Background: For patients with non-small cell lung cancer (NSCLC), the PD-1/PD-L1 blockade treatment were incorporated into first-line treatment commonly. Despite the improved survival observed in PD-1 blockade treatment, a large proportion of patients do not respond while others actually progress during treatment. Method: Transcriptomic profiling was performed on whole blood samples from 30 patients received anti-PD-1 (Tislelizumab) plus chemotherapy. Expression levels of differentially expressed genes (DEGs) identified from two comparisons (post-and pre-treatment, responders and non-responders) were validated by real-time quantitative PCR, analyzed within tissue database and meta-analysis database, then followed by enrichment analysis in high-level representations and in silico leukocyte deconvolution. Results: A panel of blood-based gene signatures (FDR p<0.05, fold change<-2 or >2) were identified (DEG n=155 and 112 in two comparisons) and validated that not only differentially expressed between post- and pre- treatment or responders and non-responders but also in tissue samples between normal and tumor. Genes DLG5 and H3C10 were found negatively associated with overall survival (p<0.05). Enrichment of immunological and metabolism pathways and gene sets indicating activated circulating leukocytes were observed. Conclusion: The molecular and cellular signatures characterized in this study may provide potential blood-based predictors of the response to PD-1 blockade treatment in NSCLC patients.