack more cancer cells. In other words, it is like issuing a signal to launch a concentrated strike when friendly forces have surrounded the enemy.
Many of the patients in the trial are still receiving treatment. Continued follow-up is needed to assess the long-term benefits of early administration. While an increase in T cells in the blood was confirmed, a limitation is that changes in tumor tissue have not yet been analyzed.
Lévi said, "We need further research on whether giving the drug at a specific time, like 11 a.m., is better than setting only a rough window of several hours." Because people's body clocks vary, the optimal time to administer anticancer drugs may also differ by individual. Lévi noted, "Morning types and night owls can show clearly different daily patterns in their immune systems."
Another task is to see whether the findings apply to other cancers. Pasquale Innominato of the University of Warwick medical school said, "Cancers where immune checkpoint inhibitors are effective, such as skin cancer or bladder cancer, are expected to show similar results, but the likelihood is lower for prostate or pancreatic cancers that do not respond to this therapy."
◇ COVID-19 vaccines are more effective in the afternoon for younger people
Vaccines also appear to be affected by circadian rhythms. A team led by Elizabeth Klerman of Harvard Medical School and Jane McKeating of the University of Oxford reported in 2021 in the Journal of Biological Rhythms that antibody levels were higher when COVID-19 vaccines were given in the afternoon than in the morning.
The team evaluated levels of virus-neutralizing antibodies after COVID vaccinations in 2,190 health care workers during the pandemic. Generally, those vaccinated in the afternoon showed higher antibody responses. The researchers said that is because immune cells have a stronger learning effect for vaccines in the afternoon.
Vaccines work by introducing viruses or bacteria with their toxicity removed to trigger an immune response. It is like encountering and preparing for a small number of enemy troops in advance so that, when a large-scale attack comes later, the body can respond immediately. The immune system is designed to prepare for invaders such as viruses and bacteria during the day, when external activity is high.
Dendritic cells, the scouts that recognize viral or bacterial proteins (antigens), move to the lymph nodes—the rally point for immune cells—in the afternoon. The density of T cells and B cells that attack invaders also peaks in the lymph nodes in the afternoon. Therefore, if a vaccine arrives then, it can be seen as the most effective time for the body to gear up its defenses.
The researchers also divided COVID vaccines into those from Pfizer in the United States and AstraZeneca in the United Kingdom. The Pfizer and Moderna COVID vaccines deliver messenger ribonucleic acid (mRNA), the genetic material that makes the virus's spike protein, directly into the body, while AstraZeneca uses another harmless virus to deliver the spike gene into the body.
Those who received mRNA Vaccine shots, women and younger people showed higher antibody responses. That contrasts with earlier trials in older adults where influenza (flu) vaccines worked better in the morning. The researchers said that is because COVID vaccines and influenza vaccines work differently. Since COVID vaccines fight a completely new virus, getting the shot in the afternoon, when immune learning is stronger, is better; but for influenza viruses that older adults have encountered for a long time, administering the vaccine in the morning, the scouting time for immune cells, is preferable.
References
Nature Medicine (2026), DOI: https://doi.org/10.1038/s41591-025-04181-w
Journal of Biological Rhythms (2021), DOI: https://doi.org/10.1177/07487304211059315