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© The Author(s) 2025. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

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.

Details

Title
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
Author
Lin, Yu-Chen 1   VIAFID ORCID Logo  ; Chu, Cheng-Ying 2 ; Hsieh, Tsung-Han 3 ; Lin, Bo-Jyun 1 ; Liou, Jing-Ping 4 ; Yen, Yun 5 ; Chen, Chun-Han 6   VIAFID ORCID Logo 

 Taipei Medical University, Graduate Institute of Medical Sciences, College of Medicine, Taipei, Taiwan (GRID:grid.412896.0) (ISNI:0000 0000 9337 0481); Taipei Medical University, Department of Pharmacology, School of Medicine, College of Medicine, Taipei, Taiwan (GRID:grid.412896.0) (ISNI:0000 0000 9337 0481) 
 Taipei Medical University, CRISPR Gene Targeting Core, Taipei, Taiwan (GRID:grid.412896.0) (ISNI:0000 0000 9337 0481); Taipei Medical University, TMU Research Center of Cancer Translational Medicine, Taipei, Taiwan (GRID:grid.412896.0) (ISNI:0000 0000 9337 0481) 
 Taipei Medical University, Precision Health Center, Taipei, Taiwan (GRID:grid.412896.0) (ISNI:0000 0000 9337 0481) 
 Taipei Medical University, School of Pharmacy, College of Pharmacy, Taipei, Taiwan (GRID:grid.412896.0) (ISNI:0000 0000 9337 0481) 
 Taipei Medical University, Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei, Taiwan (GRID:grid.412896.0) (ISNI:0000 0000 9337 0481); Tzu Chi University, Center for Cancer Translational Research, Hualien, Taiwan (GRID:grid.411824.a) (ISNI:0000 0004 0622 7222) 
 Taipei Medical University, Graduate Institute of Medical Sciences, College of Medicine, Taipei, Taiwan (GRID:grid.412896.0) (ISNI:0000 0000 9337 0481); Taipei Medical University, Department of Pharmacology, School of Medicine, College of Medicine, Taipei, Taiwan (GRID:grid.412896.0) (ISNI:0000 0000 9337 0481); Taipei Medical University, Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei, Taiwan (GRID:grid.412896.0) (ISNI:0000 0000 9337 0481) 
Pages
485
Publication year
2025
Publication date
Dec 2025
Publisher
Springer Nature B.V.
e-ISSN
20414889
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3226546372
Copyright
© The Author(s) 2025. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.