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The review summarizes molecular, genetic, and epigenetic mechanisms, linking them to treatment approaches from earlier methods to modern targeted therapies, especially for advanced 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Banciu 1, Cristina Soare 1,3 and Sanda-Maria Cretoiu 4, *  \nCitation: Cozma, E.-C.; Banciu, L.M.; Soare, C.; Cretoiu, S.-M. Update on the Molecular Pathology of Cutaneous Squamous Cell Carcinoma. Int. J. Mol. Sci. 2023, 24, 6646. [https://doi.org/10.3390/](https://doi.org/10.3390/)  \nijms24076646  \nAcademic Editor: Terrence Piva  \nReceived: 29 January 2023  \nRevised: 24 March 2023  \nAccepted: 30 March 2023  \nPublished: 2 April 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Dermatology Department, Elias University Emergency Hospital, 011461 Bucharest, Romania; [codrutadobrica@gmail.com](codrutadobrica@gmail.com) (E.-C.C.)  \n2 Pathophysiology Department, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania  \n3 Surgery Department, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania  \n4 Department of Cell and Molecular Biology and Histology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania  \n* Correspondence: [sanda.cretoiu@umfcd.ro](sanda.cretoiu@umfcd.ro)  \nAbstract: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, originating from keratinocytes of the spinous layer. Numerous risk factors have been discovered for the initiation and growth of this type of cancer, such as exposure to UV and ionizing radiation, chemical carcinogens, the presence of immunosuppression states, chronic inflammation, infections with high-risk viral strains, and, last but not least, the presence of diseases associated with genetic alterations. The important socio-economic impact, as well as the difficulty associated with therapy for advanced forms, has made the molecular mechanisms underlying this neoplasia more and more intensively studied, with the intention of achieving a better understanding and advancing the treatment of this pathology. This review aims to provide a brief foray into the molecular, genetic, and epigenetic aspects of this cancer, as well as the treatment methods, ranging from the first used to the latest targeted therapies.  \nKeywords: squamous cell carcinoma; skin cancer; cancer stem cells; epigenetics; targeted therapies  \n1. Introduction  \nSquamous cell carcinoma (SCC) is one of the most common neoplasms (second place among all neoplasia), originating from keratinocytes in the spinous layer of keratinized stratified squamous epithelium [1] . This origin makes possible the occurrence of SCC types at the level of all organs and tissues that contain stratified squamous epithelia, such asthe skin or mucous membranes lining the hollow organs (digestive tract, oral cavity, and respiratory tract epithelium) . Regarding cutaneous SCC (cSCC), it ranks second among non-melanocytic skin cancers, after basal cell carcinoma, with an increasing incidence in recent years in Europe, although the incidence rate is stable in the USA and Australia [2,3] . Regarding risk factors, exposure to ultraviolet radiation (UVA and UVB) is the main cause of carcinogenesis in cSCC; by inducing DNA alterations in tumor suppressor genes or in pro-oncogenes, the risk increases through cumulative exposure throughout life. Other incriminated risk factors are represented by immunosuppression, chronic infections (especially with Human Papilloma Virus—HPV), genetic changes in genes involved in DNA repair, chronic ulceration, and chronic inflammation (Figure 1) [4,5] .  \nThe complex molecular mechanisms involved in the occurrence of cSCC, as well as the important mutational burden, translate into the presence of a large number of precursor fo","cbCaidbbLWZHPeTf","https://ap.wps.com/l/cbCaidbbLWZHPeTf","pdf",696611,16,"English","# Introduction\n# Mechanisms of SCC Carcinogenesis: Molecular Pathogenesis of SCC","[{\"question\":\"What is cutaneous squamous cell carcinoma (cSCC) and where does it originate?\",\"answer\":\"cSCC is the second most common skin cancer and originates from keratinocytes of the spinous layer.\"},{\"question\":\"What are the main risk factors associated with cSCC?\",\"answer\":\"Key risk factors include exposure to UV (UVA/UVB) and ionizing radiation, chemical carcinogens, immunosuppression, chronic infections such as HPV, genetic alterations in DNA repair genes, chronic ulceration, and chronic inflammation.\"},{\"question\":\"What does the review cover regarding molecular pathology and treatment?\",\"answer\":\"It highlights molecular, genetic, and epigenetic aspects of cSCC and discusses treatment methods ranging from earlier approaches to latest targeted therapies, including mechanisms that can influence resistance.\"}]","Update on the Molecular Pathology of Cutaneous Squamous Cell Carcinoma | PDF",1790220519]