Jianhua Liu,1,* Yin Cai,2,* Jiang Liu,2 Dadong Chen,2 Xiang Wu2 

1Department of Otorhinolaryngology, Xinghua People’s Hospital Affiliated to Yangzhou University, Xinghua, Jiangsu, People’s Republic of China; 2Department of Oncology, Xinghua People’s Hospital Affiliated to Yangzhou University, Xinghua, Jiangsu, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Jiang Liu, Department of Oncology, Xinghua People’s Hospital Affiliated to Yangzhou University, 419 Ying Wu Nan Road, Xinghua, Jiangsu, 225700, People’s Republic of China, Email liujiang8901@163.com Xiang Wu, Department of Oncology, Xinghua People’s Hospital Affiliated to Yangzhou University, 419 Ying Wu Nan Road, Xinghua, Jiangsu, 225700, People’s Republic of China, Email 64681385@qq.com

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.

Keywords: PD-L1, non-small cell lung cancer, immunotherapy, immunotherapy resistance, biomarkers