大多数肺癌患者在抗PD-1免疫治疗后表现出耐药性，导致患者生存时间缩短。先前的研究表明甲基化等表观遗传异常与抗PD-1免疫治疗的临床反应之间存在关联，而SUMO化在抗PD-1抗体免疫治疗耐药中的作用仍不清楚。这里，15 SUMO的mRNA表达使用实时 PCR 分析接受抗 PD-1 免疫治疗的肺癌患者的 PBMC 中的机械成分。根据mRNA水平的百分比变化，评估SUMO机械元件的表达与抗PD-1免疫治疗结果之间的关系以及SUMO化的影响因素。体外用不同浓度的2-D08（SUMO化特异性抑制剂）处理PBMC，通过流式细胞术分析淋巴细胞亚群的活化率和死亡率。基于三个SUMO机械部件基因表达的预测方法（SUMO1、SUMO3 和 UBE2I）是为了区分对 PD-1 抑制剂无反应者而开发的。此外，SUMO化失调组（百分比变化>100或-50〜-100组）外周血中淋巴细胞数量显着减少。体外研究证实，稍低的SUMO化水平可以改善T和NK淋巴细胞的活化状态，但极低的SUMO化水平会导致淋巴细胞的死亡率增加。我们的研究结果表明，SUMO机械元件的基因表达失调可以诱导抗肿瘤药物的耐药性。 -通过上调外周血淋巴细胞死亡来治疗肺癌的PD-1免疫疗法。这些数据可能为预测抗PD-1免疫治疗的疗效提供有效的循环生物标志物，并揭示抗PD-1免疫治疗耐药的新调节机制。版权所有©2024 Wang，Sun，Liu，Xu，Li，Zhang and黄.

The majority of patients with lung cancer exhibit drug resistance after anti-PD-1 immunotherapy, leading to shortened patient survival time. Previous studies have suggested an association between epigenetic abnormalities such as methylation and clinical response to anti-PD-1 immunotherapy, while the role of SUMOylation in resistance to anti-PD-1 antibody immunotherapy is still unclear.Here, the mRNA expression of 15 SUMO machinery components in PBMC from lung cancer patients receiving anti-PD-1 immunotherapy were analyzed using real-time PCR. Base on the percentage change in mRNA levels, the relationship between the expression of SUMO machinery components and outcomes of anti-PD-1 immunotherapy, and the influencing factors of SUMOylation were evaluated. PBMC was treated with different concentrations of 2-D08 (a specific inhibitor of SUMOylation) in vitro, and analyzed the activation and the death rates of lymphocyte subsets by flow cytometry analysis.A predictive method, base on the gene expression of three SUMO machinery components (SUMO1, SUMO3 and UBE2I), were developed to distinguish non-responders to PD-1 inhibitors. Furthermore, the number of lymphocytes in peripheral blood significantly reduced in the dysregulated SUMOylation groups (the percentage change >100 or -50 ~ -100 groups). In vitro studies confirmed that lightly low SUMOylation level improved the activation status of T and NK lymphocytes, but extremely low SUMOylation level lead to the increased death rates of lymphocytes.Our findings implied that dysregulated gene expression of SUMO machinery components could induce the resistance of anti-PD-1 immunotherapy in lung cancer by upregulating the death of peripheral blood lymphocytes. These data might provide effective circulating biomarkers for predicting the efficacy of anti-PD-1 immunotherapy, and uncovered a novel regulatory mechanism of resistance to anti-PD-1 immunotherapy.Copyright © 2024 Wang, Sun, Liu, Xu, Li, Zhang and Huang.