Patients with advanced lung or skin cancer who received a COVID-19 mRNA vaccine within 100 days of starting immunotherapy lived significantly longer than those who did not, researchers report.

The observation—made by scientists at the University of Florida (UF) and the University of Texas MD Anderson Cancer Center and presented at the 2025 European Society for Medical Oncology and published in Nature—marks a defining moment in more than a decade of work exploring how mRNA-based therapeutics can “wake up” the immune system to fight cancer. Building on years of preclinical findings, the study suggests that a readily available vaccine designed for infectious disease may also sensitize tumors to immunotherapy and dramatically extend survival.

“The implications are extraordinary—this could revolutionize the entire field of oncologic care,” said senior investigator Elias Sayour, MD, PhD, a UF Health pediatric oncologist and the Stop Children’s Cancer/Bonnie R. Freeman Professor for Pediatric Oncology Research. “We could design an even better nonspecific vaccine to mobilize and reset the immune response, in a way that could essentially be a universal, off-the-shelf cancer vaccine for all cancer patients.”

Resetting the tumor microenvironment

Although immune checkpoint inhibitors (ICIs) have transformed cancer treatment, most patients do not respond to these drugs. Poor responses are largely attributed to immunosuppressive tumor microenvironments (TMEs), which contain inhibitory immune cells. In some cancers, low intratumoral PD-L1 expression before therapy predicts poor response.

Until now, there have been no clinically available ways to modify the TME to improve ICI efficacy. Sayour’s lab and others have shown that systemic delivery of highly immunogenic mRNA nanoparticles can induce a powerful, virus-like cytokine and chemokine response that resets both the systemic and intratumoral immune environments, sensitizing resistant tumors to ICIs.

“For the last 12 years, we’ve been working on personalized mRNA cancer vaccines,” Sayour said. “Over this time, we made an absolutely fascinating discovery, which is even if the mRNA is completely nonspecific to a patient’s cancer, that mRNA could wake up the sleeping giant that is the immune system to fight cancer.”

The next leap came from Adam Grippin, MD, PhD, a former UF graduate student now at MD Anderson. “A brilliant graduate student who was working with us, Adam, asked a brilliant question,” Sayour recalled. “Which is, if nonspecific mRNA vaccines can rouse the immune system against cancer, what happens to patients receiving the COVID-19 mRNA vaccine? What happens to those patients who are also receiving conventional immunotherapies?”

To answer that, researchers examined clinical data from 2019 to 2023 in patients with stage 3 or 4 non-small cell lung cancer and metastatic melanoma treated with ICIs. 180 advanced lung cancer patients received a COVID vaccine within a 100-day period before or after starting immunotherapy drugs. Another 704 were treated with the same drugs but did not receive the vaccine.

Real-world evidence of a survival boost

The results were striking. Patients who received a COVID-19 mRNA vaccine within 100 days before or after starting immunotherapy nearly doubled their median survival compared with those who did not—from 20.6 months to 37.3 months in lung cancer and from 26.7 months to 30–40 months in melanoma.

“The results were absolutely remarkable,” Sayour said. “Patients with some of the most aggressive forms of skin and lung cancer had a near doubling in survival outcome if they received these COVID-19 mRNA vaccines within 100 days of also receiving conventional immunotherapy.”

Receiving other, non-mRNA vaccines such as flu or pneumonia shots did not improve survival, underscoring that the effect was unique to mRNA-based immunization.

Mechanistic insights: Awakening the immune system

In mechanistic studies, Sayour’s team demonstrated that the innate immune response to SARS-CoV-2 spike mRNA vaccination resets the cancer immunotherapy cycle and primes adaptive immunity for synergy with ICIs. The COVID-19 spike mRNA vaccines, even though they do not encode tumor antigens, were shown to induce body-wide activation of antigen-presenting cells (APCs), leading to the expansion of tumor-specific T cells capable of driving tumor regression when combined with ICIs.

This effect required a surge in type I interferon (IFN) signaling that enhanced T-cell priming in lymphoid organs. The team also observed that mRNA vaccination increased PD-L1 expression on tumor cells, rendering them more responsive to checkpoint blockade.

To validate these mechanisms, UF researchers used mouse models pairing immunotherapy drugs with an mRNA vaccine targeting the COVID spike protein. These experiments demonstrated that the combination could convert treatment-resistant tumors into responsive ones and thwart tumor growth.

“One of the mechanisms for how this works is when you give an mRNA vaccine, that acts as a flare that starts moving all of these immune cells from bad areas like the tumor to good areas like the lymph nodes,” Sayour explained.

Immunotherapy relies on pre-existing anticancer immunity, which is absent in most patients. The study provides proof-of-concept that off-the-shelf mRNA vaccines—even those originally designed for infectious diseases—can supply that missing immune stimulus, effectively “resetting” the immune system to work in concert with ICIs.

The researchers propose that unmodified mRNA formulations, which generate stronger innate immune activation than the modified mRNA used in COVID vaccines, could potentially enhance these antitumor effects even further.

“The surprising effectiveness of this approach may explain the relative success of mRNA vaccines compared with other methodologies that also generate T cells reactive against targeted neoepitopes,” the authors wrote in Nature.

Next step: A confirmatory clinical trial

Sayour and colleagues are now organizing a Phase III randomized trial through the OneFlorida+ Clinical Research Network, which spans hospitals and clinics across six states. “I think the confirmatory work in a prospective trial is of the utmost importance and urgency,” says Duane Mitchell, MD, PhD, director of the UF Clinical and Translational Science Institute. “The notion that we may be able to use a simple vaccine to awaken a patient’s immune response to better fight their disease may totally change the way we think about treating cancer for the foreseeable future.”

Adds Sayour, “If proven to be true, this could revolutionize the field of cancer by allowing something like a universal cancer vaccine to be instantly available to patients around the globe, to wake up their immune system and now keep it active with some of the conventional therapies available.”