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

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

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 onc...

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Main Authors: 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 Pedersen, Shane Foo, Amarin Wongariyapak, Antonio Rullan, Tencho Tenev, Pascal Meier, Richard Vile, Hardev Pandha, Alan Melcher, Martin McLaughlin, Kevin J. Harrington
Format: Article
Language:English
Published: Nature Portfolio 2025-05-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-60133-5
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Summary: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.
ISSN:2041-1723

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