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KRAS-elicited PDIA6 blocks PERK-dependent immunogenic cell death in pancreatic carcinoma

Liwei Zhao1,2, Peng Liu1,2, Guido Kroemer1,2,3

  • 1Institut Universitaire de France, Sorbonne Université, Inserm, Centre de Recherche des Cordeliers, Equipe Labellisée Par La Ligue Contre Le Cancer, Université Paris Cité, Paris, France.

Oncoimmunology
|March 9, 2026
PubMed

Insights

Pancreatic cancer with KRAS mutations resists immunotherapy. Researchers found PDIA6 blocks immune cell death, causing immune exclusion. Inhibiting PDIA6 may restore T-cell immunity and improve immunotherapy response in PDAC.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) exhibits resistance to immune checkpoint blockade.
  • Understanding resistance mechanisms is crucial for improving PDAC treatment outcomes.

Purpose of the Study:

  • To identify novel targets that overcome immune exclusion in KRAS-mutant PDAC.
  • To investigate the role of PDIA6 in regulating immunogenic cell death and T-cell immunity.

Main Methods:

  • Utilized molecular biology techniques to study PDIA6 function in PDAC.
  • Assessed the impact of PDIA6 inhibition on PERK-dependent cell death and immune cell infiltration.

Main Results:

  • PDIA6 was identified as a KRAS-driven suppressor of PERK-dependent immunogenic cell death.
  • PDIA6 inhibition was shown to restore CD8+ T-cell immunity.
  • Inhibition of PDIA6 sensitized PDAC to immunotherapy.

Conclusions:

  • PDIA6 represents a targetable resistance mechanism in KRAS-mutant PDAC.
  • Targeting PDIA6 holds potential for enhancing immunotherapy efficacy in pancreatic cancer.
Keywords:
Cancer immunotherapycell stressimmune exclusionsmall molecule

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