GSH-responsive nanovaccine triggers immunogenic cell death and potent memory T cell immunity for durable, recurrence-free tumor eradication.

Abstract

Although nanovaccines hold promise for cancer immunotherapy, the engineering platforms that respond to tumor-specific cues and activate antitumor immunity remains challenging. Herein, a glutathione (GSH)-responsive immunogenic nanovaccine (SHINE) is developed, integrating immunogenic cell death (ICD)-inducing chemodynamic therapy (CDT) with immunotherapy to elicit synergistic <i>in situ</i> antitumor immunity. Constructed from a hollow MnO₂ nanostructure, SHINE selectively degrades in GSH-enriched tumors, depleting intracellular GSH while releasing Mn²⁺ to catalyze Fenton-like reactive oxygen species generation. Concurrently, SHINE facilitates the controlled release of the TLR7/8 agonist R848 and, through surface-conjugated anti-PD-L1 antibodies, enables immune checkpoint blockade and enhances active tumor targeting. This design integrates CDT as the "initiator" and R848/anti-PD-L1 as dual immune "boosters," thereby eliciting a synergistic cascade that drives potent ICD and promotes dendritic cell maturation and T cell priming. Transcriptomics confirms robust immune activation, while <i>in vivo</i> SHINE suppresses both primary tumor growth and lung metastasis. Remarkably, SHINE establishes durable immune memory, characterized by elevated effector memory T cells and upregulation of memory T cell-related genes, thereby conferring rechallenge protection and preventing tumor recurrence. Collectively, SHINE represents a robust <i>in situ</i> cancer nanovaccine for systemic, long-term tumor control.