{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T20:37:15Z","timestamp":1782506235589,"version":"3.54.5"},"reference-count":184,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,26]],"date-time":"2022-12-26T00:00:00Z","timestamp":1672012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82274018"],"award-info":[{"award-number":["82274018"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Hepatocellular carcinoma (HCC), the most prevalent subtype of liver cancer, is the second main reason for cancer-related deaths worldwide. In recent decades, sufficient evidence supported that immunotherapy was a safe and effective treatment option for HCC. However, tolerance and frequent recurrence and metastasis occurred in patients after immunotherapy due to the complicated crosstalk in the tumor immunosuppressive microenvironment (TIME) in HCC. Therefore, elucidating the TIME in HCC and finding novel modulators to target TIME for attenuating immune suppression is critical to optimize immunotherapy. Recently, studies have shown the potentially immunoregulatory activities of natural compounds, characterized by multiple targets and pathways and low toxicity. In this review, we concluded the unique role of TIME in HCC. Moreover, we summarized evidence that supports the hypothesis of natural compounds to target TIME to improve immunotherapy. Furthermore, we discussed the comprehensive mechanisms of these natural compounds in the immunotherapy of HCC. Accordingly, we present a well-grounded review of the naturally occurring compounds in cancer immunotherapy, expecting to shed new light on discovering novel anti-HCC immunomodulatory drugs from natural sources.<\/jats:p>","DOI":"10.3390\/molecules28010195","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T03:03:31Z","timestamp":1672110211000},"page":"195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Potential of Compounds Originating from the Nature to Act in Hepatocellular Carcinoma Therapy by Targeting the Tumor Immunosuppressive Microenvironment: A Review"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5622-7787","authenticated-orcid":false,"given":"Yunheng","family":"Li","sequence":"first","affiliation":[{"name":"Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaojun","family":"He","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochun","family":"Yang","sequence":"additional","affiliation":[{"name":"Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"},{"name":"Shandong (Linyi) Institute of Modern Agriculture, Zhejiang University, Linyi 276000, China"},{"name":"Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,26]]},"reference":[{"key":"ref_1","unstructured":"(2021). 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