Defining the role of succinate in physical activity-induced tumor immunogenicity

• Grant number: 24/13876-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2025
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Luiz Henrique Marchesi Bozi
• Grantee: Brenda Araujo Camargo
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cancer is a major cause of death worldwide. Although the immune system provides a critical defense against cancer cells, many tumors evolve to evade eradication by generating an immunosuppressive microenvironment that prevents immune cells activation, infiltration and cytotoxicity. However, recent findings suggest that regular physical activity inhibits cancer progression through an immunological reprogramming that increases tumor immunogenicity. Despite the huge interest in the pharmacological manipulation of the anticancer effect of physical activity, the mechanisms behind this response are still unknown. Usually, systemic adaptions to physical activity requires skeletal muscle-released paracrine factors. Indeed, we recently found that muscle fibers secrete succinate during physical activity. Release of succinate in the systemic milieu initiates a transcriptional response in non-myofibrillar cells (including immune cells) through succinate receptor 1 (SUCNR1) that is critical for skeletal muscle adaptation to physical activity. Although some evidences suggest that succinate promotes immune cells activation and cytotoxicity, it is still unclear whether this metabolite mediates physical activity-induced tumor immunogenicity. To test this, we will generate a mouse model lacking SUCNR1 to study in vivo whether muscle-released succinate is critical for the anticancer effect of physical activity. Moreover, we will determine the role of extracellular succinate in physical activity-induced immune cells mobilization to the tumor microenvironment.