2. Academic Validation
  3. FGFR inhibitors promote the autophagic degradation of IFN-γ-induced PD-L1 and alleviate the PD-L1-mediated transcriptional suppression of FGFR3-TACC3 in non-muscle-invasive bladder cancer

FGFR inhibitors promote the autophagic degradation of IFN-γ-induced PD-L1 and alleviate the PD-L1-mediated transcriptional suppression of FGFR3-TACC3 in non-muscle-invasive bladder cancer

  • Cell Death Dis. 2025 Jul 2;16(1):485. doi: 10.1038/s41419-025-07821-8.
Yu-Chen Lin 1 2,  Cheng-Ying Chu 3 4,  Tsung-Han Hsieh 5,  Bo-Jyun Lin 1 2,  Jing-Ping Liou 6,  Yun Yen 7 8,  Chun-Han Chen 9 10 11
Affiliations

Affiliations

  • 1 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 2 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 3 CRISPR Gene Targeting Core, Taipei Medical University, Taipei, Taiwan.
  • 4 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
  • 5 Precision Health Center, Taipei Medical University, Taipei, Taiwan.
  • 6 School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 7 Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
  • 8 Center for Cancer Translational Research, Tzu Chi University, Hualien, Taiwan.
  • 9 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan. brianchc@tmu.edu.tw.
  • 10 Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. brianchc@tmu.edu.tw.
  • 11 Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. brianchc@tmu.edu.tw.
PMID: 40603902 DOI: 10.1038/s41419-025-07821-8
Abstract

Bladder Cancer (BC) is the second most prevalent genitourinary malignancy worldwide. Treatment options remain limited for patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder Cancer (NMIBC). Up to 70% of NMIBC cases harbor Fibroblast Growth Factor receptor 3 (FGFR3) alterations, and FGFR inhibition has shown potential to enhance the efficacy of immune checkpoint inhibitor (ICI). Interferon (IFN)-γ, a cytokine produced by activated T cells and associated with better response to immunotherapy in BC, is a key inducer of PD-L1 expression in the tumor microenvironment. However, the interaction between FGFR inhibitors and IFN-γ-induced PD-L1 expression in FGFR3-activated NMIBC cells remains unclear. Here, we show that FGFR inhibitors significantly reduced IFN-γ-induced PD-L1 expression in NMIBC cells harboring FGFR3-TACC3 fusions. Mechanistically, FGFR inhibitors restored IFN-γ-suppressed SIRT1 expression, promoted LC3B deacetylation and nuclear export, and enhanced autophagy-lysosomal degradation of PD-L1. Blocking Autophagy, overexpression SIGMAR1, or inhibiting lysosomal activity significantly reversed PD-L1 degradation. Notably, we demonstrate for the first time that IFN-γ-induced PD-L1 directly binds to the FGFR3 promoter and represses FGFR3-TACC3 transcription-an effect that can be rescued by FGFR inhibitors or PD-L1 knockdown. Functionally, FGFR inhibitors ameliorated PD1/PD-L1-mediated T cell suppression in co-culture assays. Together, these findings highlight a novel mechanism by which FGFR inhibitors suppress IFN-γ-induced PD-L1 via Autophagy and suggest a potential strategy to improve ICI therapy in FGFR3-altered NMIBC.

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