Background <p>Lung adenocarcinoma (LUAD) with high expression of PD-L1 (TPS ≥ 50%) is a distinct subset of NSCLC and a potential immunotherapy candidate. An improved understanding of the heterogeneity of PD-L1-high LUAD patients and the recognition of other biomarkers combined with PD-L1 could facilitate more precise use of PD-1 inhibitors in clinical practice.</p> Methods <p>Surgically resected tumour tissues from 69 LUAD patients with a PD-L1 TPS ≥ 50% defined by 22C3 antibody were tested for p53 and IFN-γ protein expression using immunohistochemistry. The densities of CD8 and Granzyme B-positive T cells were evaluated by immunohistochemistry. EGFR mutation was detected by RT‒PCR, ALK rearrangement was examined by a fluorescence in situ hybridization (FISH) assay, and TP53 gene mutations were sequenced using Sanger sequencing.</p> Results <p>Differences in clinicopathological features, including age and spread through the air space (STAS), were observed between patients with higher PD-L1 expression (TPS ≥ 50%, &lt; 70%) and those with the highest PD-L1 expression (TPS ≥ 70%). LUAD patients whose PD-L1 TPS was ≥ 70% and whose p53 protein abnormal expression or NLR was &lt; 5 had higher densities of CD8-positive tumour-infiltrating lymphocytes (TILs) and Granzyme B-positive T cells as well as higher IFN-γ protein expression than those whose TPS was &lt; 70%, those whose p53 protein expression was normal, or those whose NLR was ≥ 5.</p> Conclusions <p>The present study is the first to reveal that distinct subtypes of PD-L1-high LUAD can be identified on the basis of p53 protein expression and the NLR. p53 expression and the NLR can recognize a subtype with brisk immune cell cytotoxicity that might potentially respond better to PD-1 inhibitors.</p>