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In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...

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Author Spotlight: Quantitative Detection of DNA Protein Crosslinks and Their Post-Translational Modifications

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DNA-Damaging Agents Induce PD-L1 Expression through the Src-STAT1-IRF1 Pathway.

Yuri Suzuki¹, Soshi Nishibu¹, Akihiro Nohara¹

¹Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.

Biological & Pharmaceutical Bulletin

|December 24, 2025

Summary

Chemotherapy agents like SN-38 and cisplatin boost programmed cell death-ligand 1 (PD-L1) expression via a JAK-independent pathway. This finding may enhance immune checkpoint inhibitor (ICI) efficacy in various cancers.

Keywords:

DNA damage Janus kinase immunotherapy interferon regulatory factor 1 (IRF1)programmed cell death-ligand 1 (PD-L1)

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Area of Science:

Oncology
Immunology
Molecular Biology

Background:

Immune checkpoint inhibitors (ICIs) show promise in cancer treatment but face resistance.
Downregulated programmed cell death-ligand 1 (PD-L1) expression, often due to impaired Janus kinase 1/2 (JAK1/2) signaling, is a key resistance mechanism.
Discovering JAK-independent pathways to enhance PD-L1 is crucial for improving ICI therapy.

Purpose of the Study:

To investigate alternative signaling pathways that can upregulate PD-L1 expression independently of JAK1/2.
To determine if chemotherapeutic agents can restore PD-L1 expression in cancers resistant to ICIs.
To explore the potential of enhancing ICI efficacy through novel therapeutic strategies.

Main Methods:

Utilized melanoma cell line A2058 and multiple cancer cell lines.
Administered chemotherapeutic agents SN-38 and cisplatin.
Analyzed the expression of interferon regulatory factor 1 (IRF1) and PD-L1.
Investigated the roles of JAK1/2, signal transducer and activator of transcription 1 (STAT1), Src tyrosine kinase, and IRF1 in PD-L1 regulation.

Main Results:

SN-38 and cisplatin significantly upregulated IRF1 and PD-L1 expression in A2058 melanoma cells.
This induction was JAK-independent but STAT1-dependent.
STAT1 activation was mediated by the Src tyrosine kinase.
SN-38 demonstrated efficacy in upregulating PD-L1 across various cancer types.

Conclusions:

DNA-damaging chemotherapeutic agents activate a Src-STAT1-IRF1 signaling axis to enhance PD-L1 expression.
This pathway offers a potential strategy to overcome ICI resistance in tumors with defective JAK signaling.
Targeting this axis could improve the clinical efficacy of ICIs in a broader patient population.