Keratinocytes are major components of the melanoma tumor microenvironment (TME). Although keratinocytes normally limit melanocyte proliferation, they appear to support cancer cell invasion and resistance in melanoma. However, the interactions between melanoma cells and keratinocytes aren’t clear. To learn more, researchers recently used in vitro models to transform normal HaCaT keratinocytes into cancer-associated keratinocytes. Culture with melanoma-conditioned medium or indirect co-culture with melanoma cells started to de-differentiate the keratinocytes and the cancer-activated keratinocytes may connect to cancer cells instead of each other. In addition, the keratinocytes secreted numerous proteases, including several not previously reported in activated keratinocytes. Consistent with their protease secretion, the activated keratinocytes were highly proteolytic, exhibiting high MMP9/MMP14 activity, reduced TIMP expression, and upregulated ERK activity, as well as increased levels of the MMP regulators RUNX2 and galectin 3. Furthermore, the keratinocytes co-cultured with melanoma cells had slightly elevated migration and invasion abilities. Although the reciprocal effects of keratinocytes on melanoma cells still need to be clarified, the findings increase understanding of the melanoma TME and reveal changes in keratinocytes that may promote melanoma progression.