CD274 and neoplasm: In parallel, smoke exposure modulates expression of PDL1 and the secretory phenotype of HNSCC cells resulting in an altered tumor immune microenvironment (TIME) in syngeneic mouse models and downregulated expression of antigen presentation and costimulatory genes in myeloid cells.<h4>Conclusion</h4>The cigarette smoke exposome is a potent activator of the Nrf2 pathway and appears to be the primary trigger for a tripartite phenotype of aggressive HNSCC consisting of: (1) reduced chemotherapy sensitivity, (2) enhanced metastatic potential and (3) suppressed anti-tumor immunity.