美国纪念斯隆-凯特琳癌症中心Scott W. Lowe小组的一项最新研究提出了趋同的uPAR阳性肿瘤生态系统对CAR-T细胞治疗具有广泛的脆弱性。该项研究成果发表在2026年3月30日出版的《细胞》上。
课题组研究人员之前发现尿激酶纤溶酶原激活剂受体（uPAR）在衰老的促纤维化细胞中上调，并表明uPAR导向的CAR-T细胞可以安全地逆转小鼠的纤维化。综合分析显示，uPAR在富含TP53和RAS通路突变的实体瘤中广泛表达。这些肿瘤采用由具有衰老特征的uPAR阳性基质细胞支持的祖细胞样状态。人类uPAR CAR-T细胞消除肿瘤细胞及其基质支持，在不同的模型中诱导持久的退化，根除全身转移，并通过诱导衰老的疗法增强。重要的是，这些细胞在用人类免疫系统重建的小鼠中实现了完全的抗肿瘤活性，而没有持续的骨髓抑制。总之，这些发现确立了uPAR作为一种广泛适用的CAR-T靶点，能够克服实体肿瘤治疗中的主要障碍。
据介绍，嵌合抗原受体（CAR） T细胞已经改变了血液学癌症治疗，但由于抗原异质性和促纤维化微环境的抑制，在实体肿瘤中仍然受到限制。
附：英文原文
Title: A convergent uPAR-positive tumor ecosystem creates broad vulnerability to CAR T cell therapy
Author: Zeda Zhang, Yu-Jui Ho, Xin Fang, Minseo Kim, Marguerite Li, Wei Luan, Clemens Hinterleitner, Sascha Haubner, Friederike Kogel, Edwin C. Pratt, Elif Ozcelik, José Reyes, Qingwen Jiang, Vincent W. Yang, Yu-Jung Chen, Tao Wang, Haijiao Liu, Haonan Hu, Xueqian Zhuang, Jin Park, Stella V. Paffenholz, Kevin Chen, Qing Chang, Amanda Kulick, Jing Zhang, Eric Chan, Eric Rosiek, Ning Fan, Riley A. Williams, Adam C. Wang, Samuel Freeman, Sha Tian, Gertrude Gunset, Andreina Garcia Angus, Nicolas Lecomte, Selma Yeni Yildirim, Emily Ali, Michelle Wu, Ileana C. Miranda, Cristina R. Antonescu, Olca Basturk, Zeynep Tarcan, Natasha Rekhtman, Christina Wilson, Merve Basar, Jennifer L. Sauter, Hikmat A. Al-Ahmadie, Samuel Singer, Christine Iacobuzio-Donahue, Charles Rudin, Elisa de Stanchina, Karuna Ganesh, Paul B. Romesser, Britta Weigelt, Dan Dongeun Huh, Josef Leibold, Judith Feucht, Ignacio Vázquez-García, Matthew J. Bott, Dmitriy Zamarin, Sohrab P. Shah, Jason S. Lewis, Corina Amor, Dana Pe’er, Jorge Mansilla-Soto, Aveline Filliol, Michel Sadelain, Scott W. Lowe
Issue&Volume: 2026-03-30
Abstract: Chimeric antigen receptor (CAR) T cells have transformed hematologic cancer therapy but remain limited in solid tumors by antigen heterogeneity and a suppressive, pro-fibrotic microenvironment. We previously identified the urokinase plasminogen activator receptor (uPAR) as upregulated in senescent, pro-fibrotic cells and showed that uPAR-directed CAR T cells could safely reverse fibrosis in mice. Integrative analyses now reveal that uPAR is broadly expressed in solid tumors enriched for TP53 and RAS pathway mutations. These tumors adopt a progenitor-like state supported by a niche of uPAR-positive stromal cells with senescence features. Human uPAR CAR T cells eliminate tumor cells and their stromal support, induce durable regressions across diverse models, eradicate systemic metastases, and are potentiated by senescence-inducing therapies. Importantly, these cells achieve robust antitumor activity without sustained myelosuppression in mice reconstituted with human immune systems. Together, these findings establish uPAR as a broadly applicable CAR T target capable of overcoming major barriers in solid tumor therapy.
DOI: 10.1016/j.cell.2026.03.002
Source: https://www.cell.com/cell/abstract/S0092-8674(26)00269-2