近日，中山大学宋尔卫及其小组研究出化疗诱导的乳腺癌CA重复DNA片段引发抗肿瘤免疫反应。2025年9月29日，国际知名学术期刊《自然—免疫学》发表了这一成果。

本研究表明，在低MSH2肿瘤中，DNA损伤化疗产生的富含CA的DNA片段以强亲和力优先结合cGAS，并在细胞质中通过相分离形成生物分子凝聚物，从而产生抗肿瘤免疫。

然而，高MSH2肿瘤细胞释放的经典CA-poor DNAs参与AIM2，通过上调PD-L1和IDO导致免疫抑制。肿瘤内给予富含CA的DNA片段增强了合成PyMT肿瘤的抗肿瘤免疫。临床上，化疗后乳腺癌中CA-富DNA丰度与肿瘤抗原反应性T细胞增加和更好的化疗反应相关。因此，不同的肿瘤DNA片段可以触发相反的免疫反应，这取决于它们对差异传感器的偏好。这项研究强调了基因组不稳定性和免疫调节之间的另一种机制联系，以及富含CA的DNA增强抗肿瘤免疫的治疗潜力。

研究人员表示，癌症治疗产生的损伤相关分子模式可以调节抗肿瘤免疫，但这种作用的潜在机制尚不清楚。

附：英文原文

Title: Chemotherapy-induced CA-repeat DNA fragments in breast cancer trigger antitumor immune responses

Author: Zhang, Xiaoqian, Huang, Penghan, Chen, Huiping, Yang, Chaoqun, Yang, Xinyu, Liu, Yujie, Wu, Baixing, Zeng, Wenfeng, Saw, Phei Er, Ye, Shuying, Li, Jiaqian, Wang, Jiayi, Wu, Zizhen, Wang, Jiawen, Li, Heliang, Huang, Jian-Dong, Zeng, Musheng, Li, Mengfeng, Liu, Qiang, Su, Shicheng, Song, Erwei, Chen, Jianing

Issue&Volume: 2025-09-29

Abstract: Damage-associated molecular patterns generated by cancer treatment can modulate antitumor immunity, but the underlying mechanisms of this effect are unclear. Here we show that CA-enriched DNA fragments resulting from DNA-damaging chemotherapy in MSH2-low tumors preferentially bind cGAS with strong affinity and form biomolecular condensates by phase separation in the cytoplasm, resulting in antitumor immunity. However, classical CA-poor DNAs released from MSH2-high tumor cells engage AIM2, resulting in immunosuppression by upregulating PD-L1 and IDO. Intratumoral administration of CA-rich DNA fragments enhanced antitumor immunity in syngrafted PyMT tumors. Clinically, CA-rich DNA abundance in breast cancer following chemotherapy was associated with increased tumor-antigen-reactive T cells and better chemotherapeutic responses. Therefore, different tumor DNA fragments can trigger opposing immune responses depending on their preference for differential sensors. This study highlights another mechanistic link between genome instability and immune modulation and the therapeutic potential of CA-rich DNAs to enhance antitumor immunity.

DOI: 10.1038/s41590-025-02289-2

Source: https://www.nature.com/articles/s41590-025-02289-2