Abstract
Nearly two million cases of cutaneous squamous cell carcinoma (cSCC) are diagnosed every year in the United States alone. cSCC is notable for both its prevalence and its propensity for invasion and metastasis. For many patients, surgery is curative. However, patients experiencing immunosuppression or recurrent, advanced, and metastatic disease still face limited therapeutic options and significant mortality. cSCC forms after decades of sun exposure and possesses the highest known mutation rate of all cancers. This mutational burden complicates efforts to identify the primary factors driving cSCC initiation and progression, which in turn hinders the development of targeted therapeutics. In this review, we summarize the mutations and alterations that have been observed in patients' cSCC tumors, affecting signaling pathways, transcriptional regulators, and the microenvironment. We also highlight novel therapeutic opportunities in development and clinical trials.