Loss of DUSP1 expression creates a cold tumor microenvironment in cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent cancer. In most of the cases, surgical removal of the tumor is a curative treatment but 3-5% of the tumors will progress or produce metastasis having a poor prognosis. Here we demonstrated the tumor suppressive role of DUSP1, a dual phosphatase that negatively regulates ERK activity. We demonstrated that DUSP1 constrains ERK signaling during inflammation and wound healing to sustain homeostasis by transiently decreasing its levels, but its permanent downregulation promotes progression to squamous cell carcinoma. Using mouse and human models we demonstrated that DUSP1 loss enhances ERK signaling, and tumor growth. RNAseq analysis revealed that DUSP1 null tumors are enriched in cancer stem cell gene signatures, but surprisingly, are also depleted from CD4, CD8, macrophages and DC cells, and DUSP1 null cancer cells express lower levels of chemo and cytokines, been immune excluded. Our data suggest that DUSP1 acts restricting cancer cell proliferation and promoting immune recruitment, presenting promising diagnostic and therapeutic potential.