Regulating Tumor Metabolic Reprogramming with Biomimetic Co‐Delivery of Simvastatin and Kynureninase for Immunotherapy

Abstract The metabolic reprogramming of immunosuppressive tumor microenvironment (ITME) greatly influences the anti‐tumor immunity. Bioinformatic analysis demonstrates that indoleamine 2,3‐dioxygenase 1 and 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase (key enzymes of kynurenine (Kyn) and cholesterol metabolism, respectively), are overexpressed in human colon adenocarcinoma tissues. Herein, biomimetic and pH/ROS dual‐responsive nanoparticles (PTSK@CRM) loaded with simvastatin and kynureninase (KYNase) are prepared to regulate Kyn and cholesterol metabolism, thereby enhancing the immunotherapeutic efficacy of PD‐1 antibody (αPD‐1). The monodisperse spherical PTSK@CRM is stable at pH 7.4, while it can release simvastatin and KYNase under low pH and high H 2 O 2 concentration. PTSK@CRM achieves excellently homologous tumor targeting to CT26 cells and induces cell apoptosis more effectively than PTSK. Moreover, PTSK@CRM significantly reduces the contents of Kyn and cholesterol and decreases the activation of the Kyn‐AhR pathway in tumor metabolism. In vivo experiments show that PTSK@CRM possesses a favorable tumor‐targeting ability to effectively suppress tumor growth and increase the infiltration of immune cells, including CD8 + T cells, CD4 + T cells, M1‐like macrophages, and mature dendritic cells. Further, PTSK@CRM reduces the infiltration of immunosuppressive cells, thereby reversing ITME to improve the therapeutic efficacy of αPD‐1. Overall, this immune‐metabolic therapeutic strategy provides a potential route for remodeling ITME to enhance tumor immunotherapy.