In an extraordinary turn for cancer research, a research group led by The University of Texas MD Anderson Cancer Center has discovered that COVID-19 mRNA vaccines may do more than prevent infection: they could also enhance responses to immune checkpoint inhibitors (ICIs) in advanced solid tumors, including non-small cell lung cancer (NSCLC).[1]
mRNA Vaccines
COVID-19 mRNA vaccines work by introducing into the body a short, harmless piece of genetic code from the SARS-CoV-2 virus (messenger ribonucleic acid, or mRNA), which instructs the body to produce a spike protein normally used by the virus to enter human cells. Produced in isolation, the spike protein activates an immune emergency drill that allows the immune system to safely practice recognizing the protein as foreign, produce antibodies designed to neutralize it, and prime cytotoxic T cells to destroy any cell that carries it in the event of a viral infection.
mRNA technology in cancer vaccines is in its investigational stages, largely focused on personalized approaches designed to train the immune system to recognize and attack tumor-associated or -specific antigens.[2]
Despite promising results, however, personalized mRNA cancer vaccines face significant biological and practical hurdles. Each formulation must be custom-designed for an individual’s tumor, requiring accurate predictions of which neoantigens are most likely to solicit a strong enough T-cell immune response, delivery systems capable of releasing the neoantigens in a targeted, controlled manner, rapid sequencing, and bespoke manufacturing, all within a narrow therapeutic window.[3] In addition, tumor-specific antigens tend to elicit weaker immune responses than viral antigens, particularly in the immune-suppressive tumor microenvironment (TME).
Building on their discovery that mRNA vaccines with tumor-unspecific antigens can act as potent immune activators, rendering immunologically cold tumors “hot” and improving the efficacy of ICIs,[4] a research group at the MD Anderson explored whether the widely available mRNA COVID-19 vaccines could similarly enhance tumor sensitivity to ICIs.
The Discovery
The researchers analyzed the records of almost 900 patients who were treated at the MD Anderson between 2015 and 2022 for Stage III/IV NSCLC, 180 of whom had received a COVID-19 mRNA vaccine within 100 days of starting treatment with immunotherapy.
The findings were striking: the average survival of patients who happened to have been vaccinated within that window was almost twice that of the non-vaccinated group (37.3 months, compared with 20.6 months), with 55.7% of vaccinated patients alive at 3 years compared with 30.8% of those unvaccinated. [5]
The research group found a similar trend across over 200 patients treated with a first round of ICIs for metastatic melanoma, 43 of whom had received a COVID-19 mRNA vaccine within 100 days of beginning therapy. By contrast, patients who had received a COVID-19 vaccine within 100 days of beginning chemotherapy, or patients who received influenza or pneumonia vaccines within 100 days of beginning treatment with ICIs had no detectable improvement in survival, implying a synergistic effect of the COVID-mRNA vaccine on adaptive immunity with ICIs.
Next, the researchers turned to animal models, generating a working laboratory version of the COVID-19 vaccine and testing it in mouse tumor models that are normally resistant to ICIs, to assess whether immune activation with the vaccine could help overcome that resistance. They replicated the mRNA architecture of BNT162b2 (the Pfizer/BioNTech vaccine) and encapsulated it within lipid nanoparticles (LNPs), which protect the mRNA from degradation, deliver it efficiently into cells, and trigger viral-like activation of the immune system for its immunostimulatory effect.
In these resistant mouse models, combining the vaccine with anti-PD-1 and -PD-L1 antibodies resulted in significantly slowed tumor growth and reduced metastases, demonstrating that non-tumor mRNA vaccine-driven immune activation can restore sensitivity to checkpoint inhibitors. Interestingly, the anti-tumor effect persisted when the group tested mRNA encoding an entirely different antigen from human herpesvirus (cytomegalovirus antigen pp65) encapsulated within LNPs, showing that the immune activation is driven by the combination of mRNA-LNPs, rather than by the spike protein sequence itself.
The mechanistic studies carried out by the group further confirmed that the cyotokine Type I interferon (type I IFN), a substance secreted by cells in response to viral infections, was the key driver of the response; blocking IFN signaling not only eliminated the anti-tumor benefit of the mRNA-LNP vaccine combined with ICIs, but also the vaccine-induced upregulation of PD-L1 on tumor and antigen-presenting immune cells. Their retrospective analysis of patient biopsies supported this mechanism: the biopsies of patients who had been recently vaccinated showed higher expression of PD-L1 in tumor tissues, providing a real-world parallel with the type I IFN-driven immune activation observed in mice, and helping to explain why these patients responded better to PD-1/PD-L1 inhibitors.
The authors and their collaborators are now moving forward with a multicenter, randomized Phase III study designed to validate these findings in patients receiving immune checkpoint inhibitors.[6] The study will specifically investigate whether administering an mRNA COVID-19 vaccine alongside cancer therapy with immune checkpoint inhibitors should become part of the standard of care for cancers such as NSCLC.
