2. Academic Validation
  3. Modulating the PPARγ pathway upregulates NECTIN4 and enhances chimeric antigen receptor (CAR) T cell therapy in bladder cancer

Modulating the PPARγ pathway upregulates NECTIN4 and enhances chimeric antigen receptor (CAR) T cell therapy in bladder cancer

  • Nat Commun. 2025 Sep 10;16(1):8215. doi: 10.1038/s41467-025-62710-0.
Kevin Chang 1 2 3,  Henry M Delavan # 1 2,  Elizabeth Yip # 1 2,  Corynn Kasap 1 2 4,  Jun Zhu 1 5,  Roshan Lodha 1 2,  Sheng-You Liao 6,  Sarah C Berman 1 2,  Alberto Carretero-Gonzalez 1 2,  Merve Basar 7,  Gamze Gokturk Ozcan 7,  Min Yuen Teo 8,  David B Solit 8 9,  Jonathan E Rosenberg 8,  Hikmat Al-Ahmadie 7,  Cornelia C K Ding 1 10,  Emily Chan 1 10 11,  Veronica Steri 1,  Sima P Porten 1 3,  Vadim S Koshkin 1 2,  Terence W Friedlander 1 2,  Felix Y Feng 1 2 3 5,  John K Lee 6,  Arun P Wiita 1 4,  Carissa E Chu 1 3 9,  Jonathan Chou 12 13
Affiliations

Affiliations

  • 1 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
  • 2 Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA.
  • 3 Department of Urology, University of California, San Francisco, CA, USA.
  • 4 Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
  • 5 Department of Radiation Oncology, University of California, San Francisco, CA, USA.
  • 6 Division of Hematology/Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
  • 7 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 8 Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 9 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 10 Department of Pathology, University of California, San Francisco, CA, USA.
  • 11 Department of Pathology, Stanford University, Stanford, CA, USA.
  • 12 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA. jonathan.chou@ucsf.edu.
  • 13 Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA. jonathan.chou@ucsf.edu.
  • # Contributed equally.
PMID: 40931013 DOI: 10.1038/s41467-025-62710-0
Abstract

With the approval of the antibody-drug conjugate enfortumab vedotin (EV), NECTIN4 has emerged as a bona fide therapeutic target in urothelial carcinoma (UC). Here, we report the development of a NECTIN4-directed chimeric antigen receptor (CAR) T cell, which exhibits reactivity across cells expressing a range of endogenous NECTIN4, with enhanced activity in high expressors. We demonstrate that the PPARγ pathway, critical for luminal differentiation, transcriptionally controls NECTIN4, and that the PPARγ Agonist rosiglitazone primes and augments NECTIN4 expression, thereby increasing sensitivity to NECTIN4-CAR T cell-mediated killing. NECTIN4-CAR T cells have potent anti-tumor activity even against EV resistant cells, which largely retain NECTIN4 expression, including in a post-EV biopsy cohort. Our results elucidate a therapeutically actionable mechanism that UC cells use to control NECTIN4 expression and suggest therapeutic approaches that leverage PPARγ agonists for rational combinations with NECTIN4-targeting agents in UC, as well as future potential treatment options for EV-refractory patients.

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