Wu Jingjing, Deng Yuan, Gao Yong, Wei Bin
Department of Oncology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China.
Department of Hematology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai'an, China.
Cancer Immunol Immunother. 2025 Aug 25;74(9):293. doi: 10.1007/s00262-025-04150-9.
The prognosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is poor. Therefore, searching for new therapeutic agents is particularly important to improve therapeutic efficacy. Targeting the ubiquitin-proteasome system is a potential therapeutic strategy for treating DLBCL. In this study, we investigated the role of the deubiquitase inhibitor Spautin-1 in the treatment of DLBCL. Spautin-1 significantly inhibited the growth of DLBCL, including the growth of cells and transplanted tumors in mice. Notably, Spautin-1 showed enhanced tumor suppression in immune-competent versus immunodeficient mice models, mediated by CD8 T cell infiltration and activation. Mechanistically, Spautin-1 promotes PANoptosis by inducing mitochondrial damage mediated by USP13-ACLY inhibition in DLBCL cells, which in turn induces the release of injury-related molecular patterns and cytokines. Moreover, high USP13 expression in DLBCL is associated with poor prognosis and blocks CD8 T cell infiltration. In summary, Spautin-1 may inhibit the growth of DLBCL cells by promoting mitochondrial damage-mediated PANoptosis and anti-tumor immunity, providing a potential strategy for DLBCL therapy.
复发或难治性弥漫性大B细胞淋巴瘤（DLBCL）的预后较差。因此，寻找新的治疗药物对于提高治疗效果尤为重要。靶向泛素-蛋白酶体系统是治疗DLBCL的一种潜在治疗策略。在本研究中，我们研究了去泛素化酶抑制剂Spautin-1在DLBCL治疗中的作用。Spautin-1显著抑制了DLBCL的生长，包括细胞生长和小鼠体内移植瘤的生长。值得注意的是，在免疫健全与免疫缺陷小鼠模型中，Spautin-1通过CD8 T细胞浸润和激活表现出更强的肿瘤抑制作用。机制上，Spautin-1通过诱导DLBCL细胞中USP13-ACLY抑制介导的线粒体损伤来促进PAN凋亡，进而诱导损伤相关分子模式和细胞因子的释放。此外，DLBCL中USP13的高表达与预后不良相关，并阻碍CD8 T细胞浸润。总之，Spautin-1可能通过促进线粒体损伤介导的PAN凋亡和抗肿瘤免疫来抑制DLBCL细胞的生长，为DLBCL治疗提供了一种潜在策略。
