H ₂ S Self‐Supplied Micelles Reverse Tumor‐Immune Effector Cells Energy Metabolisms to Boost Breast Cancer Immunotherapy With Microenvironment Normalization

Abstract

ABSTRACT Reversing the immunosuppressive tumor microenvironment by targeting metabolic competition between tumors and immune effector cells could induce tumor starvation and enhance the activity of immune cells, representing a potential approach to boost tumor immunotherapy. However, its actual efficacy is limited by compensatory oxidative phosphorylation (OXPHOS) energy replenishment and low delivery efficiency. Herein, we report a hydrogen sulfide (H 2 S)‐self‐supplying nanoplatform that orchestrates a dual blockade of glycolysis and OXPHOS for improved triple‐negative breast cancer (TNBC) immunotherapy. The micellar system, HA‐ADT@W, achieves tumor‐targeted delivery of a glycolysis inhibitor (WZB117) and H 2 S continually released in GSH‐overexpressed tumor cells. This strategy concurrently suppresses glucose uptake in tumor cells by reversing the acidic tumor microenvironment (TME) and disrupts compensatory OXPHOS via H 2 S‐mediated inhibition of cytochrome c oxidase. Consequently, we demonstrate a significant rewiring of tumor energy metabolism that not only induces immunogenic cell death with remodeling of the immunosuppressive TME but also alleviates nutrient constraints of immune effector cells, leading to enhanced infiltration and function of cytotoxic immune cells. This work exhibits a smart nanoplatform‐based H 2 S self‐supplied micelle for reinforced TNBC immunotherapy via regulated metabolic competition between tumors and immune effector cells with TME normalization.