Abstract

Despite remarkable advances in cancer immunotherapy, immunoresistance remains a critical barrier to its broader success. To address this challenge, we develop an adjuvant system that combines polyinosinic:polycytidylic acid (poly(I:C)) with QS-21 and functions as an in situ cancer vaccine, effectively boosting antitumor immunity across diverse tumor types. This synergistic formulation leverages QS-21-mediated cytosolic delivery of poly(I:C) to potentiate the TBK1-IRF3-type I interferon axis. This activation licenses robust IRF1 nuclear translocation as a downstream transcriptional integrator, thereby inducing immunogenic cell death in tumor cells. Intratumoral administration of this system enhances dendritic cell maturation and neoantigen presentation, which elicits a robust neoantigen-specific T cell response and generates protective immune memory that prevents tumor recurrence. Moreover, the adjuvant sensitizes tumors to anti-PD-1 therapy and, when combined with microwave ablation, significantly improves antitumor efficacy. Collectively, this approach offers a promising strategy to overcome immunoresistance and advance combination immunotherapies.