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.