Zhang Yongli, Li Cang, Chen Jianxin
School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing 102488, China.
Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Zhejiang Provincial Clinical Research Center for CANCER; Cancer Center of Zhejiang University, Hangzhou 310058, China.
Int Immunopharmacol. 2025 Dec 3;166:115567. doi: 10.1016/j.intimp.2025.115567. Epub 2025 Sep 22.
Melanoma is a highly aggressive malignancy, and resistance to immune checkpoint inhibitors (ICIs) remains particularly pronounced in acral and mucosal subtypes among Chinese patients. A key driver of this resistance is glycolysis-driven lactate accumulation, which fosters an immunosuppressive tumor microenvironment (TME). Salvianolic acid B (Sal B), a natural compound derived from Salvia miltiorrhiza, has shown therapeutic promise, but its anti-melanoma mechanism remains largely undefined. Here, we used network pharmacology to predict the potential core targets of Sal B in melanoma, and validated the antitumor effect of Sal B in A375 cells and xenograft mouse models. Sal B markedly inhibited cell proliferation, migration, and invasion, induced G2/M cell cycle arrest and apoptosis, and suppressed glycolytic activity. In vivo, Sal B significantly reduced tumor growth, and transcriptomic profiling revealed upregulation of immune-related genes, including those in the TNF pathway. Consistently, Sal B treatment increased the proportions of NK and CD8 T cells, indicating that it may reshape the TME through metabolic reprogramming and immune activation. Compared to single-agent ICIs, Sal B offers dual metabolic-immune modulation, providing a new avenue for integrative immunotherapy in refractory melanoma prevalent in Chinese patients. Its natural origin and multi-target features may further reduce toxicity and enhance therapeutic precision, supporting the development of personalized treatment strategies.
黑色素瘤是一种侵袭性很强的恶性肿瘤，在中国患者中，肢端和黏膜亚型对免疫检查点抑制剂（ICI）的耐药性尤为明显。这种耐药性的一个关键驱动因素是糖酵解驱动的乳酸积累，它会形成一个免疫抑制性肿瘤微环境（TME）。丹酚酸B（Sal B）是一种从丹参中提取的天然化合物，已显示出治疗前景，但其抗黑色素瘤机制在很大程度上仍不明确。在此，我们利用网络药理学预测了Sal B在黑色素瘤中的潜在核心靶点，并在A375细胞和异种移植小鼠模型中验证了Sal B的抗肿瘤作用。Sal B显著抑制细胞增殖、迁移和侵袭，诱导G2/M期细胞周期阻滞和凋亡，并抑制糖酵解活性。在体内，Sal B显著降低肿瘤生长，转录组分析显示免疫相关基因上调，包括肿瘤坏死因子（TNF）途径中的基因。一致地，Sal B治疗增加了自然杀伤（NK）细胞和CD8 T细胞的比例，表明它可能通过代谢重编程和免疫激活重塑TME。与单药ICI相比，Sal B具有双重代谢免疫调节作用，为中国患者中普遍存在的难治性黑色素瘤的综合免疫治疗提供了一条新途径。其天然来源和多靶点特性可能进一步降低毒性并提高治疗精准度，支持个性化治疗策略的开发。
