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Squamous cell carcinoma of the skin or cutaneous squamous cell carcinoma is the second most common form of skin cancer in the United States, behind basal cell carcinoma. Squamous cell carcinoma has precursor lesions called actinic keratosis, exhibits tumor progression and has the potential to metastasize in the body. Ultraviolet (UV) solar radiation is the primary risk factor in the development of cutaneous squamous cell carcinoma and the cumulative exposure received over a lifetime plays a major part in the development of this cancer. Surgical excision is the primary treatment modality for cutaneous squamous cell carcinoma, with Mohs micrographic surgery being the preferred excisional technique for squamous cell carcinoma of the head and neck, and in other areas of high risk or squamous cell carcinoma with high-risk characteristics. Radiation therapy is reserved for squamous cell carcinoma in older patients or those who will not tolerate surgery, or when it has not been possible to obtain clear margins surgically. Adjuvant radiotherapy is commonly after surgical treatment in very high tumors. Immunosuppression significantly increases the risk of squamous cell carcinoma over the course of an individual’s life. Metastasis is uncommon for squamous cell carcinomas arising in areas of chronic sun exposure, but it can take place, and the risk is increased in immunosuppressed patients. Patients with cutaneous squamous cell carcinoma should be examined regularly and remember to use measures to protect from UV damage.

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and its incidence continues to rise. Although CSCC usually display a benign clinical behavior, it can be both locally invasive and metastatic. The signaling pathways involved in CSCC development have given rise to targetable molecules in recent decades. In addition, the high mutational burden and increased risk of CSCC in patients under immunosuppression were part of the rationale for developing the immunotherapy for CSCC that has changed the therapeutic landscape. This review focuses on the molecular basis of CSCC and the current biology-based approaches of targeted therapies and immune checkpoint inhibitors