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

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 H₂O₂ 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.