Targeting STING-induced immune evasion with nanoparticulate binary pharmacology improves tumor control in mice

Harnessing the stimulator of IFN genes (STING) signaling pathway to trigger innate immune responses has shown remarkable promise in cancer immunotherapy; however, overwhelming resistance to intratumoral STING monotherapy has been witnessed in clinical trials, and the underlying mechanisms remain to be fully explored. Herein, we show that pharmacological STING activation following the intratumoral injection of a nonnucleotide STING agonist (i.e., MSA-2) resulted in apoptosis of the cytolytic T cells, IFN-mediated overexpression of indoleamine 2,3-dioxygenase 1 (IDO1), and evasion from immune surveillance. We leveraged a noncovalent chemical strategy for developing immunomodulatory binary nanoparticles (iBINP) that include both the STING agonist and an IDO1 inhibitor for treating immune-evasive tumors. This iBINP platform, developed by dual prodrug engineering and subsequent nanoparticle assembly, enabled tumor-restricted STING activation and IDO1 inhibition, achieving immune activation while mitigating immune tolerance. A systemic treatment of preclinical models of colorectal cancer with iBINP resulted in robust antitumor immune responses, reduced infiltration of Tregs, and enhanced activity of CD8+ T cells. Importantly, this platform exhibits great therapeutic efficacy by overcoming STING-induced immune evasion and controlling the progression of multiple tumor models. This study unveils the mechanisms by which STING monotherapy induces immunosuppression in the tumor microenvironment and provides a combinatorial strategy for advancing cancer immunotherapies.