Engineered virus-derived platform enables glutathione depletion and cuproptosis for enhanced cancer immunotherapy

Virus-derived platforms hold significant promise for drug delivery and cancer therapy; however, they face challenges related to stability and functional versatility. To address these limitations, we present a peptide derived from both the human immunodeficiency virus and influenza A virus, demonstrating its potential as an adjuvant and drug delivery platform. This peptide, especially when combined with polyphenols known for their affinity to a broad spectrum of biomolecules, offers promising therapeutic capabilities. The engineered neoadjuvant facilitates intracellular glutathione (GSH) depletion via in situ Michael addition reactions, thereby enhancing the synergistic effects of cuproptosis, immunogenic cell death (ICD), and dendritic cell (DC) maturation, while simultaneously improving structural stability. Moreover, the neoadjuvant serves as a versatile platform that can be further functionalized by loading model antigens, such as ovalbumin (OVA), or chemotherapeutic agents like doxorubicin (DOX). These multifunctional formulations can augment DC-mediated antigen presentation or enhance the ICD effects induced by DOX. Consequently, DOX-loaded formulations stimulate a potent antitumor immune response and significantly inhibit tumor growth and metastasis. This approach not only broadens the application scope of protein-based virus-derived platforms but also provides a new avenue for cancer immunotherapy.