Environmental Determinants of Ferroptosis in Cancer

Simple Summary The environment which cancer cells are exposed to can heavily influence the rate of their growth, progression, and metastasis. Many metastasizing cancer cells are vulnerable to a particular type of cell death known as ferroptosis, which is an iron-dependent form of cell death caused by accumulative oxidative stress. Interestingly, many intracellular and extracellular factors can influence ferroptosis and, therefore, dictate the efficiency and route of tumor metastasis. In this review, we will go over key established intracellular factors and highlight major emerging understandings of extracellular factors of ferroptosis in the context of cancer. Given the enormous suffering and death associated with human cancers, there is an urgent need for novel therapeutic approaches to target tumor growth and metastasis. While initial efforts have focused on the dysregulated oncogenic program of cancer cells, recent focus has been on the modulation and targeting of many cancer-friendly, non-genetic tumor microenvironmental factors, which support and enable tumor progression and metastasis. Two prominent examples are anti-angiogenesis and immunotherapy that target tumor-supporting vascularization and the immune-suppressive tumor microenvironment (TME), respectively. Lately, there has been significant interest in the therapeutic potential of ferroptosis, a natural tumor suppression mechanism that normally occurs as a result of oxidative stress, iron imbalance, and accumulation of lipid peroxides. While numerous studies have identified various cell intrinsic mechanisms to protect or promote ferroptosis, the role of various TME stress factors are also recently recognized to modulate the tumor cells' susceptibility to ferroptosis. This review aims to compile and highlight evidence of these factors, how various TME stresses affect ferroptosis, and their implications in various stages of tumor development and expected response to ferroptosis-triggering therapeutics under development. Consequently, understanding ways to enhance ferroptosis sensitivity both intracellularly and in the TME may optimize therapeutic sensitivity to minimize or prevent tumor growth and metastasis.

Automated summary

The environment can significantly affect the growth, progression, and metastasis of cancer cells. Ferroptosis, an iron-dependent form of cell death caused by oxidative stress, can influence the metastasis of cancer cells. Understanding both intrinsic and extrinsic factors that modulate ferroptosis can optimize therapeutic sensitivity to prevent tumor growth and metastasis.