Immunologically modified enzyme-responsive micelles regulate the tumor microenvironment for cancer immunotherapy.

Immune checkpoint blockade has been proven to have great therapeutic potential and has revolutionized the treatment of tumors. However, various limitations remain, including the low response rate of exhausted T cells and mutual regulation of multiple immunosuppressive cell types that compromise the effect of single-target therapy. Nano-delivery systems can be used to regulate the tumor immune microenvironment in favor of immunotherapy. In this study, we constructed a polypeptide-based micellar system that encapsulates an aryl hydrocarbon receptor (AhR) inhibitor (CH223191) conjugated to T cell activator anti-CD28. The inhibition of AhR activation downregulates the fraction of immunosuppressive cells and effectively inhibits tumor cell metastasis. In addition, the combination with co-stimulatory antibodies improves T-cell activation and synergistically enhances the antitumor effect of AhR inhibitors. The micellar system developed in this study represents a novel and effective tumor immunotherapy approach.