Abstract

The stimulator of interferon genes (STING) has emerged as a promising target for cancer immunotherapy. However, STING agonists alone have demonstrated limited clinical success. Indoleamine 2,3-dioxygenase 1 (IDO1) has been implicated as a key resistance mechanism that undermines the antitumor effects of STING activation, yet the cell-type-specific roles and the combined impact of STING and IDO1 on tumor immune orchestration remain poorly understood. In this study, we report that a co-delivery nanosystem of STING agonists and IDO1 inhibitors, rather than their simple combination, yields synergistic antitumor responses. This nanomedicine exhibits tropism toward myeloid cell populations in vivo , particularly dendritic cells (DCs), and facilitates pH-responsive cytosolic delivery of both agents. As a result, it enhances antigen cross-presentation, DC maturation, and cytokine secretion, driving effective priming of cytotoxic T lymphocytes. Compared to monotherapies or physical nanoparticle combinations of STING agonists and IDO1 inhibitors, this two-in-one nanomedicine significantly suppresses tumor growth and confers a survival benefit. Depletion of STING in the host ( Tmem173 −/− mice) or deficiency in type I conventional DCs (cDC1s, Batf3 −/− mice) abolishes therapeutic efficacy, whereas depletion of STING in tumor cells exerts minimal impact. A bone marrow chimera experiment further supports the STING-cDC1 dependence. Its capability to overcome tumor resistance and the underlying mechanism were further investigated in a well-established tumor model. Our findings highlight the cooperative role of STING activation and IDO1 blockade within cDC1s and introduce an integrated drug delivery system to combat immune tolerance in cancer therapy.