Triple‐Combination Immunogenic Nanovesicles Reshape the Tumor Microenvironment to Potentiate Chemo‐Immunotherapy in Preclinical Cancer Models

Immune checkpoint blockade (ICB) therapies have had a tremendous impact on cancer therapy. However, most patients harbor a poorly immunogenic tumor microenvironment (TME), presenting overwhelming de novo refractoriness to ICB inhibitors. To address these challenges, combinatorial regimens that employ chemotherapies and immunostimulatory agents are urgently needed. Here, a combination chemoimmunotherapeutic nanosystem consisting of a polymeric monoconjugated gemcitabine (GEM) prodrug nanoparticle decorated with an anti-programmed cell death-ligand 1 (PD-L1) antibody (αPD-L1) on the surface and a stimulator of interferon genes (STING) agonist encapsulated inside is developed. Treatment with GEM nanoparticles upregulates PD-L1 expression in ICB-refractory tumors, resulting in augmented intratumor drug delivery in vivo and synergistic antitumor efficacy via activation of intratumor CD8+ T cell responses. Integration of a STING agonist into the αPD-L1-decorated GEM nanoparticles further improves response rates by transforming low-immunogenic tumors into inflamed tumors. Systemically administered triple-combination nanovesicles induce robust antitumor immunity, resulting in durable regression of established large tumors and a reduction in the metastatic burden, coincident with immunological memory against tumor rechallenge in multiple murine tumor models. These findings provide a design rationale for synchronizing STING agonists, PD-L1 antibodies, and chemotherapeutic prodrugs to generate a chemoimmunotherapeutic effect in treating ICB-nonresponsive tumors.