Overcoming radiation-induced PD-L1 and COX-2 upregulation by nitric oxide gas nanogenerator to sensitize radiotherapy of lung cancer

Currently, certain lung cancer patients exhibit resistance to radiotherapy due to reduced DNA damage under hypoxic conditions and the cytoprotective and immune-resistance effect caused by increased programmed death ligand-1 (PD-L1) and Cyclooxygenase 2 (COX-2) expression after radiotherapy. At present, existing nanoparticles or drugs could hardly effectively, and easily address these obstacles faced by highly effective radiotherapy simultaneously, especially the simultaneous depression of PD-L1 and COX-2. In this study, it is newly proved that some typical nitric oxide (NO) gas donors could co-inhibit PD-L1 and COX-2 expression, revealing the possible not fully proven role of NO in reversing tumor immunotherapy resistance. Then, to realize selective NO generation in tumors, a simple tumor glutathione (GSH) responsive NO gas nanogenerator named SAB-NO nanoparticles was designed and prepared, which was composed of the NO donor Isoamyl Nitrite conjugated with serum albumin (SAB). By doing this, SAB-NO nanoparticles more effectively sensitized radiotherapy through breaking the cytoprotective effects faced by radiotherapy in vitro by generating more DNA damage through reversing tumor hypoxia and impairing the DNA damage repair process through decreasing PD-L1 expression. Then, the combination therapy of SAB-NO nanoparticles and radiotherapy effectively transformed cold tumors into hot ones through avoiding some potential immune-resistance effects induced by radiotherapy treatment alone through PD-L1 and COX-2 co-inhibition. In conclusion, the combined treatment of radiotherapy and SAB-NO nanoparticles finally almost completely suppressed the growth of lung tumors, revealing the novel role of NO donors in sensitizing tumor immunotherapy by avoiding the potential cytoprotective and immune-resistance effects.