Chirality-dependent reshaping of immunosuppressive microenvironment for gas/chemodynamic enhanced immunotherapy

The complex tumor microenvironment (TME) turns into a tumor-supportive environment that protects tumor cells while erecting obstacles to antitumor therapy. Herein, a chiral nanosystem (L-/D-Cu CDs) with multienzyme-like and NO-generating activities was designed to efficiently remodel the tumor immunosuppressive microenvironment and achieve gas/chemodynamic enhanced immunotherapy by chirality-dependent interactions with biological systems. D-Cu CDs exhibited a stronger binding affinity for the CD47 receptor on tumor cell surfaces compared to L- and DL-Cu CDs, facilitating their internalization through clathrin-mediated endocytosis. Additionally, D-Cu CDs acted as homeostatic regulators, generating reactive species, O₂ and NO to disrupt redox and copper homeostasis, as well as alleviating hypoxia of TME, which co-activated tumor cells apoptosis and cuproptosis while efficiently inducing an immune response with the macrophages repolarized from the anti-inflammatory M2 phenotype to the pro-inflammatory M1. In vitro and in vivo results confirmed the immunostimulatory efficacy and tumor inhibition capability of D-Cu CDs, validating their ability to remodel the tumor immunosuppressive microenvironments and achieve gas/chemodynamic enhanced immunotherapy. This work not only elucidates the mechanism of chiral Cu CDs-mediated reshaping of tumor immunosuppressive microenvironments but also offers a novel perspective for the application of chiral nanomaterials in antitumor therapy.