Lu Jiahui, Zhang Tinghuang, Jiang Chenying, Hu Hongtao, Fei Yunxuan, Yang Yaqin, An Hai, Qin Haixin, Zhu Zhihui, Yang Yanzi, Tian Shasha, Huang Lili, Zhao Huajun
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 311402, China.
Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
Int Immunopharmacol. 2025 Aug 28;161:114989. doi: 10.1016/j.intimp.2025.114989. Epub 2025 Jun 7.
BACKGROUND: The tumor microenvironment (TME) plays a crucial role in cancer progression, with tumor-associated macrophages (TAMs) constituting the core cell population of the tumor immune microenvironment. TAMs can differentiate into M1 or M2 types based on the TME, either inhibiting or promoting tumor development. Ganoderma lucidum, a medicinal and edible fungus, has a long history of use for extending lifespan and improving health. Ganoderic acid A (GAA), a bioactive compound extracted from G. lucidum, is considered the most abundant monomer among ganoderic acids and has wide applications in clinical anti-tumor therapies. METHODS: In this study, the effects of GAA against hepatocellular carcinoma (HCC) by modulating TAMs were investigated. The orthotopic and subcutaneous HCC mouse models were established and administrated with GAA at doses of 30 mg/kg/day and 60 mg/kg/day. Additionally, the toxicity of GAA towards tumor cells and macrophages in vitro at concentrations ranging from 25 to 100 μM were evaluated and the phagocytic capacity of macrophages against HCC cells were assessed. The polarization of macrophages was analyzed, along with the expression of CSF1R. RESULTS: Our data demonstrated that GAA could suppress the growth of both orthotopic and subcutaneous HCC, which was closely associated with macrophage modulation, confirming that its anti-HCC activity was mediated by enhancing macrophage efficacy. GAA exhibited no significant toxicity to tumor cells and macrophages in vitro while enhancing the phagocytic capacity of macrophages against HCC cells. Furthermore, GAA promoted M1 polarization of macrophages while inhibiting M2 polarization. These effects were mechanistically linked to the suppression of CSF1R expression on macrophages, both in vivo and in vitro. CONCLUSION: Our findings suggest that GAA exerts immunotherapeutic effects in HCC by regulating macrophage polarization through CSF1R inhibition. As a promising natural bioactive compound with the potential to modulate the TME of HCC, GAA may provide novel insights into HCC immunotherapy through the reprogramming of TAMs.
背景：肿瘤微环境（TME）在癌症进展中起关键作用，肿瘤相关巨噬细胞（TAM）构成肿瘤免疫微环境的核心细胞群。TAM可根据TME分化为M1或M2型，分别抑制或促进肿瘤发展。灵芝是一种药食两用真菌，长期以来用于延年益寿和改善健康。灵芝酸A（GAA）是从灵芝中提取的一种生物活性化合物，被认为是灵芝酸中含量最丰富的单体，在临床抗肿瘤治疗中有广泛应用。 方法：本研究探讨GAA通过调节TAM对肝细胞癌（HCC）的影响。建立原位和皮下HCC小鼠模型，并分别以30mg/kg/天和60mg/kg/天的剂量给予GAA。此外，评估了GAA在25至100μM浓度下对体外肿瘤细胞和巨噬细胞的毒性，并评估了巨噬细胞对HCC细胞的吞噬能力。分析了巨噬细胞的极化情况以及集落刺激因子1受体（CSF1R）的表达。 结果：我们的数据表明，GAA可抑制原位和皮下HCC的生长，这与巨噬细胞调节密切相关，证实其抗HCC活性是通过增强巨噬细胞功效介导的。GAA在体外对肿瘤细胞和巨噬细胞无明显毒性，同时增强了巨噬细胞对HCC细胞的吞噬能力。此外，GAA促进巨噬细胞向M1极化，同时抑制M2极化。这些作用在体内和体外机制上均与抑制巨噬细胞上CSF1R的表达有关。 结论：我们的研究结果表明，GAA通过抑制CSF1R调节巨噬细胞极化，从而在HCC中发挥免疫治疗作用。作为一种有潜力调节HCC肿瘤微环境的天然生物活性化合物，GAA可能通过对TAM的重编程为HCC免疫治疗提供新的见解。
Int Immunopharmacol. 2025-8-28
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