Innovating from Strength
This new discovery, which was published in Nature in October 2025, is a powerful example of what we mean when we talk about “innovating from strength”: leveraging proven science in novel ways to shift the odds in difficult settings. It validates, moreover, that the future of NSCLC treatment will not be about single agents, but about intelligent combinations, turning hard-to-treat scenarios into one of strategic opportunity.[7] NSCLC remains one of the most challenging cancers to treat and the leading cause of cancer-related deaths worldwide. Today, inhibitors of PD-1/PD-L1 are only about 20% effective in treating lung cancer, and development of co-therapies is essential to expanding the NSCLC patient population that may benefit from these therapies.
That the next potential co-therapy is one which is already approved, is widely available, and has already proven scalable under the immense pressures of the COVID-19 pandemic is an extraordinary advantage for individuals just beginning their treatment journey. It demonstrates how innovation rooted in proven science can improve outcomes for those affected by a diagnosis right now, rather than in some hypothetical future.
And insofar as our lead candidate, Tumor Defense Breaker™, L-DOS47, is concerned, these findings reinforce the premise of our rationale: modulating the TME can meaningfully enhance the efficacy of ICIs, such as pembrolizumab. Whereas the COVID-19 mRNA vaccine amplifies immune activation and effectively increases PD-L1 availability for ICI binding, L-DOS47 neutralizes tumor acidity to support immune infiltration and T-cell effectiveness, thereby improving the conditions under which ICIs can unleash a sustained T-cell attack on tumors. In time, we may see patients with NSCLC and other solid tumors receive next-generation multimodal regimens: L-DOS47 to prime the TME, mRNA vaccination to activate and mobilize immunity, and ICIs to sustain T-cell-mediated attack, offering the potential to overcome the limitations of monotherapies.
REFERENCES
[1] https://www.mdanderson.org/newsroom/research-newsroom/-esmo-2025–mrna-based-covid-vaccines-generate-improved-response.h00-159780390.html
[2] https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-06033-6
[3] https://pmc.ncbi.nlm.nih.gov/articles/PMC11949952/
[4] https://www.nature.com/articles/s41551-025-01380-1
[5] https://www.nature.com/articles/s41586-025-09655-y
[6] https://www.mdanderson.org/newsroom/research-newsroom/-esmo-2025–mrna-based-covid-vaccines-generate-improved-response.h00-159780390.html
[7] https://www.helixbiopharma.com/blog/pd-1-pd-l1-inhibitors-co-therapies-the-future-of-nsclc-therapy-lies-in-smart-combinations/
mRNA Vaccines
COVID-19 mRNA vaccines work by introducing into the body a short, harmless piece of genetic code from the SARS-CoV-2 virus (messenger ribonucleic acid, or mRNA), which instructs the body to produce a spike protein normally used by the virus to enter human cells. Produced in isolation, the spike protein activates an immune emergency drill that allows the immune system to safely practice recognizing the protein as foreign, produce antibodies designed to neutralize it, and prime cytotoxic T cells to destroy any cell that carries it in the event of a viral infection.
mRNA technology in cancer vaccines is in its investigational stages, largely focused on personalized approaches designed to train the immune system to recognize and attack tumor-associated or -specific antigens.[2]
Despite promising results, however, personalized mRNA cancer vaccines face significant biological and practical hurdles. Each formulation must be custom-designed for an individual’s tumor, requiring accurate predictions of which neoantigens are most likely to solicit a strong enough T-cell immune response, delivery systems capable of releasing the neoantigens in a targeted, controlled manner, rapid sequencing, and bespoke manufacturing, all within a narrow therapeutic window.[3] In addition, tumor-specific antigens tend to elicit weaker immune responses than viral antigens, particularly in the immune-suppressive tumor microenvironment (TME).
Building on their discovery that mRNA vaccines with tumor-unspecific antigens can act as potent immune activators, rendering immunologically cold tumors “hot” and improving the efficacy of ICIs,[4] a research group at the MD Anderson explored whether the widely available mRNA COVID-19 vaccines could similarly enhance tumor sensitivity to ICIs.
The Discovery
The researchers analyzed the records of almost 900 patients who were treated at the MD Anderson between 2015 and 2022 for Stage III/IV NSCLC, 180 of whom had received a COVID-19 mRNA vaccine within 100 days of starting treatment with immunotherapy.
The findings were striking: the average survival of patients who happened to have been vaccinated within that window was almost twice that of the non-vaccinated group (37.3 months, compared with 20.6 months), with 55.7% of vaccinated patients alive at 3 years compared with 30.8% of those unvaccinated. [5]
The research group found a similar trend across over 200 patients treated with a first round of ICIs for metastatic melanoma, 43 of whom had received a COVID-19 mRNA vaccine within 100 days of beginning therapy. By contrast, patients who had received a COVID-19 vaccine within 100 days of beginning chemotherapy, or patients who received influenza or pneumonia vaccines within 100 days of beginning treatment with ICIs had no detectable improvement in survival, implying a synergistic effect of the COVID-mRNA vaccine on adaptive immunity with ICIs.
