Setayeshpour Yasaman, Lee Yunji, Chi Jen-Tsan
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27708, USA.
Department of Cell and Molecular Biology, Duke University Medical Center, Durham, NC 27708, USA.
Cancers (Basel). 2023 Jul 29;15(15):3861. doi: 10.3390/cancers15153861.
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.
鉴于人类癌症所带来的巨大痛苦和死亡，迫切需要新的治疗方法来靶向肿瘤生长和转移。虽然最初的努力集中在癌细胞失调的致癌程序上，但最近的重点是调节和靶向许多“有利于癌症”的非基因肿瘤微环境因素，这些因素支持并促进肿瘤进展和转移。两个突出的例子分别是抗血管生成和免疫疗法，它们分别靶向支持肿瘤的血管生成和免疫抑制性肿瘤微环境（TME）。最近，铁死亡的治疗潜力引起了人们的极大兴趣，铁死亡是一种自然的肿瘤抑制机制，通常由于氧化应激、铁失衡和脂质过氧化物积累而发生。虽然众多研究已经确定了各种细胞内在机制来保护或促进铁死亡，但最近也认识到各种TME应激因素在调节肿瘤细胞对铁死亡的易感性方面的作用。本综述旨在汇总并强调这些因素的证据、各种TME应激如何影响铁死亡，以及它们在肿瘤发展的各个阶段的意义以及对正在开发的铁死亡触发疗法的预期反应。因此，了解在细胞内和TME中增强铁死亡敏感性的方法可能会优化治疗敏感性，以最小化或预防肿瘤生长和转移。
