Targeted therapy for lung squamous cell carcinoma (LUSC) remains a challenge due to the lack of robust targets. Here, we identified MECOM as a candidate of therapeutic target for LUSC by screening 38 genes that were commonly amplified in three pairs of primary tumors and patient-derived xenografts (PDXs) using a clustered regularly interspaced short palindromic repeats (CRISPR)-mediated approach. High MECOM expression levels were associated with poor prognosis. Forced expression of MECOM in LUSC cell lines promoted cancer stem cell (CSC) properties, and its knockout inhibited CSC phenotypes. Furthermore, systemic delivery of CRISPR-mediated MECOM depletion cassette using adenovirus with an adaptor, which is composed of a single-chain fragment variable (scFv) against epithelial cell adhesion molecules (EpCAM) fused to the ectodomain of coxsackievirus and adenovirus receptor, and a protector, which consists of the scFv connected to the hexon symmetry of the adenovirus, could specifically target subcutaneous and orthotopic LUSC and retard tumor growth. This study could provide a novel therapeutic strategy for LUSC with high efficacy and specificity.

由于缺乏强有力的靶点，肺鳞状细胞癌（LUSC）的靶向治疗仍然是一个挑战。在这里，我们通过使用成簇规则间隔短回文重复序列 (CRISPR) 介导的方法筛选 38 个基因，这些基因通常在三对原发性肿瘤和患者来源的异种移植物 (PDX) 中扩增，从而确定 MECOM 作为 LUSC 的候选治疗靶点。高 MECOM 表达水平与不良预后相关。MECOM 在 LUSC 细胞系中的强制表达可促进癌症干细胞 (CSC) 特性，而其敲除则会抑制 CSC 表型。此外，使用具有适配器的腺病毒系统地递送CRISPR介导的MECOM消耗盒，该适配器由融合到柯萨奇病毒和腺病毒受体的胞外域的针对上皮细胞粘附分子（EpCAM）的单链片段变量（scFv）和保护器由与腺病毒六邻体对称性连接的 scFv 组成，可以特异性靶向皮下和原位 LUSC 并延缓肿瘤生长。该研究可为 LUSC 提供一种高效、特异性的新治疗策略。