Abstract
The clinical efficacy of immune checkpoint blockade (ICB) therapy is significantly compromised in the metabolically disordered tumor microenvironment (TME), posing a formidable challenge that cannot be ignored in current antitumor strategies. In this study, TME-responsive nanoparticles (HMP1G NPs) loaded with 1-methyltryptophan (1-MT; an indoleamine 2,3-dioxygenase 1 [IDO1] inhibitor,) and S-nitrosoglutathione (GSNO; a nitric oxide donor) is developed to enhance the therapeutic efficacy of 1-MT-mediated ICB. The HMP1G NPs responded to H+ and glutathione in the TME, releasing Mn2+, GSNO, and 1-MT. The released Mn2+ catalyzed the production of abundant reactive oxygen species and nitric oxide from hydrogen peroxide and GSNO, and the generated nitric oxide, synergistically with 1-MT, inhibited the accumulation of kynurenine mediated by IDO1 in the tumor. Mechanistically, HMP1G NPs downregulated tumor cell-derived IDO1 via the aryl hydrocarbon receptor/signal transducer and activator of transcription 3/interleukin signaling axis to improve kynurenine/tryptophan metabolism and immunosuppression. In a murine breast cancer model, treatment with HMP1G NPs elicited effective antitumor immunity and enhanced survival outcomes. This study highlights a novel nano-platform that simultaneously improves metabolism and enhances ICB efficacy to achieve a new and efficient antitumor strategy.