Bioinformatics profiling of NECTIN4 in lung cancer and comparative evaluation of NECTIN4-targeted 68Ga-N188 and 18F-FDG PET/CT

Background The nectin cell adhesion molecule 4 (NECTIN4) has been implicated in tumor progression and immune evasion. However, its role and translational imaging potential in lung cancer remain unclear. Therefore, this study aims to elucidate the molecular characteristics of NECTIN4 by integrating multi-omics bioinformatics analyses with clinical PET/CT validation, and evaluate the diagnostic efficacy of the NECTIN4-targeted radiotracer ⁶⁸Ga-N188 compared to ¹⁸F-FDG. Methods Transcriptomic and proteomic datasets from The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Omnibus and other bioinformatic tools were used to characterize NECTIN4 expression levels, genomic alterations, associated regulatory networks and prognostic value. Subsequently, in a prospective clinical cohort study involving 20 patients with suspected primary lung cancer, paired PET/CT imaging using ⁶⁸ Ga-N188 and ¹⁸ F-FDG was conducted. The diagnostic performance of imaging modalities was assessed by quantitatively comparing the tumor-to-blood pool ratio between malignant and inflammatory lesions. Results Bioinformatics analyses indicated that NECTIN4 was significantly upregulated across multiple cancer types and correlated with genomic instability and poor prognosis in non-small cell lung cancer. NECTIN4 expression was positively associated with DNA methyltransferases and RNA modifications, suggesting its regulation by epigenetic and post-transcriptional. Clinically, ⁶⁸Ga-N188 PET/CT exhibited superior specificity (100% vs. 50%) and comparable sensitivity (87.5% vs. 93.8%) to ¹⁸F-FDG PET/CT in differentiating malignant from inflammatory lung lesions, but with lower sensitivity (42.2% vs 100.0%) for detecting lymph node metastases and fewer identified distant metastatic lesions (21 vs 51). Conclusion Our findings revealed that NECTIN4 as a promising biomarker and imaging target in lung cancer. The NECTIN4-targeted ⁶⁸Ga-N188 PET/CT outperforms ¹⁸F-FDG PET/CT in diagnosing primary lung cancer, supporting its role as a promising complementary imaging modality in clinical practice.