肺癌是全球肿瘤相关死亡的主要原因。KRAS基因突变是肺癌中最常见的致癌基因变异。遗憾的是，治疗KRAS突变型腺癌（ADC）仍然是一个重大的肿瘤治疗挑战。本研究使用自发性和移植型KRAS突变瘤模型，研究了肿瘤源性CUL4B在KRAS驱动的肺癌中的作用。我们发现敲除或沉默CUL4B促进了两种模型中肺腺癌的生长和进展。从机制上讲，CUL4B直接与Cxcl2的启动子结合并表观遗传地抑制其转录。CUL4B的缺失增加了CXCL2的表达，CXCL2与髓源性抑制细胞（MDSCs）上的CXCR2结合，促进它们向肿瘤微环境的迁移。靶向MDSCs显著延缓了CUL4B沉默的KRAS突变瘤的生长。总之，我们的研究揭示了CUL4B在调控KRAS驱动肺肿瘤发展中具有类肿瘤抑制因子功能的机制洞见。© 2023. 作者，归属于Springer Nature Limited的独家许可。

Lung cancer is the leading cause of cancer-related death worldwide. KRAS mutations are the most common oncogenic alterations found in lung cancer. Unfortunately, treating KRAS-mutant lung adenocarcinoma (ADC) remains a major oncotherapeutic challenge. Here, we used both autochthonous and transplantable KRAS-mutant tumor models to investigate the role of tumor-derived CUL4B in KRAS-driven lung cancers. We showed that knockout or knockdown of CUL4B promotes lung ADC growth and progression in both models. Mechanistically, CUL4B directly binds to the promoter of Cxcl2 and epigenetically represses its transcription. CUL4B deletion increases the expression of CXCL2, which binds to CXCR2 on myeloid-derived suppressor cells (MDSCs) and promotes their migration to the tumor microenvironment. Targeting of MDSCs significantly delayed the growth of CUL4B knockdown KRAS-mutant tumors. Collectively, our study provides mechanistic insights into the novel tumor suppressor-like functions of CUL4B in regulating KRAS-driven lung tumor development.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.