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This study investigated the therapeutic potential of the Antrodia cinnamomea formula (XIANZHIFANG formula, XZF), comprising Antrodia cinnamomea, Sanghuangporus sanghuang, Ganoderma lucidum, Ganoderma sinense, and Inonotus obliquus, in prostate cancer treatment. HPLC analysis confirmed the presence of key triterpenoids, including Antcin A, B, C, K, and Zhankuic acid B, C, and 4,7-dimethoxy-5-methyl-1,3-benzodioxole. Cytotoxicity assays demonstrated that XZF (50\u2013200 \u03bcg\/mL) exhibited selective activity, maintaining viability in non-cancerous 293T-cells while enhancing the viability of activated CD8+ and CD4+ T-cells in a dose-dependent manner. XZF significantly reduced PD-1 expression in CD8+ T-cells but not in CD4+ T-cells and inhibited the PD-L1\/PD-1 interaction, achieving 93% inhibition at 200 \u03bcg\/mL. Furthermore, when combined with atezolizumab (1 \u03bcg\/mL), XZF demonstrated complete blockade of PD-L1\/PD-1 interaction. In prostate cancer cells, XZF exhibited differential antiproliferative effects. In PC-3 cells, XZF significantly reduced viability across a concentration range of 25\u2013200 \u03bcg\/mL, whereas DU145 cells showed only partial inhibition at higher concentrations (100\u2013200 \u03bcg\/mL). LNCaP cells exhibited a dose-dependent reduction in viability, mirroring the response pattern of PC-3 cells. Conditioned medium from XZF-treated macrophages, particularly human THP-1 cells, significantly suppressed the viability and migration of prostate cancer cells in a dose-dependent manner. Notably, the conditioned medium from XZF-treated THP-1 cells exhibited a stronger inhibitory effect on prostate cancer cell viability and migration compared to murine RAW 264.7 macrophages. These findings indicate that XZF exerts its therapeutic potential through multiple mechanisms, including direct antiproliferative effects on cancer cells, enhancement of T-cell responses, modulation of immune checkpoint pathways, and macrophage-mediated suppression of prostate cancer cell survival and migration. The pronounced effects observed in human macrophage models suggest a promising avenue for further investigation in clinical settings, particularly in combination with existing immunotherapies.<\/jats:p>","DOI":"10.3390\/ijms26062684","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T06:36:23Z","timestamp":1742193383000},"page":"2684","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Antrodia cinnamomea Formula Suppresses Prostate Cancer Progression via Immune Modulation and PD-1\/PD-L1 Pathway Inhibition"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7722-3331","authenticated-orcid":false,"given":"Ming-Yen","family":"Tsai","sequence":"first","affiliation":[{"name":"Department of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chung-Kuang","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-Hsin","family":"Shu","sequence":"additional","affiliation":[{"name":"Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hung-Te","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Huei","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Shih","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Chiayi Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao-Hsu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"},{"name":"School of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Health Information and Epidemiology Laboratory, Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4995-5364","authenticated-orcid":false,"given":"Wei-Tai","family":"Shih","sequence":"additional","affiliation":[{"name":"Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I-Yun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Heng","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Communications Engineering, The National Yang Ming Chiao Tung University, Hsinchu City 300093, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching-Yuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi 613016, Taiwan"},{"name":"School of Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan"},{"name":"Center for Drug Research and Development, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 33303, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. 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