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Bioinformatic analysis demonstrates that indoleamine 2,3\u2010dioxygenase 1 and 3\u2010hydroxy\u20103\u2010methylglutaryl 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\u2010responsive nanoparticles (PTSK@CRM) loaded with simvastatin and kynureninase (KYNase) are prepared to regulate Kyn and cholesterol metabolism, thereby enhancing the immunotherapeutic efficacy of PD\u20101 antibody (\u03b1PD\u20101). The monodisperse spherical PTSK@CRM is stable at pH 7.4, while it can release simvastatin and KYNase under low pH and high H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    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\u2010AhR pathway in tumor metabolism. In vivo experiments show that PTSK@CRM possesses a favorable tumor\u2010targeting ability to effectively suppress tumor growth and increase the infiltration of immune cells, including CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, M1\u2010like macrophages, and mature dendritic cells. Further, PTSK@CRM reduces the infiltration of immunosuppressive cells, thereby reversing ITME to improve the therapeutic efficacy of \u03b1PD\u20101. Overall, this immune\u2010metabolic therapeutic strategy provides a potential route for remodeling ITME to enhance tumor immunotherapy.\n                  <\/jats:p>","DOI":"10.1002\/advs.202508107","type":"journal-article","created":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T10:37:48Z","timestamp":1766486268000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Regulating Tumor Metabolic Reprogramming with Biomimetic Co\u2010Delivery of Simvastatin and Kynureninase for Immunotherapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Jiaxin","family":"Yin","sequence":"first","affiliation":[{"name":"Department of Cancer Center The First Hospital of Jilin University  Changchun 130012 China"},{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education School of Life Sciences Jilin University  Changchun 130012 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of Education School of Life Sciences Jilin University  Changchun 130012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education School of Life Sciences Jilin University  Changchun 130012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziling","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cancer Center The First Hospital of Jilin University  Changchun 130012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4115-7552","authenticated-orcid":false,"given":"Quanshun","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education School of Life Sciences Jilin University  Changchun 130012 China"},{"name":"China\u2010Singapore Belt and Road Joint Laboratory on Liver Disease Research The First Hospital of Jilin University  Changchun 130012 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