Polymeric-based neoantigen nanovaccine synergizes with PD-1/PD-L1 modulators, reprogramming the melanoma microenvironment.

Programmed cell death protein 1 (PD-1) and its ligand PD-L1 are targets of immune checkpoint blockade (ICB) therapies that have shown promise in cancer treatment. However, their effectiveness is often hindered by resistance mechanisms such as poor tumor immunogenicity, T-cell exhaustion, insufficient T-cell infiltration, and an immunosuppressive tumor microenvironment (TME). Overcoming these barriers requires strategies to enhance tumor immunogenicity and modulate the TME. In this study, we present a nanoparticle-based strategy to enhance melanoma immunotherapy and overcome ICB resistance. We developed a mannose-grafted poly(lactic-co-glycolic) acid (PLGA) nanovaccine designed to target dendritic cells and deliver melanoma neoantigens, thereby promoting T-cell activation. When combined with PD-1/PD-L1 pathway modulators, including a monoclonal antibody (αPD-L1) and a novel small-molecule inhibitor (SM56), this nanovaccine significantly suppressed tumor growth in an aggressive, ICB-resistant B16F10 melanoma mouse model and enhanced T-cell infiltration into the TME. Notably, only the combination with SM56 reduced the infiltration of immunosuppressive cell populations within the TME. These findings highlight the potential of polymeric nanovaccines to overcome key resistance mechanisms limiting ICB efficacy and underscore the promise of novel small-molecule inhibitors as effective alternatives to monoclonal antibodies in melanoma immunotherapy.