Chen Yu, Qi Yiming, Jiang Yulan, Li Ying, Yang Shaoxue, Wang Lu, Li Mingqian, Chai Kequn, Wang Yifan
School of Pharmacy, Hangzhou Normal University, Hangzhou, China; Zhejiang Key Laboratory of Disease-Syndrome Integration for Cancer Prevention and Treatment, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China.
Zhejiang Key Laboratory of Disease-Syndrome Integration for Cancer Prevention and Treatment, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province, Hangzhou, China.
Bioorg Med Chem. 2025 Nov 1;129:118317. doi: 10.1016/j.bmc.2025.118317. Epub 2025 Jul 12.
Colorectal cancer (CRC) progression is influenced by intricate interactions in the tumor microenvironment (TME), with M2-polarized macrophages being key players in enhancing tumor growth and suppressing the immune response. Icariin (ICA), a bioactive flavonoid isolated from Epimedium brevicornu Maxim., exhibits potential antitumor properties. Nevertheless, its role in modulating macrophage-mediated immunosuppression in CRC remains unclear. To assess ICA's effects on CRC malignancy within an M2-enriched microenvironment, we established a CRC cell/M2 macrophage co-culture system. ICA suppressed CRC cell proliferation, migration, and invasion in co-culture with M2 macrophages. M2 polarization markers and PI3K/AKT pathway modulation were analyzed by western blot and qRT-PCR. Mechanistic studies revealed that ICA inhibited M2 polarization and suppressed the phosphorylation of PI3K and AKT. In vivo validation utilized two models, an AOM/DSS-induced CRC model and a syngeneic CT26-WT implantation system, evaluating both tumor progression and macrophage phenotype alterations. We found that ICA attenuated tumor growth and reduced M2 macrophage infiltration. Collectively, these finding demonstrated that ICA suppressed M2 macrophage polarization via PI3K/AKT signaling pathway, thereby inhibiting CRC progression. This study reveals a previously unrecognized mechanism by which ICA inhibits CRC and demonstrates its potential as a promising therapeutic agent for CRC treatment.
结直肠癌（CRC）的进展受肿瘤微环境（TME）中复杂相互作用的影响，M2极化的巨噬细胞是促进肿瘤生长和抑制免疫反应的关键因素。淫羊藿苷（ICA）是从短角淫羊藿中分离出的一种生物活性黄酮，具有潜在的抗肿瘤特性。然而，其在调节CRC中巨噬细胞介导的免疫抑制方面的作用仍不清楚。为了评估ICA在富含M2的微环境中对CRC恶性肿瘤的影响，我们建立了CRC细胞/M2巨噬细胞共培养系统。ICA在与M2巨噬细胞共培养时抑制了CRC细胞的增殖、迁移和侵袭。通过蛋白质免疫印迹法和定量逆转录聚合酶链反应分析了M2极化标志物和PI3K/AKT信号通路的调节。机制研究表明，ICA抑制M2极化并抑制PI3K和AKT的磷酸化。体内验证采用了两种模型，即AOM/DSS诱导的CRC模型和同基因CT26-WT植入系统，评估肿瘤进展和巨噬细胞表型改变。我们发现ICA减弱了肿瘤生长并减少了M2巨噬细胞浸润。总的来说，这些发现表明ICA通过PI3K/AKT信号通路抑制M2巨噬细胞极化，从而抑制CRC进展。本研究揭示了ICA抑制CRC的一种以前未被认识的机制，并证明了其作为CRC治疗有前景的治疗剂的潜力。
