Despite numerous reports on immune checkpoint inhibitor for the treatment of non-small cell lung cancer (NSCLC), the response rate remains low but durable. Thus cisplatin still plays a major role in the treatment of NSCLC. While there are many mechanisms involved in cisplatin resistance, alteration in metabolic phenotypes with elevated levels of reactive oxygen species (ROS) are found in several cisplatin resistant tumors. These resistant cells become more reliant on mitochondria oxidative metabolism instead of glucose. Consequently, high ROS and metabolic alteration contributed to epithelial-mesenchymal transition (EMT). Importantly, recent findings indicated that EMT has a crucial role in upregulating PD-L1 expression in cancer cells. Thus, it is very likely that cisplatin resistance will lead to high expression of PD-L1/PD-1 which makes them vulnerable to anti PD-1 or anti PD-L1 antibody treatment. An understanding of the interactions between cancer cells metabolic reprogramming and immune checkpoints is critical for combining metabolism targeted therapies with immunotherapies.

The improvement of the transfection efficiency of the non-viral-based gene delivery systems is a key issue for the application in gene therapy. We have previously described an archaeal histone-like protein-based (HPhA) gene delivery system and showed that HPhA formed stable non-covalent complexes with nucleic acids and improved their delivery by using b-galactosidase as a reporter gene. In this study, the wild-type p53 gene was transfected into the cancer cells using the HPhA as a vector, and the expression level and the activity of p53 gene were evaluated both in vitro and in vivo. Gene expression was determined by real-time reverse transcriptase-PCR and western blotting analysis. The cellular growth inhibition and apoptosis of HPhA-mediated p53 transfection were assessed by XTT (sodium 3 0 -[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid hydrate) assay and annexin V-FITC (fluorescein isothiocyanate) staining, respectively. Further more, transfection of HPhA/p53 into CNE (nasopharyngeal carcinoma cell line)-xenografted nude mice was performed and tumor growth was measured. The present study demonstrates that HPhA enhances the efficiency of p53 gene transfer and antitumor activity compared with the widely used Lipofectamine. These results demonstrate that HPhA enhances the in vitro and in vivo efficiency of p53 gene transfer and suggest that it may be served as a promising tool for gene delivery and gene therapy.