Metalloimmunological hydrogel-based cancer vaccine potentiates postoperative tumor immunotherapy

Abstract

Adjuvant immune checkpoint inhibitor (AICI) therapy is limited by inadequate durable immunological memory against tumor recurrence and metastasis. Herein, we present a metalloimmunological hydrogel-based and innate immunity-focused cancer vaccine (IT-Vax) that synergizes innate-adaptive crosstalk to potentiate AICI efficacy. Through systematic screening of 9 polysaccharide hydrogels with dual crosslinking (metal coordination/Schiff base), manganese-incorporated formulations demonstrate superior dendritic cell (DC) activation capacity through orchestrating innate immune pathways. The optimized IT-Vax, incorporating with a ROCK inhibitor and mitoxantrone-treated tumor cells functionally achieves five-pronged DC modulations: enhanced lymphatic migration, antigen presentation, costimulation, and priming of effector and memory T cells. Correspondingly, this multi-faceted activation translates in vivo into a marked accumulation of key DC subsets, including cDC1s and migratory DCs. Consequently, in therapeutic models, IT-Vax culminates in a robust cellular immune response, as attested by a 3.6-fold tumor growth suppression. Notably, in orthotopic breast cancer models, one-dose personalized IT-Vax combined with AICI therapy reduces postoperative metastasis by around 60% and extends median survival from 37 to over 100 days. This study establishes a personalized vaccine platform that mechanistically bridges innate immunostimulation with sustained adaptive memory, providing a strategy with translational potential to overcome the limitations of postoperative immunotherapy. Adjuvant immune checkpoint inhibitor (AICI) therapy is promising but suffers from inadequate durable immunological memory against tumor recurrence and metastasis. Here this group design a metalloimmunological hydrogel-based cancer vaccine that synergizes innate-adaptive crosstalk to potentiate AICI efficacy.