Messenger RNA (mRNA) vaccines were designed to prevent infectious diseases, including COVID-19. They are now recognized for their capacity to stimulate potent innate and adaptive immune responses. The immunostimulatory effects may go beyond viral protection to impact cancer immunotherapy results. Immune checkpoint inhibitors (ICIs) rely on pre-existing antitumor immunity and show limited efficacy in patients with cold tumors lacking immune infiltration. Recent studies suggest that systemic immune activation triggered by mRNA vaccines can modify the tumor microenvironment and increase tumor sensitivity to ICIs.
This study investigated whether the COVID-19 mRNA vaccination induces cytokine and immune activation, affecting tumor PD-L1 expression, tumor immunogenicity, and survival in cancer patients who are receiving ICIs. It also determines whether vaccination can convert immunologically cold tumors into ICI-responsive ones.
Researchers analyzed blood from healthy individuals after receiving COVID-19 mRNA vaccines by using flow cytometry to assess immune activation. They measured markers of innate and adaptive immune activation, which include PD-L1 on CD11b⁺ myeloid cells and CD11c⁺ dendritic cells, IL-2Rα (CD25) on CD56 high natural killer (NK) cells, and CD69 on circulating T cells. Eleven individuals got the BNT162b2 (Comirnaty) vaccine, and their immune responses were compared with those induced by the mRNA-1273 (Moderna) vaccine.
The study examined two large patient cohorts for tumor-level effects. The first involved 2315 non-small cell lung cancer (NSCLC) pathology reports with the tumor proportion scores (TPS) for PD-L1. It is categorized on the basis of vaccination timing relative to tumor biopsy. The second cohort comprised 5317 pathology report forms from many cancer types, of which 2831 involved TPS data. The researchers analyzed how recent mRNA vaccines influenced PD-L1 expression and overall survival (OS) in patients who received ICIs. Survival analyses were adjusted for key clinical variables and confirmed with a propensity score match.
In healthy participants, COVID-19 mRNA vaccines transiently activated the immune system. PD-L1 expression doubled on CD11b⁺ myeloid and CD11c⁺ dendritic cells. NK cells showed increased IL-2Rα expression, and T cells displayed heightened CD69 activation. These changes peaked shortly after vaccination and normalized in a week. It indicates a transient systemic immune activation. The BNT162b2 vaccine contains less mRNA and produces a small cytokine and interferon response compared to mRNA-1273.
In NSCLC patients, those vaccinated within 100 days before tumor biopsy had a 24% higher mean PD-L1 TPS compared with unvaccinated patients and a 41% increase compared to those vaccinated ≥100 days prior. Thirty-six percent of recently vaccinated patients got a TPS ≥50% as compared with 28% of unvaccinated individuals, a clinically meaningful threshold for ICI eligibility. No similar PD-L1 elevation occurred with influenza or pneumococcal vaccination.
Expanding to the broader tumor cohort, vaccination within 100 days of biopsy increased mean PD-L1 TPS by 37% across diverse malignancies. Among 888 patients who received ICIs, those vaccinated within 100 days of initiation had significantly longer survival (HR 0.73, P = 0.0038), a benefit consistent across subgroups and pandemic periods. Strikingly, NSCLC patients with cold tumors (TPS <1%) who were vaccinated within 100 days of ICI initiation achieved survival outcomes similar to those with baseline TPS >1% which suggests restored sensitivity to immunotherapy.
COVID-19 mRNA vaccines can reprogram the tumor microenvironment by systemic immune activation. This triggers surges in antiviral cytokines, specifically type I interferons, to activate antigen-presenting cells and promote T-cell priming and infiltration in tumors. This increases PD-L1 expression on the tumor cell, which can lead to a compensatory resistance mechanism. When it is countered by ICIs, it increases the antitumor activity and improves survival. This study suggests that routine vaccination can be an alternative to influence cancer therapy results. It highlights the importance of vaccination timing relative to initiation of ICI.
Reference: Grippin AJ, Marconi C, Copling S, et al. SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade. Nature. 2025. doi:10.1038/s41586-025-09655-y
