Abstract
Tumor necrosis is a common histological feature and poor prognostic predictor in various cancers. Despite its significant clinical implications, the mechanism underlying tumor necrosis remains largely unclear due to lack of appropriate pre-clinical modeling. We propose that tumor necrosis is a synergistic consequence of metabolic stress and inflammation, which lead to oxidative stress-induced cell death, such as ferroptosis. As a natural consequence of tumor expansion, tumor cells are inevitably stripped of vascular supply, resulting in deprivation of oxygen and nutrients. The resulting metabolic stress has commonly been considered the cause of tumor necrosis. Recent studies found that immune cells, such as neutrophils, when recruited to tumors, can directly trigger ferroptosis in tumor cells, suggesting that immune cells can be involved in amplifying tumor necrosis. This article will discuss potential mechanisms underlying tumor necrosis development and its impact on tumor progression as well as the immune response to tumors.