In a development that could shape cancer treatment strategies, researchers have found evidence that COVID mRNA vaccines can enhance the effectiveness of cancer immunotherapy and significantly improve cancer outcomes.

The study revealed that receiving a COVID mRNA vaccine within 100 days of initiating immune checkpoint inhibitor (ICI) therapy was associated with a substantial improvement in overall survival among patients with advanced non-small cell lung cancer (NSCLC) and metastatic melanoma.

“Our results suggest that existing mRNA vaccines, already in use worldwide, may be repurposed to improve outcomes for cancer patients,” said Adam Grippin, MD, PhD, The University of Texas MD Anderson Cancer Center, Houston, who presented the research at the European Society for Medical Oncology (ESMO) Annual Meeting 2025 (simultaneously published in Nature). “This opens the door to developing universal immune-fortifying RNA vaccines that could benefit millions.”

The potential to develop an off-the-shelf mRNA vaccine to boost cancer immunotherapy is what’s exciting about this work, said Jeff Coller, PhD, professor of RNA biology and therapeutics at the Johns Hopkins University, Baltimore, who wasn’t involved in the research. “With additional investment in research and clinical studies, we might be able to find off-the-shelf mRNAs that have large effects on the immune system [in patients with cancer].”

But experts also cautioned that more data are needed.

“This is an intriguing finding, yet we should be cautious before drawing conclusions,” Lennard Lee, DPhil, associate professor at University of Oxford’s Center for Immuno-Oncology, Oxford, England, said in a statement from the UK Science Media Centre. “Only a randomized trial can tell us whether the vaccine itself drives the effect.” 

With that in the mind, Grippin’s team is currently planning a randomized clinical trial to validate the current findings.

That study — known as Universal Immunization to Fortify Immunotherapy Efficacy and Response or UNIFIER — may inform development of more effective universal immune fortifying RNAs, Grippin explained.

Survival Advantage in Lung Cancer, Melanoma

While ICI has “revolutionized cancer treatment,” the therapy is ineffective in patients without preexisting antitumor responses, Grippin explained during his presentation at the ESMO. Personalized mRNA cancer vaccines could sensitize tumors to immune checkpoint blockade but are expensive, slow to produce, and not well understood.

In earlier work published this year, Grippin and colleagues showed that mRNA vaccines coding for nontumor antigens also elicit antitumor immunity.

“This discovery led us to the question of whether COVID mRNA vaccines might also induce antitumor immune responses that could boost responses to immune checkpoint blockade,” Grippin explained.

In a retrospective cohort of 884 patients with unresectable stage III or stage IV NSCLC, the research team discovered that receiving a COVID mRNA vaccine within 100 days of initiating an ICI was associated with an almost twofold improvement in median overall survival (37.3 months vs 20.6 months with no vaccine) and a significantly better 3-year overall survival rate (55.7% vs 30.8%; adjusted hazard ratio [HR], 0.51).

This survival advantage was similar for patients with stage III unresectable (HR, 0.37) and stage IV disease (HR, 0.52).

Similar results were observed in a retrospective cohort of 210 patients with metastatic melanoma, 43 of whom received a COVID vaccine within 100 days of starting immunotherapy. At 3 years, patients who received a COVID mRNA vaccine demonstrated significantly improved 3-year overall survival compared to those who didn’t receive the vaccine (67.6% vs 44.1%; HR, 0.37). Patients who received a COVID mRNA vaccine also demonstrated significantly improved 3-year progression-free survival (39.5% vs 23.7%; HR, 0.63).

Grippin explained that the closer in time between receiving the vaccine and the immune checkpoint blockade, the “more magnified” the survival benefit appeared to be. “A 30-day window around starting immune checkpoint blockade seems to be an optimal timeframe,” Grippin told conference attendees.

Notably, receipt of non-mRNA influenza or pneumonia vaccines near the start of ICI therapy had no effect on survival among people receiving immunotherapy for cancer, he said.

The team also observed a benefit of the mRNA vaccine in mouse models of melanoma and NSCLC that are resistant to immunotherapy. Giving the mRNA vaccine alongside checkpoint inhibitors dramatically slowed tumor growth in the mouse model compared to immunotherapy alone.

“As in our patients, we saw that the addition of the COVID mRNA vaccine sensitized these tumors to immune checkpoint blockade leading to improved tumor control,” Grippin explained.

The Real Question: Why?

What might explain the survival benefit among patients who received the mRNA COVID vaccines alongside immunotherapy?

Cytokine analysis showed that COVID mRNA vaccines produce a surge in type I interferon, specifically interferon alpha. In the mouse models, when interferon alpha was blocked, the beneficial effect of COVID mRNA vaccine disappeared, suggesting that interferon alpha is a key necessary mediator of these antitumor responses, Grippin explained.

Similar correlates of vaccination response were found in humans, including increases in type I interferon, myeloid-lymphoid activation in healthy volunteers, and PD-L1 expression on tumors.

“The data tells a story in which the mRNA vaccines initiate an antitumor immune response that primes T-cell immunity, leading to upregulation of PD-L1 at the tumor and rendering immunologically cold tumors sensitive to immune checkpoint blockade,” Grippin said.

Combining the vaccine with immune checkpoint blockade is required to “fully unleash this antitumor immunity to mediate tumor regression,” Grippin said.

Grippin noted that the survival benefit was similar with one or two vaccine doses and across prime and booster doses and manufacturers, likely because the interferon alpha response to mRNA is what’s driving this effect. “As far as we can tell, it doesn’t have anything to do with the spike protein. It’s really the innate immune response to the mRNA,” he explained.

The findings suggest that “the COVID-19 mRNA vaccine may be a candidate for a universal therapy to sensitize ICI response,” co-author Elias Sayour, MD, PhD, principal investigator of the RNA Engineering Laboratory, University of Florida College of Medicine, Gainesville, Florida, told Medscape Medical News.

But it’s too soon to draw immediate implications, Sayour added. “Although we have tried to control for bias, a retrospective analysis like this needs to be validated prospectively, which we aim to do with a randomized phase 3 study,” Sayour said.

Coller echoed the need for more research but noted that this research further validates that COVID mRNA vaccines have additive effects outside of their ability to fight the virus; these vaccines can improve outcomes in cancer immunotherapy.

“The real question for science,” he said, “is why?”

There probably is something “unique about mRNA — a natural product that is made by the body every single day — and the body knows how to respond to it very quickly,” he said.

Although it’s too early for the study to inform clinical practice in oncology, Coller noted that people should get the COVID vaccine because it’s highly efficacious and lowers the odds of hospitalization and death.

The study had no commercial funding. Grippin reported receiving travel funding from Alamar Biosciences and being a scientific advisor for Sift Biosciences and BeyondSpring Pharmaceuticals. Sayour reported receiving royalty payments from patents licensed to iOncologi. Coller had no disclosures.