Cold physical plasma is a partially ionized gas investigated as a new anticancer tool in selectively targeting cancer cells in monotherapy or in combination with therapeutic agents. Here, we investigated the intrinsic resistance mechanisms of tumor cells towards physical plasma treatment. When analyzing the dose-response relationship to cold plasma-derived oxidants in 11 human cancer cell lines, we identified four ‘resistant’ and seven ‘sensitive’ cell lines. We observed stable intracellular glutathione levels following plasma treatment only in the ‘resistant’ cell lines indicative of altered antioxidant mechanisms. Assessment of proteins involved in GSH metabolism revealed cystine-glutamate antiporter xCT (SLC7A11) to be significantly more abundant in the ‘resistant’ cell lines as compared to ‘sensitive’ cell lines. This decisive role of xCT was confirmed by pharmacological and genetic inhibition, followed by cold physical plasma treatment. Finally, microscopy analysis of ex vivo plasma-treated human melanoma punch biopsies suggested a correlation between apoptosis and basal xCT protein abundance. Taken together, our results demonstrate that xCT holds the potential as a biomarker predicting the sensitivity of tumor cells towards plasma treatment.

冷物理等离子体是一种部分电离的气体，已被研究作为一种新的抗癌工具，可以通过单一疗法或与治疗剂联合选择性靶向癌细胞。在这里，我们调查了肿瘤细胞对物理血浆治疗的内在抗性机制。当分析11种人类癌细胞系与血浆冷氧化剂的剂量反应关系时，我们鉴定出4种“耐药”和7种“敏感”细胞系。我们仅在“抗性”细胞系中观察到血浆处理后稳定的细胞内谷胱甘肽水平，表明抗氧化机制发生了改变。对参与GSH代谢的蛋白质的评估显示，与“敏感”细胞系相比，“抗性”细胞系中胱氨酸-谷氨酸逆转运蛋白xCT（SLC7A11）的含量明显更高。xCT的决定性作用已通过药理学和基因抑制作用证实，随后进行了冷物理血浆处理。最后，显微镜分析体外血浆处理的人黑素瘤穿孔活检提示细胞凋亡与基础xCT蛋白丰度之间存在相关性。两者合计，我们的结果表明，xCT具有潜在的生物标志物的功能，可预测肿瘤细胞对血浆治疗的敏感性。