Many studies to date are centered on how SUMOylation promotes cancer cells proliferation, but emerging information suggests that SUMOylation also regulates anti-tumor immune response and the tumor microenvironment. Here, with a clinical-stage small molecular SUMOylation inhibitor, TAK-981, I investigated the effects of SUMOylation inhibition in immune-competent mouse models of head and neck cancers. TAK-981 treatment of the mouse significantly prolonged survival and induced completed regression in some cases. The “cured” mice are resistant to rechallenge with the same tumor cells, indicating the formation of immunological memory. Single-cell transcriptomic analysis showed that treatment with the SUMOylation inhibitor decreased terminal exhausted T cells and increased T helper cells in the tumor microenvironment. Besides immune cells, I observed that the SUMOylation inhibitor synergized with IFN- in upregulating major histocompatibility complex (MHC) class I, which is essential for presenting neoantigen on cancer cells. Based on these findings, I performed combination therapy of the SUMOylation inhibitor with an immune checkpoint inhibitor (anti-PD1) that showed improved efficacy than the monotherapy groups