2. Academic Validation
  3. SMARCA4 regulates the NK-mediated killing of senescent cells

SMARCA4 regulates the NK-mediated killing of senescent cells

  • Sci Adv. 2025 Jan 17;11(3):eadn2811. doi: 10.1126/sciadv.adn2811.
Virinder Reen 1 2,  Mariantonietta D'Ambrosio 1 2,  Pia Pernille Søgaard 1 2,  Katie Tyson 3,  Bryony J Leeke 1 2,  Isabelle Clément 4 5,  Isabel C A Dye 3,  Joaquim Pombo 1 2,  Adam Kuba 4 5 6,  Yemin Lan 7 8,  Joanna Burr 9,  Ida C Bomann 7 8,  Maria Kalyva 10,  Jodie Birch 1 2,  Sanjay Khadayate 1 2,  George Young 1 2,  Diane Provencher 4 11,  Anne-Marie Mes-Masson 4 12,  Santiago Vernia 1 2 13,  Nicholas McGranahan 10 14,  Hugh J M Brady 6,  Francis Rodier 4 5,  Raffaella Nativio 7 8,  Michelle Percharde 1 2,  Iain A McNeish 3,  Jesús Gil 1 2
Affiliations

Affiliations

  • 1 MRC Laboratory of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK.
  • 2 Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK.
  • 3 Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK.
  • 4 Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) et Institut du Cancer de Montréal, Montreal, QC, Canada.
  • 5 Département de Radiologie, Radio-oncologie et Médicine Nucléaire, Université de Montréal, Montreal, QC, Canada.
  • 6 Department of Hemato-Oncology, University Hospital and Faculty of Medicine and Dentistry Palacky University, Olomouc, Czech Republic.
  • 7 Department of Brain Sciences, Imperial College London, London, UK.
  • 8 UK Dementia Research Institute, Imperial College London, London, UK.
  • 9 Department of Life Sciences, Imperial College, London SW7 2AZ, UK.
  • 10 Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
  • 11 Département d'Obstétrique-Gynécologie, Université de Montréal, Montreal, QC, Canada.
  • 12 Département de Médecine, Université de Montréal, Montreal, QC, Canada.
  • 13 Instituto de Biomedicina de Valencia IBV-CSIC, Valencia 46012, Spain.
  • 14 Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
PMID: 39813356 DOI: 10.1126/sciadv.adn2811
Abstract

Induction of senescence by chemotherapeutic agents arrests Cancer cells and activates immune surveillance responses to contribute to therapy outcomes. In this investigation, we searched for ways to enhance the NK-mediated elimination of senescent cells. We used a staggered screen approach, first identifying siRNAs potentiating the secretion of immunomodulatory cytokines to later test for their ability to enhance NK-mediated killing of senescent cells. We identified that genetic or pharmacological inhibition of SMARCA4 enhanced senescent cell elimination by NK cells. SMARCA4 expression is elevated during senescence and its inhibition derepresses repetitive elements, inducing the SASP via activation of cGAS/STING and MAVS/MDA5 pathways. Moreover, a PROTAC targeting SMARCA4 synergized with cisplatin to increase the infiltration of CD8 T cells and mature, activated NK cells in an immunocompetent model of ovarian Cancer. Our results indicate that SMARCA4 inhibitors enhance NK-mediated surveillance of senescent cells and may represent senotherapeutic interventions for ovarian Cancer.

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