Bioresponsive nanoreactor initiates cascade reactions for tumor vascular normalization and lactate depletion to augment immunotherapy.

Abstract

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment. However, abnormal tumor vasculature and excess lactate contribute to tumor immunosuppression and confer resistance to ICB therapy, seriously limiting its clinical application. Here, we have developed a bioresponsive nanoreactor, ALMn, which consists of hollow manganese dioxide nanoparticles with encapsulation of lactate oxidase and L-Arginine, to overcome immunosuppression and sensitize ICB therapy. In the tumor microenvironment, lactate oxidase catalyzes lactate to produce hydrogen peroxide, which subsequently oxidizes L-Arginine to generate nitric oxide for vascular normalization. Through cascade reactions, ALMn effectively depletes excess lactate and normalize tumor vasculature, reshaping the immunosuppressive phenotype to an immune-activated one. Transcriptomics and immunological analyses prove that ALMn facilitates the infiltration and activation of effector cells, further potentiating antitumor immunity. Consequently, ALMn sensitizes anti-PD-L1 therapy, significantly suppressing tumor growth with an 83.7 % suppression, and prolonging the survival of mice, with the median survival time increasing from 29.5 days to 54.5 days. Our study demonstrates that ALMn effectively alleviates tumor immunosuppression and synergizes with anti-PD-L1, which shows promise in boosting ICB therapy.