Australia has the highest incidence of skin cancer in the world, causing considerable social and economic burden. Indeed, two out of every three Australians are likely to be diagnosed with skin cancer by the age of 70. Organ transplant recipients suffer a greatly increased risk of cutaneous squamous cell carcinoma (SCC) development due to impaired immune surveillance as a consequence of their lifelong regime of prescribed immunosuppressive drugs. We proposed to develop a first in class, topically applied, small molecule for the treatment of SCC in organ transplant recipients receiving immunosuppressive therapy. We found that Compound 1 is able to reverse the anti-proliferative effects of immune suppressing agents in both mouse and human T cells in vitro. To investigate whether Compound 1 has an effect on T cell activation and tumour regression in vivo, we used a mouse model in which an SCC cell line was derived from UV-irradiated HPV38E6E7-FVB mice. The cell line forms SCCs when injected into immuno-suppressed mice, and regresses when immunosuppression is removed. Twice-daily intratumoural injections of Compound 1 significantly reduced tumour growth in immuno-suppressed mice, compared to Vehicle treated tumours. Treatment with Compound 1 also significantly increased the percentage of activated CD8 T cells within tumours, and their expression of IFN-gamma and TNF-alpha. Furthermore, when CD8 T cells were depleted in vivo, Compound 1 was no longer able to reduce tumour growth. In summary, we have demonstrated the efficacy of Compound 1 in vivo, and established a key role of CD8 T cells in Compound 1 mediated SCC regression.