LAUSR

The unprecedented success of mRNA vaccines against COVID‐19 has inspired scientists to develop mRNA vaccines for cancer immunotherapy. However, using nucleoside modified mRNA as vaccine, though evading innate immune toxicity, diminishes its therapeutic efficacy for cancers. Here, we report a polyvalent stimulator of interferon genes (STING) activating polymer (termed as PD) to bolster the immunogenicity of mRNA vaccine. PD is made of tertiary amine units and conjugated with a biodegradable alkyl chain. Co‐formulation of PDs bearing different number of tertiary amines with lipid materials and mRNA resulted in the lipid‐like nanoparticles (PD LNPs) which effectively promoted lymphatic delivery and elicited robust immune activation via the STING signaling pathway. Notably, PD with eighteen tertiary amines (PD18) is predominant in balancing immune activity and tolerability. Subcutaneous administration of PD18 LNPs containing ovalbumin (OVA) mRNA enhanced the frequency of antigen specific CD8+ T cell with immune memory, leading to potent anticancer efficacy that surpassed 2′3’‐cGAMP in both prophylactic and therapeutic cancer models. Additionally, PD18 LNP‐based mRNA vaccine showed conferred resistance to cancer challenge for up to 60 days. Overall, this study offers a new perspective of using STING‐ activating polymer for imparting synergistic activity in mRNA vaccine‐based cancer immunotherapy.