Abstract
Ferroptosis is a recently recognized iron-dependent form of non-apoptotic regulated cell death (RCD) characterized by lipid peroxide accumulation to lethal levels. Cancer cells, which show an increased iron dependency to enable rapid growth, seem vulnerable to ferroptosis. There is also increasing evidence that ferroptosis might be immunogenic and therefore could synergize with immunotherapies. Hepatocellular carcinoma (HCC) is the most common primary liver tumor with a low survival rate due to frequent recurrence and limited efficacy of conventional chemotherapies, illustrating the urgent need for novel drug approaches or combinatorial strategies. Immunotherapy is a new treatment approach for advanced HCC patients. In this setting, ferroptosis inducers may have substantial clinical potential. However, there are still many questions to answer before the mystery of ferroptosis is fully unveiled. This review discusses the existing studies and our current understanding regarding the molecular mechanisms of ferroptosis with the goal of enhancing response to immunotherapy of liver cancer. In addition, challenges and opportunities in clinical applications of potential candidates for ferroptosis-driven therapeutic strategies will be summarized. Unraveling the role of ferroptosis in the immune response could benefit the development of promising anti-cancer therapies that overcome drug resistance and prevent tumor metastasis.
Highlights
Cell death is crucial for normal development and homeostasis throughout an organism’s lifetime [1]
We review existing studies and our current understanding regarding the molecular mechanisms of ferroptosis in cancer and immune cells, which may open the door to a new era of cancer immunotherapies targeting non-apoptotic regulated cell death (RCD) processes in primary liver cancer to improve its poor prognosis
The described dual effects of ferroptosis on tumor immunity, and with it, patient’s prognosis score, differ from person to person, but the results showed that the ferroptosis score, as an independent prognostic factor, is feasible for predicting the prognosis of different cancers and immunotherapy efficacy
Summary
Cell death is crucial for normal development and homeostasis throughout an organism’s lifetime [1]. In patients with advanced cirrhosis and HCC, liver transplant often remains the only curative treatment option [10] Classic chemotherapies such as cisplatin are not regularly used in HCC due to the rapid development of chemoresistance [11], toxicity to various organs, and limited efficacy [12]. Less is known about regulators of ferroptosis and its role in immune activation, but there is some evidence that ferroptotic cell death might be immunogenic. These considerations support the concept to develop ferroptosis-based approaches to enhance response to immunotherapy. We review existing studies and our current understanding regarding the molecular mechanisms of ferroptosis in cancer and immune cells, which may open the door to a new era of cancer immunotherapies targeting non-apoptotic RCD processes in primary liver cancer to improve its poor prognosis
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