Faculty, Staff and Student Publications

Language

English

Publication Date

11-1-2025

Journal

Nature

DOI

10.1038/s41586-025-09655-y

PMID

41125896

PMCID

PMC12611756

PubMedCentral® Posted Date

10-22-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Immune checkpoint inhibitors (ICIs) extend survival in many patients with cancer but are ineffective in patients without pre-existing immunity1–9. Although personalized mRNA cancer vaccines sensitize tumours to ICIs by directing immune attacks against preselected antigens, personalized vaccines are limited by complex and time-intensive manufacturing processes10–14. Here we show that mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to ICIs. In preclinical models, SARS-CoV-2 mRNA vaccines led to a substantial increase in type I interferon, enabling innate immune cells to prime CD8+ T cells that target tumour-associated antigens. Concomitant ICI treatment is required for maximal efficacy in immunologically cold tumours, which respond by increasing PD-L1 expression. Similar correlates of vaccination response are found in humans, including increases in type I interferon, myeloid–lymphoid activation in healthy volunteers and PD-L1 expression on tumours. Moreover, receipt of SARS-CoV-2 mRNA vaccines within 100 days of initiating ICI is associated with significantly improved median and three-year overall survival in multiple large retrospective cohorts. This benefit is similar among patients with immunologically cold tumours. Together, these results demonstrate that clinically available mRNA vaccines targeting non-tumour-related antigens are potent immune modulators capable of sensitizing tumours to ICIs.

Keywords

Humans, Immune Checkpoint Inhibitors, B7-H1 Antigen, Neoplasms, COVID-19 Vaccines, CD8-Positive T-Lymphocytes, Animals, SARS-CoV-2, Female, Mice, Cancer Vaccines, Interferon Type I, mRNA Vaccines, COVID-19, Male, Vaccines, Synthetic, Immunity, Innate, Retrospective Studies, Antigens, Neoplasm, Cancer immunotherapy, RNA vaccines, Non-small-cell lung cancer, Melanoma, Cancer therapeutic resistance

Published Open-Access

yes

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