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

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 Mansfield, Nik Matthews, Ritika Chauhan, Victoria Jennings, Charleen Chan Wah Hak, Holly Baldock, Francesca Butera, Elizabeth Appleton, Pablo Nenclares, Malin Pederson, Shane Foo, Amarin Wongariyapak, Antonio Rullan, Tencho Tenev, Pascal Meier, Richard Vile, Hardev Pandha, Alan Melcher, Martin McLaughlin and Kevin J. Harrington
Additional contact information
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

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60133-5

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