A convergent uPAR-positive tumor ecosystem creates broad vulnerability to CAR T cell therapy.
| Publication Type | Academic Article |
| Authors | Zhang Z, Ho Y, Fang X, Kim M, Li M, Luan W, Hinterleitner C, Haubner S, Kogel F, Pratt E, Ozcelik E, Reyes J, Jiang Q, Yang V, Chen Y, Wang T, Liu H, Hu H, Zhuang X, Park J, Paffenholz S, Chen K, Chang Q, Kulick A, Zhang J, Chan E, Rosiek E, Fan N, Williams R, Wang A, Freeman S, Tian S, Gunset G, Garcia Angus A, Lecomte N, Yildirim S, Ali E, Wu M, Miranda I, Antonescu C, Basturk O, Tarcan Z, Rekhtman N, Wilson C, Basar M, Sauter J, Al-Ahmadie H, Singer S, Iacobuzio-Donahue C, Rudin C, de Stanchina E, Ganesh K, Romesser P, Weigelt B, Huh D, Leibold J, Feucht J, Vázquez-García I, Bott M, Zamarin D, Shah S, Lewis J, Amor C, Pe'er D, Mansilla-Soto J, Filliol A, Sadelain M, Lowe S |
| Journal | Cell |
| Volume | 189 |
| Issue | 10 |
| Pagination | 2898-2917.e42 |
| Date Published | 03/30/2026 |
| ISSN | 1097-4172 |
| Keywords | Receptors, Urokinase Plasminogen Activator, Receptors, Chimeric Antigen, Immunotherapy, Adoptive, Neoplasms |
| 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 |
| PubMed ID | 41916312 |
| PubMed Central ID | PMC13372006 |