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.