EGFR-TKI靶向治疗是非小细胞肺癌治疗的里程碑，但耐药不可避免。CIK细胞高表达NKG2D，与肺癌细胞表面NKG2D配体识别是免疫杀伤的基础。前期研究发现：联合EGFR-TKI和CIK治疗具有协同效应。预实验发现吉非替尼可诱导肺癌细胞高表达NKG2D配体ULBP1，加强其对CIK细胞杀伤敏感性，但机制不清。SHP2是我们研究证实的肺癌顺铂耐药相关蛋白，预实验发现SHP2与ULBP1表达呈负相关。结合文献报道，我们推测吉非替尼抑制SHP2，经AKT通路下调转录抑制因子Sp3活性，导致ULBP1高表达，提高CIK对肺癌细胞的免疫识别。我们拟通过载体构建、RNAi分别建立高/低表达SHP2的肺腺癌细胞系，检测吉非替尼处理前后AKT/Sp3/ULBP1通路变化及对CIK细胞的敏感性变化，并通过动物实验加以验证。研究有助于发现潜在的抑制EGFR-TKI耐药的靶点，为优化肺癌联合治疗模式奠定基础。

Molecular targeted therapy, represented by EGFR-TKI, is a milestone in the treatment of non-small cell lung cancer(NSCLC). However, drug resistance to EGFR-TKI is inevitable. Cytokine-induced killer cells(CIKs) are induced and amplified from peripheral blood mononuclear cells (PBMCs) with multiple cytokines, which exhibited a powerful killing activity both in vitro and in vivo and transfusion of these cells have become an adjuvant treatment for tumors. NKG2D is an activating receptor that can bind to NKG2DLs(such as MIC A/B,ULBP1-6) that are expressed on the surface of tumor cells and plays a crucial role in antitumor responses.We have found that CIKs overexpress NKG2D and our previous studies have also shown that co-EGFR-TKI and CIK have synergistic effects. Pretreatment of gefitinib can induce lung cancer cells to express NKG2D ligand ULBP1, and thus enhance its sensitivity to CIK cells, but the mechanism remains unclear. SHP2 is a drug resistance-related protein in lung cancer, and our pre-experiment found that SHP2 expression is negatively correlated with ULBP1 expression. Combined with the literatures and our previous studies, we speculated that gefitinib inhibited SHP2, down-regulated the transcriptional inhibitory factor Sp3 via AKT pathway, leading to high expression of ULBP1 and enhanced CIK immune recognition on lung cancer cells. Therefore, we hope to establish lung adenocarcinoma cell lines with stable high/low SHP2 expression through vector construction, RNA interference, detect the changes of AKT/Sp3/ULBP1 pathway and sensitivity to CIK cells before and after gefitinib treatment and verified by animal experiments. The study helped to identify potential targets for inhibiting EGFR-TKI resistance, laying the foundation for exploring new approaches to lung cancer treatments.