Development of a computed tomography radiomics and CD38 integrated model: predicting immunotherapy response and investigating biological implications in non-small cell lung cancer

Background: Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancers and remains the leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) improve survival in selected patients, yet their clinical utility is limited by low objective response rates, challenges in patient selection, and suboptimal performance of existing biomarkers. Radiomics can quantitatively characterize tumor heterogeneity on computed tomography (CT) imaging and shows promise in predicting treatment response and immune microenvironment profiles. CD38, a key immunosuppressive molecule, impairs T-cell function and recruits suppressive cells via the adenosine pathway. This study aimed to integrate radiomic features with CD38 expression to build a multimodal prediction model and investigate its underlying biology. Methods: We retrospectively included 45 NSCLC patients receiving ICIs (training cohort: n=31; validation cohort: n=14). A total of 1,223 CT radiomic features were extracted and selected by least absolute shrinkage and selection operator (LASSO) regression to construct a radiomics model. CD38 expression was quantified by immunohistochemistry and combined with radiomics in a fusion model. An independent validation cohort (n=89) was derived from The Cancer Imaging Archive (TCIA) and Gene Expression Omnibus (GEO) datasets. Model performance was evaluated using receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Overall survival (OS) differences were assessed by Kaplan-Meier analysis. Molecular mechanisms were explored using differential gene expression, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT), and single-sample gene set enrichment analysis (ssGSEA). Results: T cells and M1 macrophages; low-response patients were enriched in extracellular matrix (ECM) remodeling genes and collagen metabolism pathways, with higher infiltration of M2 macrophages and regulatory T cells. Conclusions: Integrating radiomic features with CD38 expression significantly enhances specificity and clinical applicability in predicting immunotherapy response, while elucidating molecular and immunological mechanisms underlying response heterogeneity. The model supports individualized risk stratification and precision therapy planning; however, larger multicenter prospective studies and multi-omics integration are warranted to further validate and optimize its utility.