A study of IL-1β-Associated NNT Acetylation Orchestrates Iron–sulfur Cluster Maintenance and Cancer Immunotherapy Resistance. Han et al

Interleukin-1β (IL-1β) is a key protein in inflammation and contributes to tumor progression. However, the role of IL-1β in cancer is ambiguous or even contradictory due to its pro- and antitumor potential. Here, we found that upon IL-1β stimulation, nicotinamide nucleotide transhydrogenase (NNT) in cancer cells is acetylated at lysine (K) 1042 (NNT K1042ac) and thereby induces the mitochondrial translocation of p300/CBP-associated factor (PCAF). This acetylation enhances NNT activity by increasing the binding affinity of NNT for NADP+ and therefore boosts NADPH production, which subsequently sustains sufficient iron–sulfur cluster maintenance and protects tumor cells from ferroptosis. Abrogating NNT K1042 acetylation dramatically attenuates IL-1β-promoted tumor immune evasion and synergizes with PD-1 blockade. In addition, NNT K1042ac is associated with IL-1β expression and the prognosis of human gastric cancer. Our findings demonstrate a novel mechanism of IL-1β-promoted tumor immune evasion through which tumor cell metabolism is regulated, implicating the therapeutic potential of disrupting the link between IL-1β and tumor cells by inhibiting NNT acetylation. This is the original data set for the study that contains all of the unprocessed microscopy images, gels, western blots used in this study.白细胞介素-1β（Interleukin-1β，IL-1β）是炎症反应中的关键蛋白，可促进肿瘤进展。然而，由于其兼具促瘤与抗肿瘤潜能，IL-1β在癌症中的作用仍存在歧义甚至相互矛盾。本研究结果显示，在IL-1β刺激下，癌细胞中的烟酰胺核苷酸转氢酶（nicotinamide nucleotide transhydrogenase，NNT）在赖氨酸（lysine，K）1042位点发生乙酰化修饰（即NNT K1042ac），并由此介导p300/CBP相关因子（p300/CBP-associated factor，PCAF）向线粒体转位。该乙酰化修饰通过提升NNT与烟酰胺腺嘌呤二核苷酸磷酸（NADP+）的结合亲和力增强其酶活性，进而促进还原型烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的生成，随后维持足够的铁硫簇稳态，保护肿瘤细胞免于铁死亡。阻断NNT K1042位点的乙酰化修饰可显著削弱IL-1β介导的肿瘤免疫逃逸，并与PD-1阻断疗法（PD-1 blockade）产生协同效应。此外，NNT K1042ac与IL-1β的表达水平及人类胃癌患者的预后密切相关。本研究揭示了IL-1β通过调控肿瘤细胞代谢促进肿瘤免疫逃逸的全新机制，提示通过抑制NNT乙酰化修饰打断IL-1β与肿瘤细胞之间的关联具有潜在治疗价值。 本研究的原始数据集包含本研究中使用的全部未处理显微镜图像、凝胶电泳图谱及蛋白质免疫印迹（western blots）实验结果。