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SMARCA4 regulates the NK-mediated killing of senescent cells

V. Reen, M. D'Ambrosio, PP. Søgaard, K. Tyson, BJ. Leeke, I. Clément, ICA. Dye, J. Pombo, A. Kuba, Y. Lan, J. Burr, IC. Bomann, M. Kalyva, J. Birch, S. Khadayate, G. Young, D. Provencher, AM. Mes-Masson, S. Vernia, N. McGranahan, HJM. Brady, F....

. 2025 ; 11 (3) : eadn2811. [pub] 20250115

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc25010240

Grant support
Wellcome Trust - United Kingdom
MC_UP_1102/18 Medical Research Council - United Kingdom

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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