Abstract
Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, and high programmed death-ligand 1 (PD-L1) expression (≥50%) is a key biomarker for predicting clinical benefit from immune checkpoint inhibitors (ICIs). This therapy has substantially improved long-term survival rates, with a five-year survival rate exceeding 25%. Nevertheless, primary or acquired resistance occurs in 30-40% of PD-L1-high patients. This resistance arises from multifactorial mechanisms involving tumor-intrinsic adaptations, immune microenvironment reprogramming, and extrinsic immunosuppressive signals. In this review, we systematically dissect the biological and clinical drivers of ICIs resistance in PD-L1-high NSCLC and explore emerging strategies to overcome these barriers, including novel combinatorial approaches and biomarker-guided therapies.