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DNA fragmentation factor B suppresses interferon to enable cancer persister cell regrowth

August F Williams1, David A G Gervasio1, Claire E Turkal1

  • 1Department of Dermatology, School of Medicine, University of California San Diego, La Jolla, CA, USA.

Nature Cell Biology
|November 17, 2025
PubMed

Insights

Cancer therapies face resistance. Residual cancer cells survive treatment by suppressing immune signals, paradoxically using cell death pathways to regrow, complicating treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Acquired resistance is a major challenge in oncogene-targeted cancer therapies, leading to treatment failure.
  • Tumour evolution and multiple resistance mechanisms complicate therapeutic strategies for resistant cancers.
  • Understanding adaptive processes that initiate resistance is crucial for developing preventative strategies.

Purpose of the Study:

  • To investigate the mechanisms by which residual cancer persister cells survive oncogene-targeted therapy.
  • To elucidate the role of drug stress-induced signaling in persister cell growth arrest and escape.
  • To identify potential targets for preventing acquired drug resistance.

Main Methods:

  • Analysis of residual cancer persister cells surviving oncogene-targeted therapy.
  • Investigating the role of type I interferon signaling in drug stress-induced growth arrest.
  • Utilizing genetic manipulation to assess the function of apoptotic machinery components (caspases, DNA fragmentation factor B, ATF3) in persister cell regrowth.
  • Measuring interferon-stimulated gene (ISG) expression and DNA damage in persister cells.

Main Results:

  • Residual cancer persister cells are growth arrested by drug stress-induced type I interferon signaling.
  • Persister cells suppress interferon-stimulated genes (ISGs) to escape growth arrest by leveraging apoptotic machinery.
  • Sublethal engagement of apoptotic caspases activates DNA fragmentation factor B, leading to DNA damage and ATF3 induction.
  • ATF3 suppresses ISG expression, enabling persister cell regrowth; deficiency in DNA fragmentation factor B or ATF3 prevents regrowth due to high ISG expression.

Conclusions:

  • Sublethal apoptotic stress paradoxically promotes the regrowth of residual cancer cells that survive drug treatment.
  • Targeting the interplay between apoptotic pathways and interferon signaling may offer strategies to overcome acquired resistance.
  • Understanding persister cell adaptive mechanisms is key to developing more effective and durable cancer therapies.

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