A Glucose Metabolism‐Modulatory Nanobiohybrid Vaccine Platform Promotes Anti‐Tumor Immunity by Orchestrating Autophagy‐Dependent Cross‐Presentation and H ₂ S‐Enhanced NLRP3 Inflammasome Signaling

ABSTRACT The clinical translation of cancer vaccines remains limited by the inability to effectively coordinate innate and adaptive immunity. Leveraging the metabolism pattern of the immune system, herein, we report a glucose metabolism‐modulatory nanobiohybrid vaccine with superior antitumor immunity via orchestrating cross‐presentation‐enhanced adaptive immunity and proinflammatory signaling‐mediated innate immunity. This nanobiohybrid vaccine is constructed by a nanoscale hydrogen‐bonded organic framework (HOF) co‐encapsulating glucose oxidase (GOx), and a model antigen, ovalbumin (OVA) (denoted OVA/GOx@HOF). OVA/GOx@HOF enables a GOx‐mediated enzyme reaction that consumes glucose and produces H ₂ O ₂ within dendritic cells (DCs) in controlled kinetics, which disrupts intracellular glucose metabolism and causes redox imbalance but minimally impacts cell viability. These effects induce autophagic machinery in DCs that promotes antigen cross‐presentation, thereby boosting cytotoxic T cell response. Meanwhile, through RNA sequencing, we found that OVA/GOx@HOF stimulates innate immunity through an NF‐κB signaling‐mediated and endogenous hydrogen sulfide (H ₂ S)‐enhanced NLRP3 inflammasome pathway, leading to significant DC maturation. In a melanoma tumor model, this nanobiohybrid vaccine effectively inhibits tumor growth and metastasis, and can be applied to encapsulate neoantigens to generate a potent personalized cancer vaccine. Our findings suggested the remarkable potential of enzyme‐driven nanobiohybrid materials as a metabolism‐modulatory platform for cancer vaccines.