An antibiotic that mediates immune destruction of senescent cancer cells

Abstract

Drugs that eliminate senescent cells, senolytics, can be powerful when combined with pro-senescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a PANoptosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via JNK pathway activation. We show that a combination of a DR5 agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent NK and CD8+ T cell mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine IL18. SignificanceThe efficacy of multiple cancer drugs is limited by the induction of senescence, which enables cancer cells to evade cell death. We uncover here a new selective vulnerability of senescent cancer cells and we show that this vulnerability can be targeted with a commonly-used antibiotic. We show that a combination of senescence-inducing therapy, combined with this antibiotic causes a highly immunogenic cell death phenotype that further stimulates potent immune destruction of senescent cancer cells.