2. Academic Validation
  3. Alpha-Lipoic Acid Inhibits IFN-γ-Induced PD-L1 Expression in Prostate Cancer Cells and Enhances T-Cell-Mediated Anti-Tumor Cytotoxicity

Alpha-Lipoic Acid Inhibits IFN-γ-Induced PD-L1 Expression in Prostate Cancer Cells and Enhances T-Cell-Mediated Anti-Tumor Cytotoxicity

  • Antioxidants (Basel). 2026 Mar 25;15(4):413. doi: 10.3390/antiox15040413.
Yi-Jan Hsia 1 2,  Zhang-Min Lin 3,  Tien-Sheng Tseng 4 5,  Tz-Chong Chou 3 6 7 8
Affiliations

Affiliations

  • 1 Dental Department, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan.
  • 2 Devision of Oral and Maxillofacial Surgery, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan.
  • 3 Cathay Medical Research Institute, Cathay General Hospital, New Taipei City 22174, Taiwan.
  • 4 Institute of Molecular Biology, National Chung Hsing University, Taichung 402805, Taiwan.
  • 5 Doctoral Program in Microbial Genomics, National Chung Hsing University and Academia Sinica, Taipei 115024, Taiwan.
  • 6 Graduate Institute of Medical Sciences, National Defense Medical University, Taipei 11490, Taiwan.
  • 7 Department of Pharmacology, National Defense Medical University, Taipei 11490, Taiwan.
  • 8 China Medical University Hospital, China Medical University, Taichung 404327, Taiwan.
PMID: 42072056 DOI: 10.3390/antiox15040413
Abstract

The programmed death-ligand 1 (PD-L1) plays a critical role for promoting Cancer immune evasion. However, the resistance to PD-L1-targeted immunotherapy greatly limits its application. α-lipoic acid (ALA) is an endogenous antioxidant, while whether ALA affects PD-L1 expression remains unknown. In IFN-γ-stimulated castration-resistant prostate Cancer (CRPC)-mimicking PC3 and DU145 cells, the expression of PD-L1 and its regulatory genes was determined by Western blotting, RT-PCR, and immunofluorescence. The T-cell-mediated tumor-killing activity was evaluated in a co-culture system of Cancer cells and Jurkat T cells. ALA significantly inhibits IFN-γ-induced PD-L1 protein and mRNA expression without affecting its degradation. The upstream genes accounting for PD-L1 induction, including JAK1/STAT1/IRF-1 cascade, c-Myc, HIF-1α, and GSK3β activity, were markedly suppressed by ALA. The decreased expression of PD-L1 and these regulators by ALA is also modulated by attenuation of mTOR/p70S6K/4EBP1-dependent protein translation and ROS production. In the co-culture system, ALA markedly increased T-cell-mediated tumor-killing activity compared to that of ALA treatment alone, suggesting that ALA may augment the antitumor immunity. Collectively, we demonstrated that ALA-mediated inhibition of PD-L1 expression is regulated by multiple mechanisms, which indicates that ALA may be a potential agent to enhance Cancer Immunotherapy, particularly in CRPC.

Keywords

PD-L1; STAT1; c-Myc; interferon-γ; oxidative stress; prostate cancer; α-lipoic acid.

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