Adoptive cell therapy (ACT) using naturally occurring tumor-infiltrating lymphocytes (TIL) can mediate durable tumor regressions and, in some cases, cure in patients with metastatic melanoma. However, its efficacy remains highly variable and patient-specific. Two most likely reasons why some patients do not respond favorably to this therapy include: 1) lack or loss of signals in tumor cells that make them visible to immune T cells and 2) lack or insufficient infiltration and presence of tumor-fighting T cells within tumors. An important signaling pathway that contributes to interactions between tumor cells and immune T cells is the type I interferon signaling pathway. The type I interferon pathway increases expression of molecules that allow tumor cells to be recognized and killed by immune T cells. One of the key molecules in the type I interferon signaling pathway is stimulator of interferon genes (STING). When activated, STING induces expression of molecules called T cell-homing chemokines that are critical for the recruitment and localization of immune T cells within tumors. We have recently discovered an important loss and defect in STING gene expression in melanoma cells which helps them to evade from immune T cell detection and destruction. We have also shown that this loss of STING expression in melanoma cells can be reversed with a clinically available demethylating drug. In this proposal, we will test a series of STING-activating and -restoring strategies to generate and empower autologous TIL expansion and function in mouse models of melanoma. We predict the findings from these studies will provide opportunities for future development of more effective T cell–based immunotherapies in patients with metastatic melanoma who do not currently benefit from these interventions.