Natural Killer (NK) cell regulation by cancer cells requires extensive exploration for developing NK-cell based immunotherapies. Ewing sarcoma (ES) is an insidious pediatric cancer that has not benefited from immunotherapy, due to its immunologically cold nature. We previously reported that Ubiquitin-Specific Protease 6 (USP6) functions as a tumor suppressor in ES by inducing a highly immunostimulatory hot tumor microenvironment (TME), with increased infiltration and activation of multiple immune lineages. We found that USP6 expression in ES cells inhibited xenograft growth in nude mice, but not NSG mice, implicating a role for the innate immune system, particularly cytotoxic NK cells. Therefore, we hypothesize that NK cells are essential for USP6-mediated tumor suppression and seek to determine the mechanism by which their cytolytic function is activated by USP6. We discovered that NK cells are essential for ES inhibition by USP6, as NK cell depletion completely reverses USP6-mediated suppression of ES in RAG2-/- mice. USP6 expression in ES cells directly stimulates NK cell activation and degranulation in vitro, and functions by increasing surface levels of multiple NK-activating ligands. USP6 also induces surface upregulation of receptors for the apoptosis-inducing ligand TRAIL, providing an additional route for enhanced sensitivity to NK killing. Furthermore, USP6/ES and NK cells participate in a paracrine immunostimulatory feedforward loop, wherein interferon- (IFN) secreted by the activated NK cells feeds back on USP6/ES cells to induce synergistic expression of chemokines - CXCL9 and CXCL10. Remarkably, expression of USP6 in subcutaneous ES xenografts induces systemic activation of NK cells and an abscopal response in which growth of distal tumors is inhibited, coincident with increased infiltration and activation of NK cells. These observations suggest that USP6 expression in primary tumors might be able to inhibit growth of metastatic ES tumors, which will be substantial in meeting a major clinical need.