SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade

Immune checkpoint inhibitors (ICIs) extend survival in many patients with cancer but are ineffective in patients without pre-existing immunity<sup>1-9</sup>. 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 processes<sup>10-14</sup>. 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<sup>+</sup> 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.

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Journal
Nature
Published
2025-10-22
DOI
https://doi.org/10.1038/s41586-025-09655-y
Citations
49
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
51.22
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article

SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade

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Cancer Immunotherapy and Biomarkers
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SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade

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article en
49 citations

Abstract

Immune checkpoint inhibitors (ICIs) extend survival in many patients with cancer but are ineffective in patients without pre-existing immunity<sup>1-9</sup>. 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 processes<sup>10-14</sup>. 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<sup>+</sup> 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.

NatureVol. 647(8089)
University of North Carolina at Chapel Hill (US), Scripps Health (US), Allen Institute for Brain Science (US), Ascension (US), Oracle (United States) (US), The University of Texas MD Anderson Cancer Center (US), Sarah Cannon Research Institute (GB), Baylor College of Medicine (US), Medical College of Wisconsin (US), Peter MacCallum Cancer Centre (AU), University of Florida Health (US), University of Florida (US), Sarah Cannon (US), Office of Multidisciplinary Activities (US), Monash University (AU), Florida College (US), Stanford University (US)
Openalex Percentile: Top 0%
Cancer Immunotherapy and Biomarkers
51.22
DOIOpen Access PDFOpenAlex
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