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Palbociclib and dsRNA sensor co-operate to enhance anti-cancer effects through ER stress and modulation of immune evasion

Author

Listed:
  • Victoria Roulstone

    (The Institute of Cancer Research)

  • Joan Kyula-Currie

    (The Institute of Cancer Research)

  • James Wright

    (The Institute of Cancer Research)

  • Emmanuel C. Patin

    (The Institute of Cancer Research)

  • Isaac Dean

    (The Institute of Cancer Research)

  • Lu Yu

    (The Institute of Cancer Research)

  • Aida Barreiro-Alonso

    (The Institute of Cancer Research)

  • Miriam Melake

    (The Institute of Cancer Research)

  • Jyoti Choudhary

    (The Institute of Cancer Research)

  • Richard Elliott

    (The Institute of Cancer Research)

  • Christopher J. Lord

    (The Institute of Cancer Research)

  • David Mansfield

    (The Institute of Cancer Research)

  • Nik Matthews

    (The Institute of Cancer Research)

  • Ritika Chauhan

    (The Institute of Cancer Research)

  • Victoria Jennings

    (The Institute of Cancer Research)

  • Charleen Chan Wah Hak

    (The Institute of Cancer Research)

  • Holly Baldock

    (The Institute of Cancer Research)

  • Francesca Butera

    (The Institute of Cancer Research)

  • Elizabeth Appleton

    (The Institute of Cancer Research)

  • Pablo Nenclares

    (The Institute of Cancer Research)

  • Malin Pederson

    (The Institute of Cancer Research)

  • Shane Foo

    (The Institute of Cancer Research)

  • Amarin Wongariyapak

    (The Institute of Cancer Research)

  • Antonio Rullan

    (The Institute of Cancer Research)

  • Tencho Tenev

    (The Institute of Cancer Research)

  • Pascal Meier

    (The Institute of Cancer Research)

  • Richard Vile

    (Mayo Clinic)

  • Hardev Pandha

    (University of Surrey)

  • Alan Melcher

    (The Institute of Cancer Research)

  • Martin McLaughlin

    (The Institute of Cancer Research)

  • Kevin J. Harrington

    (The Institute of Cancer Research)

Abstract

Cytoplasmic pattern recognition receptors (PRR) for double-stranded RNA, such as RIG-I/MDA5, are key mediators of anti-viral responses. Here we screen for synergistic drug-virotherapy combinations and find that the reovirus type III Dearing strain (Rt3D)-palbociclib combination augments oncolytic virus-induced stress responses and increases interferon production and signaling. Data from RIG-I agonist and ER stress-inducing agents further confirms the crosstalk between RNA-sensing and ER stress in inducing cancer cell death and interferon production. Combined Rt3D-palbociclib also increases innate immune activation and IFN-induced HLA expression within tumor cells, with accompanying alterations in the epigenetic landscape and endogenous retroviral (ERV) elements. Analysis of the immunopeptidome in treated cells further reveals changes to HLA-captured peptides, including altered expression of peptides from cancer or testis antigens and ERVs. Our findings thus highlight the crosstalk between stress signaling and PRR activation for mediating enhanced anti-cancer efficacy.

Suggested Citation

  • Victoria Roulstone & Joan Kyula-Currie & James Wright & Emmanuel C. Patin & Isaac Dean & Lu Yu & Aida Barreiro-Alonso & Miriam Melake & Jyoti Choudhary & Richard Elliott & Christopher J. Lord & David , 2025. "Palbociclib and dsRNA sensor co-operate to enhance anti-cancer effects through ER stress and modulation of immune evasion," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60133-5
    DOI: 10.1038/s41467-025-60133-5
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