Spatial transcriptomics and single-cell analyses reveal the role of the cisplatin-resistant gene panel in NSCLC progression and the tumor microenvironment, identifying LOXL2 as a potential therapeutic target.

[BACKGROUND] Non-small cell lung cancer (NSCLC) patients often develop resistance to platinum-based chemotherapy, especially cisplatin, leading to treatment failure. This study aimed to identify high-score epithelial cells in tumors within the cisplatin-resistant gene panel (CRGP) and investigate their role in tumor progression and the microenvironment.

[METHODS] Using cisplatin-resistant cell datasets from GEO and TCGA for NSCLC, we identified the CRGP and its clinical significance. By integrating five single-cell datasets and applying 13 scoring methods, we identified tumor epithelial cells with high CRGP scores (CRGPhighepi). We evaluated drug sensitivity using the BeyondCell algorithm and studied intrinsic mechanisms using Cytotrace, Monocle, SCENIC, and CellCall. Spatial transcriptomics and deconvolution methods identified CRGPhighepi and other cell types. The prognostic model, designated as SuperPCCRGP, was constructed. Subsequent CRGP co-expression network analysis revealed an association between CRGP and LOXL2, implicating their roles in cisplatin resistance. The impact of LOXL2 on cisplatin sensitivity was further validated through experiments.

[RESULTS] CRGP was identified as a potential risk factor for NSCLC prognosis. High CRGP score epithelial cells (CRGPhighepi) activate pathways related to cell cycle and DNA repair and interact with smooth muscle cells. CRGPhighepi exhibits drug resistance to Cisplatin and Paclitaxel. The SuperPC model showed robust predictive performance. LOXL2 was linked to poor prognosis and therapy response. LOXL2 knockdown enhanced cisplatin sensitivity in NSCLC.

[SUPPLEMENTARY INFORMATION] The online version contains supplementary material available at 10.1186/s12935-026-04170-0.