The Tumor Stroma of Squamous Cell Carcinoma: A Complex Environment That Fuels Cancer Progression.

Simple Summary: Despite the high prevalence of cutaneous squamous cell carcinoma (cSCC), one of the most frequent human cancers, the tumor microenvironment (TME) of this specific cancer remains understudied. This review aims to comprehensively characterize the cSCC tumor stroma, examining its cellular and molecular components. We will delve into the TME's dynamic role in tumor progression, going beyond its traditionally viewed role as a passive element. Furthermore, the review will explore the TME's significant impact on cSCC therapy, highlighting its potential to both hinder treatment efficacy and offer targets for groundbreaking therapeutic approaches. The tumor microenvironment (TME), a complex assembly of cellular and extracellular matrix (ECM) components, plays a crucial role in driving tumor progression, shaping treatment responses, and influencing metastasis. This narrative review focuses on the cutaneous squamous cell carcinoma (cSCC) tumor stroma, highlighting its key constituents and their dynamic contributions. We examine how significant changes within the cSCC ECM—specifically, alterations in fibronectin, hyaluronic acid, laminins, proteoglycans, and collagens—promote cancer progression, metastasis, and drug resistance. The cellular composition of the cSCC TME is also explored, detailing the intricate interplay of cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), endothelial cells, pericytes, adipocytes, and various immune cell populations. These diverse players modulate tumor development, angiogenesis, and immune responses. Finally, we emphasize the TME's potential as a therapeutic target. Emerging strategies discussed in this review include harnessing the immune system (adoptive cell transfer, checkpoint blockade), hindering tumor angiogenesis, disrupting CAF activity, and manipulating ECM components. These approaches underscore the vital role that deciphering TME interactions plays in advancing cSCC therapy. Further research illuminating these complex relationships will uncover new avenues for developing more effective treatments for cSCC. [ABSTRACT FROM AUTHOR]

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