Here we report that the innate immune response to SARS-CoV-2 spike mRNA vaccination resets the cancer immunotherapy cycle and primes adaptive immunity for synergy with ICIs. We found that receipt of a SARS-CoV-2 mRNA vaccine within 100?days of ICI initiation was associated with substantial improvements in overall survival (OS) in patients with non-small cell lung cancer (NSCLC) and melanoma. In preclinical models, we found that this effect required a surge in type-I interferon (IFN) that enhanced antigen-presenting cell (APC) priming of T cells in lymphoid organs. Although tumour cells subvert these primed responses by increasing PD-L1 expression, co-administration of ICIs sustains T cell responses and elicits epitope spreading against tumour-associated antigens. We revealed analogous response correlates for humans receiving COVID-19 mRNA vaccines, including heightened IFNa production, innate/adaptive immune activation and increases in tumour PD-L1 expression. Together, our results demonstrate that clinically available mRNA vaccines targeting non-tumour antigens are potent immune modulators capable of sensitizing tumours to ICIs.