A convergent uPAR-positive tumor ecosystem creates broad vulnerability to CAR T cell therapy PMID: 41916312

Target-related Cytokines

2026-09-23

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

Cell. 2026 May 14;189(10):2898-2917.e42. doi: 10.1016/j.cell.2026.03.002.

Zeda Zhang ¹ , Yu-Jui Ho ¹ , Xin Fang ¹ , Minseo Kim ² , Marguerite Li ¹ , Wei Luan ¹ , Clemens Hinterleitner ¹ , Sascha Haubner ³ , Friederike Kogel ⁴ , Edwin C Pratt ⁵ , Elif Ozcelik ² , José Reyes ⁶ , Qingwen Jiang ⁵ , Vincent W Yang ¹ , Yu-Jung Chen ¹ , Tao Wang ² , Haijiao Liu ⁷ , Haonan Hu ⁷ , Xueqian Zhuang ¹ , Jin Park ⁸ , Stella V Paffenholz ⁹ , Kevin Chen ¹⁰ , Qing Chang ¹⁰ , Amanda Kulick ¹⁰ , Jing Zhang ⁴ , Eric Chan ¹¹ , Eric Rosiek ¹¹ , Ning Fan ¹¹ , Riley A Williams ¹⁰ , Adam C Wang ¹² , Samuel Freeman ¹³ , Sha Tian ¹ , Gertrude Gunset ³ , Andreina Garcia Angus ³ , Nicolas Lecomte ¹⁴ , Selma Yeni Yildirim ¹⁴ , Emily Ali ¹⁴ , Michelle Wu ¹³ , Ileana C Miranda ¹⁵ , Cristina R Antonescu ¹⁴ , Olca Basturk ¹⁴ , Zeynep Tarcan ¹⁴ , Natasha Rekhtman ¹⁴ , Christina Wilson ¹⁴ , Merve Basar ¹⁴ , Jennifer L Sauter ¹⁴ , Hikmat A Al-Ahmadie ¹⁴ , Samuel Singer ¹⁶ , Christine Iacobuzio-Donahue ¹⁴ , Charles Rudin ¹⁷ , Elisa de Stanchina ¹⁰ , Karuna Ganesh ⁵ , Paul B Romesser ¹⁸ , Britta Weigelt ¹⁴ , Dan Dongeun Huh ⁷ , Josef Leibold ¹⁹ , Judith Feucht ²⁰ , Ignacio Vázquez-García ²¹ , Matthew J Bott ²² , Dmitriy Zamarin ²³ , Sohrab P Shah ¹³ , Jason S Lewis ²⁴ , Corina Amor ²⁵ , Dana Pe'er ²⁶ , Jorge Mansilla-Soto ²⁷ , Aveline Filliol ²⁸ , Michel Sadelain ²⁹ , Scott W Lowe ³⁰

Affiliations

1. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Graduate School of Medical Sciences, New York, NY, USA.
3. Columbia Initiative in Cell Engineering and Therapy, Department of Medicine, Columbia University, New York, NY, USA.
4. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
6. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
7. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA.
8. Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
9. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, NY, USA.
10. Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
11. Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
12. Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY, USA.
13. Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
14. Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
15. Laboratory of Comparative Pathology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and The Rockefeller University, New York, NY, USA.
16. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
17. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
18. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
19. Cluster of Excellence iFIT (EXC 2180) "Image-guided and Functionally Instructed Tumor Therapies", Department of Medical Oncology and Pneumology, University Children's Hospital Tübingen, Germany.
20. Cluster of Excellence iFIT, (EXC 2180) "Image-guided and Functionally Instructed Tumor Therapies", University Children's Hospital Tübingen, Tübingen, Germany.
21. Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology, Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
22. Thoracic Service, Department of Surgery, Fiona and Stanley Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
23. Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
24. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
25. Cold Spring Harbor Laboratory, New York, NY, USA.
26. Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
27. Departments of Immunology, Bioengineering, Blood and Marrow Transplant and Cellular Immunotherapies, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
28. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: [email protected].
29. Columbia Initiative in Cell Engineering and Therapy, Department of Medicine, Columbia University, New York, NY, USA. Electronic address: [email protected].
30. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: [email protected].

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.

Keywords

CAR T cells; fibrosis; p53; senescence; senolytic; tumor microenvironment; uPAR.