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Updated: Aug 14, 2025

Characterizing DNA Repair Processes at Transient and Long-lasting Double-strand DNA Breaks by Immunofluorescence Microscopy
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Characterizing DNA Repair Processes at Transient and Long-lasting Double-strand DNA Breaks by Immunofluorescence Microscopy

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Cancer Cell Resistance to IFNγ Can Occur via Enhanced Double-Strand Break Repair Pathway Activity

Tong Han1, Xujun Wang2, Sailing Shi1

  • 1Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration, Ministry of Education, Department of Orthopedics, Tongji Hospital, Frontier Science Center for Stem Cells, School of Life Science and Technology, Tongji University, China.

Cancer Immunology Research
|January 11, 2023
PubMed

Insights

Cancer cells can resist interferon-gamma (IFNγ) therapy by activating double-strand break (DSB) repair genes. Inhibiting DSB repair enhances IFNγ effectiveness, offering new combination therapy strategies for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunotherapy

Background:

  • Interferon-gamma (IFNγ) exhibits anti-cancer properties, including cytostatic and proapoptotic effects.
  • However, many cancer cells develop resistance to IFNγ, limiting its therapeutic efficacy.
  • The molecular mechanisms underlying IFNγ resistance remain incompletely understood.

Purpose of the Study:

  • To investigate the mechanisms of IFNγ resistance in cancer cells.
  • To identify potential therapeutic strategies to overcome IFNγ resistance.

Main Methods:

  • Conducted IFNγ-sensitivity screens across over 40 cancer cell lines.
  • Utilized CRISPR screening and transcriptomic profiling to compare sensitive and resistant cells.
  • Validated findings in The Cancer Genome Atlas (TCGA) and immune checkpoint blockade (ICB) cohorts.

Main Results:

  • Activation of double-strand break (DSB) repair genes was identified as a mechanism conferring IFNγ resistance.
  • Suppression of single-strand break (SSB) repair genes increased reliance on DSB repair pathways post-IFNγ treatment.
  • Inhibition of DSB repair pathways synergized with IFNγ treatment in vitro and in vivo.

Conclusions:

  • DSB repair gene activation is a key driver of IFNγ resistance in cancer.
  • Targeting DSB repair pathways in combination with IFNγ holds promise for overcoming immunotherapy resistance.
  • This study provides evidence for novel combination therapies against cancer.

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