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SMARCA4 regulates the NK-mediated killing of senescent cells

Virinder Reen1,2, Mariantonietta D'Ambrosio1,2, Pia Pernille Søgaard1,2

  • 1MRC Laboratory of Medical Sciences (LMS), Du Cane Road, London W12 0NN, UK.

Science Advances
|January 15, 2025
PubMed

Insights

Targeting SMARCA4 enhances natural killer (NK) cell elimination of senescent cancer cells. This senotherapeutic approach boosts immune surveillance and may improve ovarian cancer treatment outcomes.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Chemotherapy-induced senescence can arrest cancer cells but requires immune clearance for optimal outcomes.
  • Natural killer (NK) cells are crucial for eliminating senescent cells and enhancing anti-cancer immunity.
  • Enhancing NK cell-mediated killing of senescent cells is a promising therapeutic strategy.

Purpose of the Study:

  • To identify novel targets for enhancing NK cell-mediated elimination of senescent cancer cells.
  • To investigate the role of SMARCA4 in regulating the immune response to senescent cells.
  • To evaluate SMARCA4 inhibition as a senotherapeutic strategy for ovarian cancer.

Main Methods:

  • Utilized a staggered siRNA screen to identify genes potentiating immunomodulatory cytokine secretion.
  • Assessed the ability of identified siRNAs to enhance NK cell-mediated killing of senescent cells.
  • Investigated the molecular mechanisms of SMARCA4 inhibition, including repetitive element derepression and SASP induction via cGAS/STING and MAVS/MDA5 pathways.
  • Tested a PROTAC targeting SMARCA4 in combination with cisplatin in an immunocompetent ovarian cancer model.

Main Results:

  • Genetic or pharmacological inhibition of SMARCA4 significantly enhanced NK cell-mediated elimination of senescent cells.
  • SMARCA4 expression is upregulated during senescence; its inhibition leads to derepression of repetitive elements and induction of the senescence-associated secretory phenotype (SASP).
  • SMARCA4 inhibition activates the cGAS/STING and MAVS/MDA5 pathways.
  • A SMARCA4-targeting PROTAC synergized with cisplatin to increase CD8 T cell and activated NK cell infiltration in an ovarian cancer model.

Conclusions:

  • SMARCA4 inhibition enhances NK cell-mediated surveillance of senescent cells.
  • Targeting SMARCA4 represents a potential senotherapeutic intervention for ovarian cancer.
  • This approach may improve treatment efficacy by boosting anti-tumor immune responses.

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