{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:00:40Z","timestamp":1790125240898,"version":"4.0.1"},"reference-count":101,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>This review focuses on two core immunosuppressive mechanisms within the tumor immune microenvironment (TIME): the polarization of tumor\u2010associated macrophages (TAMs) towards an M2 phenotype and the functional exhaustion of CD8\u207a T cells. We systematically elucidate the multi\u2010dimensional strategies by which Traditional Chinese Medicine (TCM) remodels the TIME. The article first dissects the interplay between TAMs and CD8\u207a T cells and their pivotal role in tumor immune escape. It then comprehensively reviews how TCM formulations and active components, through their characteristic multi\u2010target actions, coordinately reverse TAM polarization and T cell exhaustion by modulating key signaling pathways (e.g., STAT, PI3K\/Akt), reprogramming cellular metabolism (e.g., glycolysis, oxidative phosphorylation), and reshaping cytokine networks. Particular emphasis is placed on metabolic reprogramming as an upstream \u201cbridging\u201d mechanism that concurrently regulates both processes. Finally, the review explores the synergistic potential of combining TCM with immune checkpoint inhibitors and analyzes current challenges, including compositional complexity, insufficient mechanistic depth, and a paucity of high\u2010quality clinical evidence. This work aims to provide a theoretical foundation and forward\u2010looking perspective for developing novel TCM\u2010based strategies in cancer immunotherapy.<\/jats:p>","DOI":"10.1002\/jbt.70854","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T12:14:37Z","timestamp":1777292077000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Remodeling the Tumor Immune Microenvironment by Traditional Chinese Medicine: Mechanisms Focusing on TAM Polarization and CD8\n                    <sup>+<\/sup>\n                    T Cell Exhaustion"],"prefix":"10.1002","volume":"40","author":[{"given":"Yannan","family":"Geng","sequence":"first","affiliation":[{"name":"Department of Pharmacy Affiliated Hospital of Shandong University of Traditional Chinese Medicine Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanjun","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Affiliated Hospital of Shandong University of Traditional Chinese Medicine Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Affiliated Hospital of Shandong University of Traditional Chinese Medicine Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinfeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Affiliated Hospital of Shandong University of Traditional Chinese Medicine Jinan Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changying","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Linyi People's Hospital Linyi Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1586-1141","authenticated-orcid":false,"given":"Guangze","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Linyi People's Hospital Linyi Shandong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,27]]},"reference":[{"issue":"3","key":"e_1_2_10_2_1","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray F.","year":"2024","journal-title":"CA: A Cancer Journal for Clinicians"},{"issue":"1","key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s12964-020-0530-4","article-title":"Tumor Microenvironment Complexity and Therapeutic Implications at a Glance","volume":"18","author":"Baghban R.","year":"2020","journal-title":"Cell Communication and Signaling"},{"issue":"16","key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"4188","DOI":"10.3390\/cancers15164188","article-title":"Decoding the Complexity of Immune\u2010Cancer Cell Interactions: Empowering the Future of Cancer Immunotherapy","volume":"15","author":"Maffuid K.","year":"2023","journal-title":"Cancers"},{"issue":"45","key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"5904","DOI":"10.1038\/onc.2008.271","article-title":"The Tumor Microenvironment and Its Role in Promoting Tumor Growth","volume":"27","author":"Whiteside T. 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