Drugs that eliminate senescent cells, senolytics, can be powerful when combined with prosenescence 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 pyroptosis-apoptosis-necroptosis (PAN)optosis-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 Jun N-terminal protein kinase (JNK) pathway activation. We show that a combination of a death receptor 5 (DR5) agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent natural killer (NK) and CD8+ T cell–mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine interleukin 18 (IL18).

中文翻译：

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一种介导衰老癌细胞免疫破坏的抗生素


消除衰老细胞的药物 senolytics 在与衰老癌症疗法联合使用时可能很强大。使用基于 CRISPR/Cas9 的遗传筛选，我们在这里SLC25A23确定为衰老癌细胞的脆弱性。抑制 SLC25A23 会破坏细胞钙稳态，损害氧化磷酸化，并干扰氧化还原信号传导，导致衰老细胞死亡。这些作用可以通过盐霉素（一种阳离子离子载体抗生素）来复制。沙利霉素促进衰老细胞发生细胞焦亡-凋亡-坏死性凋亡 （PAN） 细胞凋亡样细胞死亡，包括细胞凋亡和两种形式的免疫原性细胞死亡：坏死性凋亡和焦亡。值得注意的是，我们观察到盐霉素处理或SLC25A23抑制会升高活性氧，通过 Jun N 末端蛋白激酶 （JNK） 通路激活上调死亡受体 5。我们表明，死亡受体 5 （DR5） 激动性抗体和盐霉素的组合是一种强大的 senolytic 鸡尾酒。我们提供的证据表明，这种药物组合可引发由焦亡细胞因子白细胞介素 18 （IL18） 介导的强效自然杀伤 （NK） 和 CD8+ T 细胞介导的衰老癌细胞免疫破坏。