Cutaneous squamous cell carcinoma (cSCC) is one of the most prevalent cancers in Caucasian populations, and its aggressive form poses a high risk of metastasis resulting in increased rates of mortality and morbidity. Recurrent and chronic exposure to ultraviolet (UV) radiation from the sun plays a crucial role in the initiation, development, and perpetuation of cSCC. Accumulating evidence suggests that regulatory T (Treg) cells are associated with UV-induced immunosuppression, however, a direct role for these cells in the establishment of cSCC remains elusive. Following UVB exposure, CD4+CD25+ Treg numbers were found to increase significantly in the skin-draining lymph nodes of treated mice. Mice that had been exposed to UVB showed reduced ear swelling in response to ovalbumin challenge in a contact hypersensitivity assay. Reduced ear swelling responses were lost when Tregs were depleted with anti-CTLA-4, anti-TIGIT or anti-FR4 antibodies, suggesting that UV-induced Tregs were functionally suppressive. Following the treatment of mice with UVB for different lengths of time (2w, 4w, 6w, 8w), it was determined that eight weeks of UVB treatment consistently allowed the establishment and growth of adoptively transferred cSCC tumour fragments from donor mice. We aim to target Tregs in these tumour models to determine whether Treg depletion or manipulation reverses the capacity of UVB to enable cSCC tumour establishment. Overall, this study examines the plausibility of Treg manipulation as a preventative strategy to prevent UV-induced cSCC tumour establishment.