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 Luis Reyes, Qingwen Jiang, Vincent W. Yang, Yu-Jung Chen, Tao Wang, Haijiao Liu, Haonan Hu, Xueqian Zhuang, J. H. Park, Stella Paffenholz, Kevin Chen, Qing Chang, Amanda Kulick, Jing Zhang, EM Chan, Eric Rosiek, Ning Fan, Riley A. Williams, Adam C. Wang, Samuel S. 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, S. J. Singer, Christine A. Iacobuzio-Donahue, Charles Rudin, Elisa de Stanchina, Karuna Ganesh, Paul B. Romesser, Britta Weigelt, Dan Dongeun Huh, Josef Leibold, J Feucht, Ignacio Vázquez-García, Matthew J. Bott, Dmitriy Zamarin, Sohrab P. Shah, Jason S. Lewis, Corina Amor, D. Pe’er, Jorge Mansilla-Soto, Aveline Filliol, Michel Sadelain, Scott W. Lowe
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.