Next, the researchers turned to animal models, generating a working laboratory version of the COVID-19 vaccine and testing it in mouse tumor models that are normally resistant to ICIs, to assess whether immune activation with the vaccine could help overcome that resistance. They replicated the mRNA architecture of BNT162b2 (the Pfizer/BioNTech vaccine) and encapsulated it within lipid nanoparticles (LNPs), which protect the mRNA from degradation, deliver it efficiently into cells, and trigger viral-like activation of the immune system for its immunostimulatory effect.
In these resistant mouse models, combining the vaccine with anti-PD-1 and -PD-L1 antibodies resulted in significantly slowed tumor growth and reduced metastases, demonstrating that non-tumor mRNA vaccine-driven immune activation can restore sensitivity to checkpoint inhibitors. Interestingly, the anti-tumor effect persisted when the group tested mRNA encoding an entirely different antigen from human herpesvirus (cytomegalovirus antigen pp65) encapsulated within LNPs, showing that the immune activation is driven by the combination of mRNA-LNPs, rather than by the spike protein sequence itself.
The mechanistic studies carried out by the group further confirmed that the cyotokine Type I interferon (type I IFN), a substance secreted by cells in response to viral infections, was the key driver of the response; blocking IFN signaling not only eliminated the anti-tumor benefit of the mRNA-LNP vaccine combined with ICIs, but also the vaccine-induced upregulation of PD-L1 on tumor and antigen-presenting immune cells. Their retrospective analysis of patient biopsies supported this mechanism: the biopsies of patients who had been recently vaccinated showed higher expression of PD-L1 in tumor tissues, providing a real-world parallel with the type I IFN-driven immune activation observed in mice, and helping to explain why these patients responded better to PD-1/PD-L1 inhibitors.
The authors and their collaborators are now moving forward with a multicenter, randomized Phase III study designed to validate these findings in patients receiving immune checkpoint inhibitors.[6] The study will specifically investigate whether administering an mRNA COVID-19 vaccine alongside cancer therapy with immune checkpoint inhibitors should become part of the standard of care for cancers such as NSCLC.
Innovating from Strength
This new discovery, which was published in Nature in October 2025, is a powerful example of what we mean when we talk about “innovating from strength”: leveraging proven science in novel ways to shift the odds in difficult settings. It validates, moreover, that the future of NSCLC treatment will not be about single agents, but about intelligent combinations, turning hard-to-treat scenarios into one of strategic opportunity.[7] NSCLC remains one of the most challenging cancers to treat and the leading cause of cancer-related deaths worldwide. Today, inhibitors of PD-1/PD-L1 are only about 20% effective in treating lung cancer, and development of co-therapies is essential to expanding the NSCLC patient population that may benefit from these therapies.
That the next potential co-therapy is one which is already approved, is widely available, and has already proven scalable under the immense pressures of the COVID-19 pandemic is an extraordinary advantage for individuals just beginning their treatment journey. It demonstrates how innovation rooted in proven science can improve outcomes for those affected by a diagnosis right now, rather than in some hypothetical future.
And insofar as our lead candidate, Tumor Defense Breaker™, L-DOS47, is concerned, these findings reinforce the premise of our rationale: modulating the TME can meaningfully enhance the efficacy of ICIs, such as pembrolizumab. Whereas the COVID-19 mRNA vaccine amplifies immune activation and effectively increases PD-L1 availability for ICI binding, L-DOS47 neutralizes tumor acidity to support immune infiltration and T-cell effectiveness, thereby improving the conditions under which ICIs can unleash a sustained T-cell attack on tumors. In time, we may see patients with NSCLC and other solid tumors receive next-generation multimodal regimens: L-DOS47 to prime the TME, mRNA vaccination to activate and mobilize immunity, and ICIs to sustain T-cell-mediated attack, offering the potential to overcome the limitations of monotherapies.
REFERENCES
[1] https://www.mdanderson.org/newsroom/research-newsroom/-esmo-2025–mrna-based-covid-vaccines-generate-improved-response.h00-159780390.html
[2] https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-06033-6
[3] https://pmc.ncbi.nlm.nih.gov/articles/PMC11949952/
[4] https://www.nature.com/articles/s41551-025-01380-1
[5] https://www.nature.com/articles/s41586-025-09655-y
[6] https://www.mdanderson.org/newsroom/research-newsroom/-esmo-2025–mrna-based-covid-vaccines-generate-improved-response.h00-159780390.html
[7] https://www.helixbiopharma.com/blog/pd-1-pd-l1-inhibitors-co-therapies-the-future-of-nsclc-therapy-lies-in-smart-combinations/