表皮生长因子受体酪氨酸激酶抑制剂（Epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs）为突变型肺腺癌患者带来生存和生活质量的受益，已成为其不可或缺的重要治疗方式。但临床实践中，几乎所有EGFR突变患者在治疗有效10个月左右因耐药而治疗失败。故耐药是限制靶向治疗成为肺癌治愈性手段的瓶颈。目前靶向药物及克服耐药的治疗策略仅关注肿瘤因素而忽略宿主因素，即肿瘤微环境对耐药的影响。本研究在前期建立的异质性模型及人群队列基础上，通过体内外试验及组学研究，探讨在EGFR-TKIs治疗过程中，EGFR突变异质性肺腺癌敏感和耐药克隆的相互作用模式以及细胞因子网络和免疫耐受导致EGFR-TKIs耐药的分子机制，通过循环肿瘤细胞探索预测分子标志物并建立预警、监测体系，为将来临床靶向治疗与免疫治疗的联合应用提供依据。

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has emerged as an indispensable therapeutic strategy for patients harboring EGFR mutation, bringing significant survival benefit as well as improving the quality of life. In clinical practice, however, these patients could hardly escape from treatment failure 8-12 months later due to acquired resistance, making it the bottleneck that restrains targeted therapies from becoming the curing approach of lung cancer. The current targeted drugs and therapeutic strategies to overcome resistance focus merely on tumor itself while neglecting the host, i.e. the influence of tumor microenvironment on resistance. In this study, we conducted numerous studies in vivo and vitro to explore the interaction pattern between sensitive and resistant subclones of heterogeneous lung cancer during targeted therapy, and to disclose the molecular mechanism of the targeted therapy-induced cell secreting signal network activating the resistant subclone, and to determine the immunogenicity of EGFR-TKI-resistance-related genes in non small cell lung cancer (NSCLC) and the relevance and regulatory mechanism of these genes with vital inhibitory molecules in tumor microenvironment. Further we explored the combined therapeutic strategy aiming at various resistant genes and the corresponding microenvironment changes and established a predictive system based on circulating tumor cells (CTCs), which can provide evidence for the future clinical application combining targeted therapy and immunotherapy.