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.

Cancer Genome Evolution Research Group Cancer Research UK Lung Cancer Centre of Excellence University College London Cancer Institute London UK

Cancer Research UK Lung Cancer Centre of Excellence University College London Cancer Institute London UK

Centre de Recherche du Centre Hospitalier de l'Université de Montréal et Institut du Cancer de Montréal Montreal QC Canada

Département d'Obstétrique Gynécologie Université de Montréal Montreal QC Canada

Département de Médecine Université de Montréal Montreal QC Canada

Département de Radiologie Radio oncologie et Médicine Nucléaire Université de Montréal Montreal QC Canada

Department of Brain Sciences Imperial College London London UK

Department of Hemato Oncology University Hospital and Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Department of Life Sciences Imperial College London SW7 2AZ UK

Institute of Clinical Sciences Faculty of Medicine Imperial College London Du Cane Road London W12 0NN UK

Instituto de Biomedicina de Valencia IBV CSIC Valencia 46012 Spain

MRC Laboratory of Medical Sciences Du Cane Road London W12 0NN UK

Ovarian Cancer Action Research Centre Department of Surgery and Cancer Imperial College London London W12 0NN UK

UK Dementia Research Institute Imperial College London London UK

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