Palbociclib and dsRNA sensor co-operate to enhance anti-cancer effects through ER stress and modulation of immune evasion
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.
Authors
- Aída Barreiro-Alonso (ORCID: https://orcid.org/0000-0002-3017-8550)
- Victoria Roulstone (ORCID: https://orcid.org/0000-0003-4141-8123)
- Elizabeth S. Appleton (ORCID: https://orcid.org/0000-0002-8794-3428)
- Joan Kyula (ORCID: https://orcid.org/0000-0002-9299-0544)
- Martin McLaughlin (ORCID: https://orcid.org/0000-0002-9739-7133)
- Jyoti S. Choudhary (ORCID: https://orcid.org/0000-0003-0881-5477)
- Charleen Chan Wah Hak (ORCID: https://orcid.org/0000-0002-6386-5699)
- Emmanuel Christian Patin (ORCID: https://orcid.org/0000-0001-5390-5733)
- Antonio Rullan (ORCID: https://orcid.org/0000-0002-7365-9629)
- Miriam Melake
- Amarin Wongariyapak (ORCID: https://orcid.org/0009-0009-3867-1022)
- Isaac Dean (ORCID: https://orcid.org/0000-0002-4750-5335)
- David Mansfield (ORCID: https://orcid.org/0000-0003-4165-015X)
- Shane Foo (ORCID: https://orcid.org/0000-0001-6295-7404)
- Victoria A. Jennings
- Francesca Butera (ORCID: https://orcid.org/0000-0002-6606-4678)
- Pascal Meier (ORCID: https://orcid.org/0000-0003-2760-6523)
- Holly Baldock (ORCID: https://orcid.org/0000-0003-2751-4549)
- Malin Pedersen (ORCID: https://orcid.org/0000-0003-1887-733X)
- James C. Wright (ORCID: https://orcid.org/0000-0001-6950-4328)
- Pablo Nenclares (ORCID: https://orcid.org/0000-0002-1750-3179)
- Hardev Pandha (ORCID: https://orcid.org/0000-0002-9420-7701)
- Tencho Tenev (ORCID: https://orcid.org/0000-0001-8762-1069)
- Alan A. Melcher (ORCID: https://orcid.org/0000-0002-2042-3380)
- Richard G. Vile (ORCID: https://orcid.org/0000-0003-2192-9372)
- Kevin Joseph Harrington (ORCID: https://orcid.org/0000-0002-6014-348X)
- Nik Matthews (ORCID: https://orcid.org/0000-0002-0602-1131)
- Lu Yu (ORCID: https://orcid.org/0000-0001-8378-9112)
- Christopher J. Lord (ORCID: https://orcid.org/0000-0002-3226-0515)
- Ritika Chauhan (ORCID: https://orcid.org/0000-0002-1224-9343)
- Richard Elliott (ORCID: https://orcid.org/0009-0002-0174-5488)
Institutions
- Institute of Cancer Research (GB)
- Breast Cancer Now (GB)
- University of Surrey (GB)
- Mayo Clinic in Arizona (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-24
- DOI
- https://doi.org/10.1038/s41467-025-60133-5
- Citations
- 1
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.80
Funders
- Cancer Research UK
- National Institute for Health and Care Research
- Oncolytics Biotech
- RIKEN