Transcriptomic Assessment of PD-L1 (CD274) in NSCLC: Biological Significance, Clinical Relevance, and Methodological Challenges

PD-L1 immunohistochemistry is widely used to guide immune checkpoint inhibitor therapy in non-small cell lung carcinoma (NSCLC), but its clinical performance is limited by spatial and temporal heterogeneity and assay-related variability. Transcriptomic assessment of CD274 may provide complementary information. We conducted a narrative review of PubMed to evaluate the biological and clinical significance of CD274 transcript expression in NSCLC, with additional consideration of PDCD1/PD-1 and methodological sources of heterogeneity. Overall, 29 studies were included, predominantly retrospective cohorts. CD274 transcript levels generally showed a positive, but variable, association with PD-L1 protein expression. Associations with histological subtype, tumour stage, smoking status, molecular alterations, and survival were inconsistent across studies. Treatment-associated findings were more promising in selected immune checkpoint inhibitor-treated cohorts. Associations were more pronounced in selected co-expression-defined subgroups, particularly for CD8A/CD274; however, the incremental value of multimarker models over single-gene assessment has not been consistently established. Differences in cellular composition, spatial heterogeneity, treatment exposure, reference-gene selection, and tissue preservation likely contributed to discordant results. In conclusion, CD274 transcript expression may complement PD-L1 immunohistochemistry in NSCLC, but current evidence is insufficient to support its use as a stand-alone prognostic or predictive biomarker. Prospective validation and methodological standardisation are required.