Ruolo del microambiente immuno-infiammatorio nello sviluppo del carcinoma squamocellulare cutaneo

Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer and represents an increasing public health burden due to its rising incidence, biological heterogeneity, and potential for aggressive clinical behavior. A significant proportion of cSCCs develop from actinic keratosis (AK) within a broader context of field cancerization (CC), a condition characterized by genetically altered but clinically inconspicuous skin chronically exposed to ultraviolet radiation. Although genetic alterations in keratinocytes are central to cSCC pathogenesis, growing evidence indicates that tumor progression is critically influenced by the inflammatory and immune components of the tumor microenvironment. This doctoral thesis explores the transcriptional profiles of the immune microenvironment underlying the progression from field cancerization and AK to invasive cSCC, with the aim of delineating immune-related mechanisms associated with malignant transformation. Using next generation targeted immune RNA sequencing, gene expression patterns were analyzed in paired samples of CC, AK, and cSCC obtained from patients. Multivariate and differential expression analyses revealed a progressive, condition-specific remodeling of the immune microenvironment along the AK–cSCC continuum. Invasive cSCC was characterized by the upregulation of inflammatory and cytotoxic-related transcriptional programs, together with increased macrophage-related and regulatory immune signatures, indicating a shift toward an immunoregulatory and myeloid-enriched milieu. In contrast, pre-neoplastic lesions such as AK exhibited a distinct immune profile, with relative enrichment of antigen presentation, dendritic cell–associated pathways, and selected T cell–related signatures. These findings indicate a qualitative reprogramming of immune regulation during malignant progression, rather than a uniform amplification of immune activity. Overall, this work provides the immunological framework for cSCC development, highlighting the pivotal role of the tumor microenvironment in disease evolution. The results support the concept that early immune dysregulation contributes to carcinogenesis and may represent a window for therapeutic intervention aimed at preventing progression to invasive disease.