Microbiota-derived self-adjuvanting exopolysaccharide-based codelivery system for potent cancer immunotherapy

Abstract

Cancer vaccines hold great promise by eliciting antigen-specific T cell responses against tumors; however, their efficacy remains limited by poor coordination between antigen delivery and innate immune activation. Here, microbiota-derived metabolites (exopolysaccharides, EPSs) are presented as a self-adjuvanting codelivery system that simultaneously delivers the Toll-like receptor 7/8 (TLR7/8) agonist R848 and ovalbumin (OVA). This bi-adjuvant nanovaccine (EPS@R848/OVA) rapidly accumulates in draining lymph nodes (dLNs) as early as 6 h after administration and significantly enhances the uptake and activation of CD103+CD11b− conventional dendritic cells (cDCs), thereby facilitating efficient antigen cross-presentation and eliciting robust antigen-specific cytotoxic CD8+ T lymphocyte (CTL) responses. Importantly, the nanovaccine markedly inhibits primary and metastatic melanoma growth and remodels the tumor microenvironment (TME) by increasing CD8+ T cell infiltration. Furthermore, combining the nanovaccine with the anti-PD-1 antibody yields potent synergistic antitumor efficacy and prolonged survival in melanoma models. Mechanistically, it markedly promotes DC maturation and type I interferon production through synergistic activation of the Dectin-2-Syk-CARD9 and TLR7-MyD88-IRF7 pathways. Collectively, this work demonstrates that the microbiota-derived EPS-based codelivery system offers a simple and effective strategy for developing potent cancer vaccines.