Insulin Resistance and Cutaneous Squamous Cell Carcinoma: A Narrative Review of Molecular Mechanisms.

Although the association between diabetes and cutaneous squamous cell carcinoma (cSCC) is well recognized, the specific role of insulin resistance (IR) as an independent driver of cSCC pathogenesis remains underexplored. This review synthesized emerging evidence on the ultraviolet (UV)-independent molecular mechanisms by which IR promotes cSCC initiation and progression. Hyperinsulinemia activates the insulin-like growth factor-1 receptor (IGF-1R), which triggers both the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathways, stimulating keratinocyte proliferation and suppressing apoptosis. In parallel, hyperglycemia-driven formation of advanced glycation end products (AGEs) and oxidative stress cause deoxyribonucleic acid (DNA) damage and impair tumor suppressor functions, notably that of tumor protein p53 (TP53). The resulting reactive oxygen species (ROS) activate nuclear factor-kappa B (NF-κB), establishing a chronic inflammatory milieu that remodels the tumor microenvironment through cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and by upregulating matrix metalloproteinases (MMPs). These processes collectively facilitate the malignant transformation of actinic keratosis (AK) to invasive cSCC. The analysis in the present study identified novel therapeutic targets and reaffirmed the importance of further studies on microbiome interactions and lifestyle interventions for IR-associated cSCC.