EMSY inhibits homologous recombination repair and the interferon response promoting lung cancer immune evasion

Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are characterized by worse overall outcomes and resistance to immunotherapy. Here, we identified a molecular mechanism by which KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY producing a BRCAness phenotype characterized by HRR defects and sensitivity to PARP inhibitors (PARPis). Defective HRR increases genomic instability leading to high tumor mutational burden (TMB), which prompts an innate immune response. Notably, EMSY accumulation also suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling, impairing the growth of KEAP1-mutant tumors. Our results suggest that targeting the PARP and STING pathways, individually or in combination, represent a novel therapeutic strategy in NSCLC patients harboring alterations in KEAP1. Overall design: All samples were generated by deep sequencing

携带KEAP1突变的非小细胞肺癌（Non-small cell lung cancers, NSCLCs）具有预后不良及免疫治疗耐药的临床特征。本研究阐明了一条分子机制：KEAP1可通过靶向EMSY进行泛素介导的降解，进而调控同源重组修复（Homologous Recombination Repair, HRR）与抗肿瘤免疫。非小细胞肺癌中KEAP1的缺失会导致EMSY蛋白稳定性上调，进而形成以HRR缺陷、对PARP抑制剂（PARP inhibitors, PARPis）敏感为特征的BRCAness表型。HRR缺陷会加剧基因组不稳定性，进而引发高肿瘤突变负荷（Tumor Mutational Burden, TMB），从而触发先天免疫应答。值得注意的是，EMSY的积累还会抑制I型干扰素应答并损伤先天免疫信号通路，最终促进肿瘤免疫逃逸。使用STING激动剂激活肿瘤微环境中的I型干扰素应答，可启动固有免疫与适应性免疫信号通路，从而抑制KEAP1突变型肿瘤的生长。本研究结果显示，单独或联合靶向PARP与STING通路，可为携带KEAP1变异的非小细胞肺癌患者提供全新的治疗策略。实验整体设计：所有样本均通过深度测序获得。