癌症基因组研究已发现 SWI/SNF（SWIitch/蔗糖非发酵）染色质重塑复合物的组成部分（包括 SMARCA4 和 ARID1A）频繁发生变化。重要的是，临床报告表明 SMARCA4 突变型肺癌对免疫治疗反应不佳，预后不佳。然而，免疫治疗耐药的机制基础尚不清楚。在这里，我们通过使用具有 SMARCA4 缺陷的肺癌免疫人源化、同基因和基因工程小鼠模型证实了临床发现。具体来说，我们发现 SMARCA4 缺失导致抗 PD1 免疫疗法的反应降低，并与树突状细胞 (DC) 和 CD4 T 细胞向肿瘤微环境 (TME) 的浸润显着减少相关。从机制上讲，我们发现肿瘤细胞中 SMARCA4 的缺失导致 STING、IL1β 和先天免疫系统的其他成分以及免疫细胞有效招募和活性所需的炎症细胞因子的深度下调。我们确定，这种基因表达失调是由癌细胞固有的增强子景观重编程引起的，其中涉及先天免疫反应的基因增强子（例如 STING、IL1β、I 型 IFN 和炎症细胞因子）的染色质可及性显着丧失。有趣的是，我们观察到转录因子 NF-κB 结合基序在增强子中高度富集，而这些增强子在 SMARCA4 缺陷时失去了可及性。最后，我们证实 SMARCA4 和 NF-κB 在与 STING 和 IL1β 相关的增强子上共同占据相同的基因组位点，表明 SMARCA4 和 NF-κB 之间存在功能相互作用。总而言之，我们的研究结果为 SMARCA4 突变肿瘤对抗 PD1 免疫治疗反应不佳提供了机制基础，并建立了 SMARCA4 和 NF-κB 在先天免疫和炎症基因表达调节方面的功能联系。

Cancer genomic studies have identified frequent alterations in components of the SWI/SNF (SWItch/Sucrose Non- Fermenting) chromatin remodeling complex including SMARCA4 and ARID1A . Importantly, clinical reports indicate that SMARCA4 -mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. However, the mechanistic basis of immunotherapy resistance is unknown. Here, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboring SMARCA4 deficiency. Specifically, we show that SMARCA4 loss caused decreased response to anti-PD1 immunotherapy associated with significantly reduced infiltration of dendritic cells (DCs) and CD4+ T cells into the tumor microenvironment (TME). Mechanistically, we show that SMARCA4 loss in tumor cells led to profound downregulation of STING, IL1β and other components of the innate immune system as well as inflammatory cytokines that are required for efficient recruitment and activity of immune cells. We establish that this deregulation of gene expression is caused by cancer cell-intrinsic reprogramming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in innate immune response such as STING, IL1β, type I IFN and inflammatory cytokines. Interestingly, we observed that transcription factor NF-κB binding motif was highly enriched in enhancers that lose accessibility upon SMARCA4 deficiency. Finally, we confirmed that SMARCA4 and NF-κB co-occupy the same genomic loci on enhancers associated with STING and IL1β, indicating a functional interplay between SMARCA4 and NF-κB. Taken together, our findings provide the mechanistic basis for the poor response of SMARCA4 -mutant tumors to anti-PD1 immunotherapy and establish a functional link between SMARCA4 and NF-κB on innate immune and inflammatory gene expression regulation.