The immunosuppressive actions of regulatory T (Treg) cells have limited the success of cancer immunotherapies. Grinberg-Bleyer et al. show that ablation of the canonical nuclear factor κB (NF-κB) subunit c-rel specifically impairs the generation and maintenance of activated Treg cells and reduces growth of transplanted melanoma cells in mice. Daily injections of the FDA-approved drug pentoxyfylline (PTXF; which inhibits c-rel) similarly reduced the rate of tumour growth in a mouse melanoma transplantation model by altering Treg cell identity and function. Furthermore, combining PTXF with anti-PD1 immunotherapy had an additive effect in treating established melanoma in mice.