Introduction
Data from a new MD Anderson study that was presented at ESMO 2025 and published in Nature entitled “SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade” provides evidence that mRNA vaccines targeting non-tumor antigens, in this case SARS-CoV-2, sensitize tumors to immune checkpoint inhibitor (ICI) therapy and improve survival.
Results
Survival Analysis in Advanced Non-Small Cell Lung Cancer (NSCLC)
Overall survival (OS) was assessed in patients with Stage III/IV NSCLC who received ICIs. In total, 180 patients who received a COVID-19 mRNA vaccine within 100 days of initiating ICI therapy and 704 patients who did not receive a COVID-19 vaccine were compared. Median OS was significantly improved in patients with advanced NSCLC who received a vaccine compared to patients who did not receive a vaccine (37.3 versus 20.6 months). In addition, 3-year OS was significantly better (30.8% versus 55.7%). This survival advantage was similar for patients with Stage III unresectable NSCLC and Stage IV NSCLC.
Survival Analysis in Metastatic Melanoma
Patients with metastatic melanoma who received a COVID-19 mRNA vaccine within 100 days of initiating ICIs were also investigated. In total, 43 patients who received a COVID-19 mRNA vaccine and 167 patients who did not were compared. Median OS had not yet been reached in patients with metastatic melanoma receiving a vaccine and was 26.67 months in patients who did not receive a vaccine, which represented a significant improvement. In addition, 3-year OS was significantly better in patients who received the vaccine (67.6%. versus 44.1%). Progression-free survival (PFS) was also significantly longer (median PFS, 10.3 months versus 4.0 months; 36-month PFS, 39.5% versus 23.7%).
Survival Analysis in Other Tumors
Survival was also assessed in a broad patient cohort of 888 patients who had a biopsy for PD-L1 and who received ICIs. Patients in this group who received a COVID-19 vaccine within 100 days of initiating ICI therapy experienced significantly improved survival compared to patients who did not receive a vaccine.
Preclinical Models and Studies in Healthy Volunteers
To assess if the effects observed in humans could be modelled in animals, commercial preparations of COVID-19 mRNA vaccines were developed and administered to tumor-bearing mice in conjunction with ICIs. Data showed that type I interferon mediates RNA vaccine immunity, and that RNA vaccines stimulate innate immunity, reprogram adaptive immunity, and induce T-cell infiltration. Blood and plasma samples from healthy volunteers were collected and analyzed to determine if the pathways identified in mouse models are relevant in humans. In preclinical models, there was a substantial increase in type I interferon, enabling innate immune cells to prime CD8+ T cells that target tumor-associated antigens. Similar findings were found in human volunteers, including increases in type I interferon and myeloid–lymphoid activation.
PD-L1 Expression Studies
Given that an infiltration of antigen-specific T cells in tumors is associated with increased PD-L1 expression, PD-L1 expression was assessed in tumors from patients who received and did not receive a COVID-19 mRNA vaccine.
PD-L1 expression was first investigated in 2,315 pathology reports from patients with NSCLC with biopsies reporting a tumor proportion score (TPS). These scores are used to assess the percentage of tumor cells that express PD-L1 and to predict response to therapy with ICIs. Patients who received a COVID-19 mRNA vaccine less than 100 days before biopsy experienced a 24% increase in mean TPS compared with patients who did not receive a vaccine before biopsy. In addition, a 41% increase in mean TPS was observed in patients who received a vaccine 100 or more days before biopsy compared to those who did not receive a vaccine. Furthermore, patients who received a COVID-19 mRNA vaccine were 29% more likely to meet or exceed the 50% TPS threshold to be eligible for ICI monotherapy when compared to unvaccinated patients.
When PD-L1 expression was assessed in a variety of tumors identified in 5,317 unique pathology reports, receipt of a COVID-19 mRNA vaccine within 100 days before biopsy was associated with a 37% increase in TPS.
Studies in Immunologically “Cold” Tumors
Pre-vaccine TPS was used as a surrogate for immune sensitivity because TPS <1% is associated with a reduced benefit from ICIs compared to baseline TPS >1% in NSCLC. OS was similar in patients with stage IV NSCLC and baseline TPS <1% who received a COVID-19 mRNA vaccine within 100 days of initiating ICIs and in patients who were not vaccinated. Furthermore, the association between vaccination and OS was similar for patients with TPS <1% relative to those patients with a TPS at biopsy of 1–49.9% or ≥50%.
These results show that vaccination could restore immune sensitivity in patients with immunologically “cold” tumors, ones that are not likely to trigger a strong immune response. Importantly, survival improvements were most pronounced in patients with immunologically “cold” tumors which would not be expected to respond well to immunotherapy.
Conclusions
Immunotherapy with ICIs is effective in tumors such as melanoma and NSCLC; however, pre-existing anti-cancer immunity is necessary to achieve optimal outcomes. Use of mRNA vaccines may be a promising strategy to increase the effects of ICIs, which is particularly important for sensitizing “cold” tumors that are not expected to respond to ICI therapy. The results of this study show that receiving a COVID-19 mRNA vaccine within 100 days of initiating ICIs was associated with substantial improvements in survival. In addition, the results provide insight into the mechanism by which mRNA vaccines may improve survival when combined with ICIs.
Reference
Grippin AJ, Marconi C, Copling S, et al. SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade. Nature. Published online October 22, 2025. doi:10.1038/s41586-025-09655-y
