Desrichard A, et al. - Authors explored the relationships between the mutational signature of tobacco smoking, tumor mutational load, and metrics of immune activity in squamous cell carcinoma originating in the head and neck and lung by using RNA and DNA sequencing data from The Cancer Genome Atlas head and neck and lung squamous cell carcinoma datasets and 2 independent gene expression datasets. They observed that the genetic smoking signature was linked to higher mutational load, but multiple influences on tumor immunity could take place, depending on the anatomic site in case of squamous cell carcinoma. They noted more inflammatory responses in LUSC and immunosuppressive effects in HNSC. They noted that tumor mutation load and immune microenvironment influenced the clinical response to immunotherapy. Consequently, the mutational smoking signature was considered appropriate for immunotherapeutic investigation in smoking-associated cancers.