Data underlying the research of Spatial Transcriptomics Evaluation of Drug Resistance in Non-Small Cell Lung Cancer Regulated by Multiple Mechanisms Including ABC Transporters

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer mortality worldwide, with epidermal growth factor receptor inhibitors (EGFRi) serving as a cornerstone of targeted therapy. However, acquired resistance to EGFRi severely limits clinical efficacy and is driven by multifactorial mechanisms that remain incompletely understood. This study employs spatial transcriptomics to systematically investigate resistance mechanisms within the tumor microenvironment (TME). Data from GEO and TCGA cohorts were integrated to identify resistance-associated genes, pathways, and their spatial interactions. Analysis revealed significant remodeling of the immune microenvironment, characterized by M2 macrophage predominance and T-cell exhaustion. The ABC transporter gene ABCC1 was upregulated and broadly distributed, spatially overlapping with immune-related genes such as TNFRSF17, highlighting the interplay between drug efflux and immune modulation. Enrichment analysis indicated that drug resistance is predominantly regulated by ABC transporters, metabolic reprogramming, immune evasion, and DNA repair. Prognostic evaluation identified ABCC1, GSTA1, IFNA5, and PDHA2 as protective factors, whereas ABCG2, JAK1, LDHC, and MLH1 acted as risk genes. Mendelian randomization confirmed a strong causal association between IL-6 and NSCLC, whereas lactate accumulation contributed indirectly via immune suppression. Collectively, findings demonstrate that NSCLC resistance arises from spatially coordinated mechanisms, in which drug efflux, immune dysfunction, and metabolic adaptation synergize to maintain resistant phenotypes. These insights provide a spatially resolved framework for designing future combination therapies targeting multiple resistance pathways.

非小细胞肺癌 (non-small cell lung cancer, NSCLC) 仍是全球范围内癌症相关死亡的首要病因，表皮生长因子受体抑制剂 (epidermal growth factor receptor inhibitors, EGFRi) 是其靶向治疗的核心基石。然而，EGFRi获得性耐药严重制约了临床疗效，其背后的多因素耐药机制目前仍未被完全阐明。本研究采用空间转录组学 (spatial transcriptomics) 技术，系统探究肿瘤微环境 (tumor microenvironment, TME) 内的耐药机制。研究整合GEO与TCGA队列的数据集，以筛选耐药相关基因、通路及其空间互作关系。分析结果显示免疫微环境发生显著重塑，以M2型巨噬细胞占优与T细胞耗竭为典型特征。ABC转运体基因ABCC1呈上调表达且分布广泛，其空间分布与TNFRSF17等免疫相关基因存在共定位，由此揭示了药物外排与免疫调控之间的交互调控关系。富集分析结果表明，耐药性主要受ABC转运体、代谢重编程、免疫逃逸与DNA修复通路调控。预后评估显示，ABCC1、GSTA1、IFNA5与PDHA2为保护性基因，而ABCG2、JAK1、LDHC与MLH1则为风险基因。孟德尔随机化 (Mendelian randomization) 分析证实，IL-6与NSCLC存在显著因果关联；而乳酸堆积则通过免疫抑制途径间接参与耐药进程。综合来看，本研究结果表明，NSCLC耐药源于空间协同调控的多种机制：药物外排、免疫功能异常与代谢适应协同作用，共同维持耐药表型。上述研究结果为未来靶向多条耐药通路的联合治疗方案设计提供了空间分辨率层面的理论框架。