近日，美国丹娜-法伯癌症研究所教授Judith Agudo及其小组开发出糖皮质激素-FAS轴控制转移接种期间的免疫逃避。相关论文发表在2026年3月4日出版的《自然》杂志上。

在这里，研究人员在同源CD8⁺ T细胞的三阴性乳腺癌模型中注入一种可见抗原，以研究早期转移接种中的免疫逃避机制。对存活的DTC的分析显示，糖皮质激素受体（GR）激活是对CD8⁺ T细胞和自然杀伤细胞耐药的关键驱动因素。利用优化的标记工具进行生态位分析，发现FAS-FASL是抑制DTC的关键泛细胞毒性途径，该途径被GR激活抑制。GR联合免疫治疗的药理学抑制降低了小鼠的转移负担，延长了小鼠的寿命。他们发现了一种在DTC中特异性起作用的免疫逃避机制，阐明了转移级联中这一阶段独特的免疫-癌症相互作用。他们的研究结果表明，除了针对原发性肿瘤的治疗外，还有消除DTC的治疗机会，而抑制GR是一个有希望的目标。

据了解，转移是三阴性乳腺癌和其他实体恶性肿瘤患者死亡的主要原因。癌细胞从原来的肿瘤中扩散，在系统免疫监视下存活下来，并在新器官中定居。对于播散性肿瘤细胞（DTC）在播散新器官后如何克服抗肿瘤免疫，研究组知之甚少。

附：英文原文

Title: A glucocorticoid–FAS axis controls immune evasion during metastatic seeding

Author: Cassandras, Monica, Sanchez, Xavier, Hsu, Lauren, Huang, Yu, Getzler, Adam J., Ganguly, Debolina, Baldominos, Pilar, Codinachs, Ia, Chuong, Jeffrey, Martin, Elizabeth E., Smith, Blake E., Marina, Eleonora, Spasic, Milos, Qin, Xingping, Parsons, Heather A., Mayer, Erica L., Sarosiek, Kristopher A., Dougan, Stephanie K., Mittendorf, Elizabeth A., McAllister, Sandra S., Hsu, Ya-Chieh, Agudo, Judith

Issue&Volume: 2026-03-04

Abstract: Metastasis is the major cause of death for patients with triple-negative breast cancer and other solid malignancies. Metastases arise from cancer cells that disseminate from the original tumour, survive systemic immune surveillance and colonize new organs1. Little is known about how initial disseminated tumour cells (DTCs) overcome anti-tumour immunity after seeding a new organ. Here we use a visible antigen in a model of triple-negative breast cancer with cognate CD8+ T cells to study the mechanisms of immune evasion in early metastatic seeding. Analysis of surviving DTCs revealed glucocorticoid receptor (GR) activation as a key driver of resistance to both CD8+ T cells and natural killer cells. Niche profiling using an optimized labelling tool identified FAS–FASL as a key pan-cytotoxic pathway against DTCs, which is repressed by GR activation. Pharmacological inhibition of GR in combination with immunotherapy reduced metastatic burden and expanded lifespan in mice. Thus, we identified a mechanism of immune evasion that operates specifically in DTCs, illustrating the unique immune–cancer interactions at this stage in the metastatic cascade. Our findings suggest that there are therapeutic opportunities to eliminate DTCs, separately from treatments aimed at primary tumours, and GR inhibition is one promising target.

DOI: 10.1038/s41586-026-10222-2

Source: https://www.nature.com/articles/s41586-026-10222-2