Beyond PD-L1: emerging clinical and molecular biomarkers of response to immune checkpoint inhibitors in non-small cell lung cancer

Immune checkpoint inhibitors (ICIs) have radically changed the treatment landscape of non-small cell lung cancer (NSCLC) and significantly improved patients' prognosis in many settings of the disease. Nevertheless, clinical outcomes remain highly heterogeneous, and a substantial proportion of patients do not achieve meaningful and/or durable benefit from immunotherapy. This variability in treatment response has highlighted the need to identify more robust predictive biomarkers that integrate, beyond established biomarkers such as programmed cell death ligand 1 (PD-L1) expression, additional clinical, genomic, immunologic, and microenvironmental features to better identify the biological determinants underlying sensitivity and resistance to ICIs. In this review, we will analyze the current evidence supporting established predictive biomarkers, including PD-L1 expression, while highlighting their major limitations. We will also discuss and summarize emerging clinical and molecular biomarkers and integrative predictive approaches aimed at improving the stratification of patients with NSCLC, to identify those most likely to benefit from ICI therapy and ultimately refine personalized treatment strategies.