FGL1 的上调有助于肿瘤逃避免疫监视，而针对 FGL1 的治疗抗体有潜力作为另一种免疫检查点抑制剂。然而，癌症中高 FGL1 蛋白水平的潜在机制尚不清楚。在此，我们报告 FBXO38 与 FGL1 相互作用并泛素化，从而负向调节其稳定性并介导癌症免疫反应。 FBXO38 的耗尽显着增加了 FGL1 的丰度，不仅抑制 CD8 T 细胞浸润并增强肿瘤的免疫逃避，而且还增加小鼠的炎症。重要的是，我们在非小细胞肺癌标本中观察到 FBXO38 与 FGL1 和 IL-6 呈负相关。 FGL1 和 IL-6 水平与 TNM（肿瘤、淋巴结、转移）分期呈正相关，而 FBXO38 和浸润性 CD8 T 细胞与 TNM 分期呈负相关。我们的研究确定了调节 FGL1 稳定性的机制和增强免疫治疗的靶点，并表明抗 FGL1 和抗 IL-6 的组合是癌症免疫治疗的潜在治疗策略。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

Upregulation of FGL1 helps tumors escape from immune surveillance, and therapeutic antibodies targeting FGL1 have potential as another immune checkpoint inhibitor. However, the underlying mechanism of high FGL1 protein level in cancers is not well defined. Here, we report that FBXO38 interacts with and ubiquitylates FGL1 to negatively regulate its stability and to mediate cancer immune response. Depletion of FBXO38 markedly augments FGL1 abundance, not only suppressing CD8+ T cell infiltration and enhancing immune evasion of tumor but also increasing inflammation in mice. Importantly, we observe a negative correlation of FBXO38 with FGL1 and IL-6 in non-small cell lung cancer specimens. FGL1 and IL-6 levels positively correlate with TNM (tumor, lymph node, metastasis) stages, while FBXO38 and the infiltrating CD8+ T cells negatively correlate with TNM stages. Our study identifies a mechanism regulating FGL1 stability and a target to enhance the immunotherapy and suggests that the combination of anti-FGL1 and anti-IL-6 is a potential therapeutic strategy for cancer immunotherapy.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.