A convergent uPAR-positive tumor ecosystem creates broad vulnerability to CAR T cell therapy

Zhang, Zeda, Ho, Yu-Jui, Fang, Xin, Kim, Minseo, Li, Marguerite, Luan, Wei, Hinterleitner, Clemens, Haubner, Sascha, Kogel, Friederike, Pratt, Edwin C, Ozcelik, Elif, Reyes, José, Jiang, Qingwen, Yang, Vincent W, Chen, Yu-Jung, Wang, Tao, Liu, Haijiao, Hu, Haonan, Zhuang, Xueqian, Park, Jin, Paffenholz, Stella V, Chen, Kevin, Chang, Qing, Kulick, Amanda, Zhang, Jing, Chan, Eric, Rosiek, Eric, Fan, Ning, Williams, Riley A, Wang, Adam C, Freeman, Samuel, Tian, Sha, Gunset, Gertrude, Garcia Angus, Andreina, Lecomte, Nicolas, Yildirim, Selma Yeni, Ali, Emily, Wu, Michelle, Miranda, Ileana C, Antonescu, Cristina R, Basturk, Olca, Tarcan, Zeynep, Rekhtman, Natasha, Wilson, Christina, Basar, Merve, Sauter, Jennifer L, Al-Ahmadie, Hikmat A, Singer, Samuel, Iacobuzio-Donahue, Christine, Rudin, Charles, de Stanchina, Elisa, Ganesh, Karuna, Romesser, Paul B, Weigelt, Britta, Huh, Dan Dongeun, Leibold, Josef, Feucht, Judith, Vázquez-García, Ignacio, Bott, Matthew J, Zamarin, Dmitriy, Shah, Sohrab P, Lewis, Jason S, Amor, Corina, Pe'er, Dana, Mansilla-Soto, Jorge, Filliol, Aveline, Sadelain, Michel, Lowe, Scott W (March 2026) A convergent uPAR-positive tumor ecosystem creates broad vulnerability to CAR T cell therapy. Cell, 189 (10). 2898-2917.e42. ISSN 0092-8674

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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.

Item Type:	Paper
Subjects:	diseases & disorders diseases & disorders > neoplasms organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence
CSHL Authors:	Amor, Corina
Communities:	CSHL labs > Amor lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	30 March 2026
Date Deposited:	22 May 2026 12:23
Last Modified:	22 May 2026 12:23
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/42208

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