From Molecular Alterations to Risk Prediction: Biomarkers of Actinic Keratosis Progression to Cutaneous Squamous Cell Carcinoma

The high—and in most countries steadily increasing—incidence of cutaneous squamous cell carcinoma (cSCC) represents a growing public health challenge. As the majority of cSCCs arise from pre-existing actinic keratosis (AKs), these lesions are recognized as the principal precursors of invasive disease. A comprehensive understanding of the molecular mechanisms driving the progression from AK to cSCC is essential for advancing prevention, facilitating early diagnosis, and enabling targeted therapies. Moreover, this knowledge provides a basis for identifying biomarkers that can predict the risk of malignant transformation. The progression from AK to cSCC is a complex, multistep process driven by the gradual accumulation of genetic, epigenetic, and microenvironmental alterations. Over the past decades, numerous molecular changes associated with this transition have been identified. However, no single biomarker has demonstrated sufficient predictive accuracy for clinical use. This reflects the pronounced molecular heterogeneity of AKs as no individual alteration is uniformly present in all lesions that undergo malignant progression. In addition, numerous proposed biomarkers are also detected in non-progressive AKs and even in non-neoplastic skin, which compromises their sensitivity and specificity for predicting progression to cSCC. Current evidence, therefore, suggests that the most promising strategy for identifying AKs at greatest risk of malignant transformation is the development of a multi-marker panel. This panel, ideally, should integrate molecular signatures encompassing genetic, epigenetic, proliferative, inflammatory, and microenvironmental markers. This review summarizes the molecular factors that currently represent the most promising candidates for inclusion in such a multi-marker panel and discusses their potential clinical utility, while emphasizing the need for validation in well-designed prospective longitudinal studies.