Abstract

Stimulator of interferon genes (STING) is a promising therapeutic target against cancer by bridging the innate and adaptive immunity. However, STING-based monotherapy shows compromised efficacy and dose-limited toxicity in early-stage clinical trials. Here we reveal that indoleamine 2, 3-dioxygenase 1 (IDO1) serves as an inherent negative regulator of STING signaling in dendritic cells to restrain antitumor immune responses. Besides as a consequence of STING signaling that contributes to immune suppression, IDO1 concurrently suppresses STING activity via its metabolites, thus establishing a negative feedback loop. Building on this insight, we develop a two-in-one nanosystem (SIANP) perturbing this inhibitory machinery to amplify STING-mediated antitumor activity. SIANP accumulates at tumor tissues, displays tropism toward dendritic cells in vivo , and facilitates cytosolic co-delivery of STING agonist and IDO1 siRNA at single-cell level, leading to elevated antigen presentation and CD8 + T cell priming with reduced T cell exhaustion or toxicity. This coordination suppresses tumor growth and prolongs survival in multiple established, metastatic, and recurrent tumor models. Remarkably, blockade of IDO1 by SIANP significantly amplifies STING signaling in resected human patient tissues. This work presents a robust nanoengineering approach to overcome immune tolerance arising from negative feedback loops for advanced cancer immunotherapy.