Radiomics- based biomarkers for immunotherapy in non-small cell lung cancer: advances, challenges, and future perspectives in biological interpretation and clinical translation

Immune checkpoint inhibitors (ICIs) have improved outcomes in non-small cell lung cancer (NSCLC), yet treatment benefit remains heterogeneous and resistance is common. Genomic alterations, tumor microenvironment (TME) remodeling, and metabolic reprogramming across spatial and temporal scales that are incompletely captured by single-site tissue sampling. Radiomics extracts quantitative features from routine images and offers a framework for investigating macroscopic correlates of these processes. This narrative review critically examines computed tomography (CT) and fluorine-18 fluorodeoxyglucose positron emission tomography/CT (¹ 8 F-FDG PET/CT) radiomics in relation to oncogenic alterations, immune and stromal phenotypes, programmed death-ligand 1 (PD-L1) expression, tumor mutational burden, and metabolic–immune interactions in NSCLC. It should be highlighted that such observed statistical links only generate plausible biological hypotheses and do not constitute experimental proof of true mechanistic relationships. Rather than merely summarizing predictive model performance, we emphasize evidence boundaries and interpretive caveats for radiomic-TME associations. We further elaborate on key translational bottlenecks including limited reproducibility, technical standardization deficits, and retrospective-model overfitting. We discuss ongoing efforts toward cross-scale multi-omics integration, alongside the promises and inherent limitations of explainable artificial intelligence and federated learning for clinical translation. To move beyond purely predictive tools toward mechanism-aware decision-support systems, future radiomic research requires prospective multicenter validation, rigorous data harmonization, and combined analyses integrating spatial transcriptomics, digital pathology, and circulating biomarkers for precision immuno-oncology.