Wu Zhenghao, Zheng Peng, Qi Ruobing, Xiao Yunxiao, Xi Zihan, Dai Lei, Chen Tao, Wang Qianheng, Zhang Furong, Wang Rong, Tang Zimei, Zhao Xiangwang, Tan Jie, Ming Jie, Lei Ping, Liu Chunping, Huang Tao
Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Exp Hematol Oncol. 2025 Jul 24;14(1):100. doi: 10.1186/s40164-025-00692-x.
Dysfunction of cytotoxic T cells (CTL) remains a major cause of tumor immune evasion and is correlated with poor cancer survival. Here, we found that increased soluble form of ICOSL (sICOSL) induced CTL dysfunction and was associated with shorter survival of patients with breast cancer. sICOSL emerged as a formidable adversary to CTLs, by directly triggering ICOS internalization and subsequent degradation-a critical blow to the co-stimulatory machinery essential for CTL activation. Our research shows that dipeptidyl peptidase-4 (DPP4) mainly breaks down sICOSL. Notably, certain chemotherapeutic drugs activate the histone methyltransferase Enhancer of zeste homolog 2 (EZH2), which in turn suppresses DPP4 expression. To address this issue, we have developed nanobody-DPP4 fusion proteins that can specifically degrade sICOSL, achieving substrate selectivity and tumor targeting. Overall, This work unveils that sICOSL orchestrates CTL dysfunction, and establishs targeted degradation of sICOSL as a new strategy for immunotherapy.
细胞毒性T细胞（CTL）功能障碍仍然是肿瘤免疫逃逸的主要原因，并且与癌症患者的不良生存状况相关。在此，我们发现可溶性ICOSL（sICOSL）水平升高会诱导CTL功能障碍，并与乳腺癌患者的较短生存期相关。sICOSL成为CTL的强大对手，它通过直接触发ICOS内化及随后的降解，这对CTL激活所必需的共刺激机制是一个关键打击。我们的研究表明，二肽基肽酶4（DPP4）主要负责分解sICOSL。值得注意的是，某些化疗药物会激活组蛋白甲基转移酶zeste同源物2增强子（EZH2），而EZH2反过来会抑制DPP4的表达。为了解决这个问题，我们开发了纳米抗体-DPP4融合蛋白，它可以特异性降解sICOSL，实现底物选择性和肿瘤靶向性。总体而言，这项工作揭示了sICOSL导致CTL功能障碍，并确立了靶向降解sICOSL作为一种新的免疫治疗策略。
