HO-1 and ferroptosis: a new understanding of how oxidative stress from the tumor microenvironment modulates immune cells and contributes to resistance to immunotherapy

• Grant number: 25/05907-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: May 01, 2025
• End date: April 30, 2029
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Niels Olsen Saraiva Câmara
• Grantee: Lucas de Abreu Ferreira Machado
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 23/07482-2 - Sensing extra and intracellular stressors by renal and immune cells: new insights into signal reception and transduction, and their relevance for understanding renal diseases, AP.TEM

Abstract

The tumor microenvironment (TME) plays a crucial role in cancer progression and resistance to immunotherapy. This project aims to investigate the role of heme oxygenase-1 (HO-1) in regulating oxidative stress and ferroptosis in immunosuppressive cells within the TME, such as tumor-associated macrophages (TAMs) and regulatory T cells (Tregs). By exploring the HO-1-ferroptosis axis, we aim to develop strategies for the selective elimination of these cells, promoting TME reprogramming and increasing sensitivity to immunotherapy. Treatments with ferroptosis inducers, HO-1 modulators, and immune checkpoint inhibitors will be applied in in vitro and in vivo models of tumors resistant to immunotherapy. Furthermore, the identification of biomarkers related to redox balance may provide insights into the equilibrium between oxidative stress and ferroptosis, with potential applications in diagnosis, prognosis, and therapeutic monitoring. This study offers a translational basis for improving the effectiveness of immunotherapy by targeting immunosuppressive mechanisms and leveraging oxidative stress in cancer. The results are expected to contribute to the development of innovative therapeutic strategies and personalized approaches for tumors refractory to conventional treatments. (AU)