Molecular interplay between inflammation and skin cancer: Focus on NF-κB signalling

Skin cancer is the most commonly occurring malignancy globally, especially in light-skinned individuals and ultraviolet (UV) radiation has been identified as its main etiological factor. Although the mutagenic action of UV-induced DNA damage has been clearly demonstrated, recent evidence has underscored chronic inflammation as an important contributor to skin carcinogenesis. Chronic inflammation contributes to tumour initiation and growth by triggering several signalling cascades, with the nuclear factor-kappa B (NF-kB) being a key mediator. NF-kB is a transcription factor that regulates gene expression in immunity, cell survival, inflammation and resistance to apoptosis. This narrative review discusses the dual role of NF-kB in skin cancer pathogenesis, addressing its tumour-supportive and tumour-suppressive functions under specific conditions drawing on publications indexed in PubMed, Scopus and Web of Science from January 2010 to June 2025. The review examines the relationship between chronic inflammation and transformation of normal cells into cancerous cells, focusing specifically on how NF-kB signalling influences the tumour microenvironment via key cellular pathways, including PI3K/AKT, Wnt/β-catenin and MAPK. This article further addresses preclinical and clinical attempts to therapeutically modulate the NF-kB pathway via small molecule inhibitors, anti-inflammatory agents, monoclonal antibodies and natural products. This manuscript reviews the various experimental models, ie, 2D cultures, 3D skin organoids and humanised mouse models, utilised to analyse inflammation-cancer crosstalk to improve translational applicability. Thus, this review emphasises the need for precise modulation of the NF-kB signalling pathway to develop novel therapeutics for skin cancer treatment.