Facile integration of a binary nano-prodrug with αPD-L1 as a translatable technology for potent immunotherapy of TNBC.

Immune checkpoint blockers (ICBs)-based immunotherapy is a favorable approach for efficient triple-negative breast cancer (TNBC) treatment. However, the therapeutic efficacy of ICBs is greatly compromised by immunosuppressive tumor microenvironments (TMEs) and low expression levels of programmed cell death ligand-1 (PD-L1). Herein, we constructed an amphiphilic prodrug by linking a hydrophobic STING agonist, MSA-2 and a hydrophilic chemotherapeutic drug, gemcitabine (GEM) via an ester bond, which can self-assemble into GEM-MSA-2 (G-M) nanoparticles (NPs) with a tumor growth inhibition (TGI) value of 87.1 % in a murine 4T1 transplantation tumor model. Notably, the immunogenic cell death (ICD)-triggering effect of GEM together with the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation properties of MSA-2 enables efficient infiltration of non-exhausting T cells and repolarization of macrophages from M2 to M1 types in the tumor microenvironment for transforming a cold tumor to a hot one. Most importantly, G-M NPs treatment increases the PD-L1 expression levels, thus providing a unique opportunity for further integration with anti-PD-L1 monoclonal antibody (αPD-L1) for eliciting stronger immunity that ultimately leads to a TGI value of 98.0 % in the primary tumor and significantly protects against distal and disseminated tumor rechallenge. Overall, this study presents a minimalist nano-prodrug combined with αPD-L1 as a simple yet robust translatable nanotechnology for potent chemo-immunotherapy of TNBC. STATEMENT OF SIGNIFICANCE: Enhancing the therapeutic efficacy of αPD-L1 for tumor immunotherapy via a translatable technology remains a challenge. We report herein facile integration of a binary nano-prodrug with αPD-L1 for potent immunotherapy of TNBC. An amphiphilic prodrug is constructed by linking a hydrophobic STING agonist, MSA-2 and a hydrophilic chemotherapeutic drug, gemcitabine (GEM) via an ester bond. The resulting self-assembled GEM-MSA-2 (G-M) nanoparticles (NPs) show a tumor growth inhibition (TGI) value of 87.1 % in a murine 4T1 transplantation tumor model. Besides the induced immunogenic cell death (ICD) and activated cGAS-STING pathway, G-M NPs increase the PD-L1 expression levels, providing a unique opportunity for further integration with αPD-L1 to elicit stronger immunity that ultimately leads to a TGI value of 98.0 % in the primary tumor and significantly protects against distal and disseminated tumor rechallenge.