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Understanding the mechanisms underlying anti-tumor immunity is pivotal for improving immune-based cancer therapies. Here, we report that growth of BRAF-mutant melanoma cells is inhibited, up to complete rejection, in  Siah2   −/−   mice. Growth-inhibited tumors exhibit increased numbers of intra-tumoral activated T cells and decreased expression of  Ccl17,   Ccl22 , and  Foxp3 . Marked reduction in Treg proliferation and tumor infiltration coincide with G1 arrest in tumor infiltrated  Siah2   −/−   Tregs in vivo or following T cell stimulation in culture, attributed to elevated expression of the cyclin-dependent kinase inhibitor p27, a Siah2 substrate. Growth of anti-PD-1 therapy resistant melanoma is effectively inhibited in  Siah2   −/−   mice subjected to PD-1 blockade, indicating synergy between PD-1 blockade and  Siah2  loss. Low  SIAH2  and  FOXP3  expression is identified in immune responsive human melanoma tumors. Overall, Siah2 regulation of Treg recruitment and cell cycle progression effectively controls melanoma development and Siah2 loss in the host sensitizes melanoma to anti-PD-1 therapy.

Siah2 control of T-regulatory cells limits anti-tumor immunity