加州大学Matthew J. Hangauer团队的一项最新研究提出了DNA断裂因子B抑制干扰素，使癌细胞再生。这一研究成果发表在2025年11月17日出版的国际学术期刊《自然—细胞生物学》上。

在这里，该团队报告了残留的癌症持续细胞在肿瘤基因靶向治疗中存活下来，被药物应激诱导的内在I型干扰素信号阻滞生长。为了避免生长停滞，持久性细胞利用凋亡机制来转录抑制干扰素刺激基因（ISGs）。从机制上讲，持久性细胞亚致命性地与凋亡的胱天蛋白酶结合，激活DNA内切酶DNA片段化因子B（也称为胱天蛋白酶激活的DNase），从而诱导DNA损伤、诱变和应激反应因子激活转录因子3 （ATF3）。ATF3充分限制了激活蛋白1介导的ISG表达，从而允许持久性细胞再生。缺乏DNA断裂因子B或ATF3的持久性细胞表现出高的ISG表达，因此无法再生。因此，亚致死性凋亡应激矛盾地促进了药物治疗后残留癌细胞的再生。

据介绍，针对癌基因的癌症治疗可以提供深层的反应，但经常遭受获得性耐药。由于肿瘤的持续进化和多种共同发生的耐药机制，治疗获得耐药的肿瘤的治疗方法变得复杂。与其在耐药性出现后进行治疗，还不如通过抑制引发耐药性的适应性过程来预防它，但人们对这些还知之甚少。

附：英文原文

Title: DNA fragmentation factor B suppresses interferon to enable cancer persister cell regrowth

Author: Williams, August F., Gervasio, David A. G., Turkal, Claire E., Stuhlfire, Anna E., Wang, Michael X., Mauch, Brandon E., Plawat, Rhea, Nguyen, Ariel H., Paw, Michelle H., Hairani, Mehrshad, Lathrop, Cooper P., Harris, Sophie H., Page, Jennifer L., Hangauer, Matthew J.

Issue&Volume: 2025-11-17

Abstract: Oncogene-targeted cancer therapies can provide deep responses but frequently suffer from acquired resistance. Therapeutic approaches to treat tumours that have acquired drug resistance are complicated by continual tumour evolution and multiple co-occurring resistance mechanisms. Rather than treating resistance after it emerges, it may be possible to prevent it by inhibiting the adaptive processes that initiate resistance, but these are poorly understood. Here we report that residual cancer persister cells that survive oncogene-targeted therapy are growth arrested by drug stress-induced intrinsic type I interferon signalling. To escape growth arrest, persister cells leverage apoptotic machinery to transcriptionally suppress interferon-stimulated genes (ISGs). Mechanistically, persister cells sublethally engage apoptotic caspases to activate DNA endonuclease DNA fragmentation factor B (also known as caspase-activated DNase), which induces DNA damage, mutagenesis and stress response factor activating transcription factor 3 (ATF3). ATF3 limits activator protein 1-mediated ISG expression sufficiently to allow persister cell regrowth. Persister cells deficient in DNA fragmentation factor B or ATF3 exhibit high ISG expression and are consequently unable to regrow. Therefore, sublethal apoptotic stress paradoxically promotes the regrowth of residual cancer cells that survive drug treatment.

DOI: 10.1038/s41556-025-01810-x

Source: https://www.nature.com/articles/s41556-025-01810-x