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Background Personalized mRNA vaccines sensitize tumors to ICIs in part by unleashing a cytokine/chemokine cascade that broadly activates immune cells. Since this cascade is not dependent on mRNA species, we hypothesized that mRNA vaccines encoding non-tumor-specific antigens might also be used to reset immunotolerance and sensitize response to ICIs.Methods We utilized institutional databases to extract clinical data for patients with Stage IV non-small cell lung cancer (NSCLC) (n=2406) and metastatic melanoma (n=757) with biopsy specimens between August 2019 and August 2023, as well as a separate ‘tissue agnostic’ cohort with pathology reports quantifying ‘PD-L1’ from August 2020 to November 2023 (n=5,524). We utilized subcutaneous murine melanoma (B16F0) and NSCLC (LLC) to understand mechanisms of antitumor immunity, and analyzed blood samples from a cohort of healthy volunteers (n=5) after SARS-COV-2 mRNA vaccination with NULISA-Seq and flow cytometry.Results Multivariate analysis of our retrospective cohort revealed that receipt of an mRNA vaccine within 100 days of initiating ICI was associated with a near doubling of OS among patients with Stage IV NSCLC (555 days vs 1120 days, adj HR 0.5, 95% CI 0.4-0.7) and Stage IV melanoma (HR 0.42, 95% CI 0.24-0.74, p=0.003). Survival benefits were concentrated in patients with TPS < 1% compared to those with TPS 1-50% (HR 0.4, 95% CI 0.31-0.63 vs HR 0.67, 95% CI 0.40-1.13). In contrast, OS was unchanged for vaccinated patients who did not receive ICI. In preclinical models, SARS-COV-2 mRNA vaccines enhanced the antitumor immunity achieved with PD1 or PDL1-directed ICIs against established B16F0 (p<0.001) and LLC (p<0.001). In these models, SARS-CoV-2 mRNA vaccines stimulate a massive surge in IFN-α that drives systemic innate immune activation, leading to expansion of tumor-reactive, tumor-infiltrating T cells, and increased PD-L1 expression on tumor cells quantified by both flow cytometry and immunofluorescence. In healthy humans, SARS-COV-2 mRNA vaccines were associated with similar increases in IFN-α (>265-fold change over baseline, p<0.001), myeloid activation, and T cell activation. In patients, SARS-CoV-2 mRNA vaccines were associated with a 23% increase in mean tumor proportion score (TPS) of PD-L1 in patients with NSCLC (31% vs 26%, p=0.029) and a 55% increase in mean TPS (14% vs 8.9%, p=0.029) in the tissue agnosticConclusions SARS-COV-2 mRNA vaccines stimulate expansion of tumor-reactive T cells in preclinical models and are associated with improved sensitivity to ICIs in patients with immunologically ‘cold’ tumors.Ethics Approval This study was completed with approval of the MD Anderson Cancer Center IRB under protocol 2020-0348.