Work

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

Year: 2025

Type: article

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.

Source: Advanced Science

DOI: 10.1002/advs.202508107