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Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated mortality. Therapies targeting programmed cell death 1 ligand 1 (PD1L1) have promising effects on NSCLC. However, resistance to targeted therapy has become the main problem and the underling molecular mechanism remains unclear. In the present study, the expression of PD1L1 in NSCLC was determined and the association with clinicopathological characteristics was analyzed. A combination therapy was also constructed, including pembrolizumab (Pem) and iodine-125 ( 125 I), which represented an efficient strategy for the treatment of NSCLC. The expression of PD1L1 was upregulated in NSCLC tissues and positively correlated with the Ki-67 index, pathological subtypes and risk stages. A higher level of PD1L1 expression was associated with poorer survival in patients with NSCLC, which could be used as a prognostic indicator. When NSCLC cells were cultured in the presence of Pem and 125 I seeds, the combination treatment significantly abrogated the tumor proliferation and aggressiveness through the inhibition of matrix metalloproteinase-2 and -9 secretion. Flow cytometry analysis revealed pembrolizumab combined with 125 I contributed to a higher rate of apoptosis and cell cycle arrest, indicating that the combination treatment improved the resistance to immunotherapy. Furthermore, the associated molecular mechanism was the dysregulation of ADAM metallopeptidase domain 17. The findings from the present study revealed that PD1L1 could be used as a predictive biomarker, and the application of combination treatment of pembrolizumab and 125 I showed promising effects on NSCLC., (Copyright © 2020, Spandidos Publications.)