Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance

Abstract

Microscopic hemorrhage is a common aspect of cancers. Using spatial transcriptomics, we found that NRF2-activated myeloid cells possessing characteristics of procancerous TAMs cluster in perinecrotic hemorrhagic tumor regions. We identified heme as a pivotal microenvironmental factor steering macrophages toward protumorigenic activities.

Key Findings

• Intratumoral hemorrhage drives cancer-promoting TAMs via NRF2 activation
• Heme from red blood cell breakdown activates NRF2 in macrophages
• NRF2-activated TAMs are resistant to reprogramming by IFN-γ and anti-CD40
• Spatial transcriptomics revealed NRF2-TAMs cluster in hemorrhagic regions

Clinical Significance

Citation

Schaer, D.J. et al. (2024). Hemorrhage-activated NRF2 in TAMs. Journal of Clinical Investigation.