黄芪四君子汤通过cGAS-STING通路调控TAMs代谢重编程促进M1极化抑制前列腺癌进展的研究

Investigating the Mechanism of Huangqi Sijunzi Decoction in Promoting M1 Polarization and Suppressing Prostate Cancer Progression via cGAS-STING Pathway-Mediated Metabolic Reprogramming of Tumor-Associated Macrophages (TAMs)

摘要: 目的：探讨黄芪四君子汤对前列腺癌荷瘤小鼠肿瘤进展的影响及机制。方法：建立C57BL/6小鼠前列腺癌荷瘤模型，随机分为模型对照组、PD-1单抗组、中药 + PD-1单抗组、中药 + PD-1单抗 + STING抑制剂组，每组5只，记录小鼠肿瘤大小及质量。检测外周血IFN-γ、TNF-α、TGF-β指标变化。qRT-PCR检测M1/M2巨噬细胞标志物，IL-12和TNF-α (M1标志物)，IL-10和Arg 1 (M2标志物)的表达。Western blot方法检测通路蛋白表达变化。结果：与PD-1单抗治疗组相比，联合中药治疗组明显抑制肿瘤生长，联合STING抑制剂使用，则消减中药组的抗肿瘤疗效；与模型对照组相比，中药联合PD-1单抗可以显著提高TNF-α水平、降低TGF-β水平，差异具有统计学意义(P < 0.05)，这一作用较PD-1单抗治疗组更明显，联合STING抑制剂使用，则逆转这一现象；中药治疗组增加了M1标志物IL-12和TNF-α，降低了M2标志物IL-10和Arg 1的表达；中药治疗组STING蛋白表达水平显著升高，在使用STING抑制剂之后，中药治疗所产生的促M1极化作用随之降低。结论：黄芪四君子汤通过cGAS-STING通路重塑M2型TAMs向M1型极化，改善肿瘤免疫抑制微环境，增敏前列腺癌的免疫治疗效力，发挥抗肿瘤免疫的作用。

Abstract: Objective: To investigate the therapeutic effects and underlying mechanisms of Huangqi Sijunzi Decoction (HSD) on tumor progression in a prostate cancer bearing mice. Methods: Prostate cancer xenografts were established in C57BL/6 mice and randomly divided into: (1) Model control, (2) PD-1 mAb group, (3) HSD + PD-1 mAb, and (4) HSD + PD-1 mAb + STING inhibitor. Tumor volume and weight were monitored. Serum levels of IFN-γ, TNF-α, and TGF-β were measured. M1/M2 macrophage polarization was assessed via qRT-PCR for markers (IL-12/TNF-α for M1; IL-10/Arg1 for M2). Pathway proteins were analyzed by Western blot. Results: Compared to PD-1 monotherapy, the HSD combination group showed significantly enhanced tumor suppression (P < 0.05), which was attenuated by STING inhibition. HSD+PD-1 markedly increased TNF-α while decreasing TGF-β levels versus controls (P < 0.05), effects that were reversed by STING inhibition. HSD upregulated M1 markers (IL-12/TNF-α) and downregulated M2 markers (IL-10/Arg1). STING protein expression was significantly elevated in the HSD group, while STING inhibitor abolished HSD-induced M1 polarization. Conclusion: HSD reprograms M2-type tumor-associated macrophages (TAMs) toward M1 polarization via the cGAS-STING pathway, thereby ameliorating the immunosuppressive tumor microenvironment and enhancing anti-PD-1 efficacy in prostate cancer.