近日，荷兰Oncode研究所Wilbert Zwart团队的最新研究探明了禁食通过糖皮质激素激活提高乳腺癌治疗效果。相关论文于2025年12月10日发表于国际顶尖学术期刊《自然》杂志上。

本研究表明，当与内分泌治疗联合时，禁食诱导ERα阳性乳腺癌异种移植物中广泛的表观遗传重编程，糖皮质激素受体（GR）和孕激素受体信号大规模激活，同时激活蛋白-1 （AP-1）家族成员活性降低。GR驱动的基因程序在ERα阳性乳腺癌体内模型中在禁食期间被选择性激活，GR敲除会阻碍禁食联合他莫昔芬的抗肿瘤作用。外源性给药GR配体再现了禁食增强的抗雌激素作用，它们促进肿瘤的消退。接受循环禁食模拟饮食的患者表现出血液中黄体酮和皮质醇浓度升高。

此外，模拟禁食饮食后收集的肿瘤显示GR激活与增殖标志物呈负相关，这为他们在动物模型中的观察提供了临床证实。他们的研究结果表明，GR激活在禁食增强乳腺癌内分泌治疗活性的能力中起着关键作用，并建议在这种情况下应评估皮质类固醇给药作为内分泌治疗的辅助手段。

研究人员表示，大多数乳腺癌是由雌激素受体-α (ERα)激活引起的，内分泌治疗是这些患者的主要治疗方法。然而，耐药性是常见的，肿瘤往往在内分泌抑制多年后继续发展。定期禁食可提高标准内分泌治疗的疗效，延缓获得性耐药，尽管其潜在机制尚不清楚。

附：英文原文

Title: Fasting boosts breast cancer therapy efficacy via glucocorticoid activation

Author: Padro, Nuno, Severson, Tesa M., Gregoricchio, Sebastian, Guijarro, Ana, Lutz, Catrin, Taranto, Daniel, Hutten, Stefan, Ligorio, Francesca, Persia, Angelica, Roest, Merel, Sanders, Joyce, Song, Ji-Ying, Pires-Oliveira, Sara, Donaldson Collier, Maria, Horlings, Hugo, Pisciotta, Livia, de Braud, Filippo, Vernieri, Claudio, Akkari, Leila, Jonkers, Jos, Nencioni, Alessio, Caffa, Irene, Zwart, Wilbert

Issue&Volume: 2025-12-10

Abstract: The majority of breast cancers are driven by oestrogen receptor-α (ERα) activation, and endocrine therapy represents the mainstay treatment for these patients1. However, resistance is common and tumours often progress after years of endocrine suppression2. Periodic fasting enhances the efficacy of standard endocrine therapy and delays acquired drug resistance, although the underlying mechanisms remain unclear3. Here we show that fasting induces extensive epigenetic reprogramming in ERα-positive breast cancer xenografts when combined with endocrine therapy, with large-scale activation of glucocorticoid receptor (GR) and progesterone receptor signalling and concomitant reduction in the activity of activator protein-1 (AP-1) family members. GR-driven gene programmes are selectively activated in in vivo models of ERα-positive breast cancer during fasting, and GR knockout hinders the anti-tumour effects of fasting combined with tamoxifen. Exogenous administration of GR ligands recapitulates fasting-enhanced anti-oestrogen action, thus promoting tumour regression. Patients undergoing a cyclic fasting-mimicking diet exhibited increased blood progesterone and cortisol concentrations. Additionally, tumours collected after the fasting-mimicking diet showed an inverse correlation of GR activation with proliferation markers, providing clinical confirmation of our observations in animal models. Our results indicate that GR activation has a pivotal role in the ability of fasting to enhance endocrine therapy activity in breast cancer and suggest that corticosteroid administration should be evaluated as an adjuvant to endocrine therapy in this setting.

DOI: 10.1038/s41586-025-09869-0

Source: https://www.nature.com/articles/s41586-025-09869-0