The impact of short-term fasting and STING activation on metabolic-functional alterations of T lymphocytes and antitumor therapeutic efficacy

Abstract

Cutaneous melanoma is the leading cause of death from skin cancer in the world and has relatively high resistance to treatment with radiotherapy and chemotherapy. The partial success achieved with the use of immunotherapy, especially checkpoint inhibitors, suggests that immunological interventions are the way forward. STING-dependent DNA recognition pathway signaling in tumor, endothelial, and dendritic cells is important for the induction of an anti-tumor immune response. In particular, the activation of dendritic cells by DNA uptake from apoptotic tumor cells and the production of type I IFN are key factors for CD8+ T lymphocyte activation and tumor control. Although very effective in experimental models, therapies based on STING activation still need to be improved in the clinical context. Short-term fasting (JCP) has been considered an accessory strategy to anticancer therapy, as it induces the effect of differential stress resistance, in which tumor cells are more harmed than normal cells by low energy during cancer treatment, increasing its efficiency. In this project, we hypothesize that short-term fasting and STING activation lead to metabolic-functional changes in T lymphocytes that promote an effective immune response against tumors. Therefore, we will make phenotypic and functional assessments of T lymphocytes. Additionally, we will assess the role of the metabolic sensor AMPK in T lymphocytes in the context of short-term fasting associated with STING ligand therapy (DMXAA). Finally, we intend to evaluate the role of STING in immunological changes and tumor control induced by short-term fasting associated with chemotherapy.