Reprogrammed immuno-metabolic environment of cancer: the driving force of ferroptosis resistance

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2025-06-03 DOI:10.1186/s12943-025-02337-3

Sramana Bhowmick, Saptak Banerjee, Viji Shridhar, Susmita Mondal

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Abstract

Ferroptosis, the non-apoptotic, iron-dependent form of cell death is an unavoidable outcome and byproduct of cellular metabolism. Reactive oxygen species generation during metabolic activities transcends to Fe2+-induced lipid peroxidation, leading to ferroptosis. Cancer cells being highly metabolic are more prone to ferroptosis. However, their neoplastic nature enables them to bypass ferroptosis and become ferroptosis-resistant. The capability of cancer cells to reprogram its metabolic activities is one of its finest abilities to abort oxidative damage, and hence ferroptosis. Moreover, the reprogrammed metabolism of cancer cells, also associates with the radical trapping antioxidant systems to enhance the scavenging of ferroptosis and thereby tumor progression. Additionally, the TME, which is an inevitable part and regulator of carcinogenesis, presents an intricate cooperation with tumor metabolism to build an immuno-metabolic environment to regulate the sustenance of cell proliferation and survival. This review focuses on the current understanding of ferroptosis in carcinogenesis and its resistance acquired by cancer cells via several modulators including the radical trapping antioxidant systems, the reprogrammed metabolism, the TME, and intertwined role of cancer metabolism and tumor immunity. The reprogrammed metabolism section further comprehends the functional role of lipids, iron and glucose metabolism against ferroptosis defense separately. The affiliation of TME in ferroptosis regulation is further sectioned with reference to different immune cells present within the TME such as tumor-associated macrophages, tumor-infiltrating neutrophils, myeloid-derived suppressor cells, T-cells, natural killer cells, dendritic cells, and B-cells, modifying the TME in both pro and anti-tumorigenic manner. Subsequently, this review also discusses the convergence of immuno-metabolic environment in ferroptosis regulation, and eventually brings up research gaps in this context providing consequential and significant questions to explore for better understanding of the immuno-metabolic environment’s role in driving ferroptosis resistance for anti-cancer treatment progress.

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癌症的重编程免疫代谢环境：铁下垂抵抗的驱动力

铁下垂是一种非凋亡、铁依赖性的细胞死亡形式，是细胞代谢不可避免的结果和副产品。代谢活动中活性氧的产生超越了Fe2+诱导的脂质过氧化，导致铁下垂。高代谢的癌细胞更容易发生铁下垂。然而，它们的肿瘤性质使它们能够绕过铁下垂而变得耐铁下垂。癌细胞重编程其代谢活动的能力是其中止氧化损伤的最佳能力之一，从而导致铁死亡。此外，癌细胞的重编程代谢也与自由基捕获抗氧化系统相关，以增强对铁凋亡的清除，从而促进肿瘤的进展。此外，TME作为癌变不可避免的组成部分和调节因子，与肿瘤代谢有着复杂的合作关系，共同构建免疫代谢环境，调控细胞增殖和生存的维持。本文综述了目前对铁凋亡在癌变过程中的作用，以及癌细胞通过自由基捕获抗氧化系统、重编程代谢、TME以及肿瘤代谢和肿瘤免疫相互交织的作用等多种调节因子获得的耐药性。重编程代谢部分进一步了解脂质、铁和葡萄糖代谢分别对铁下沉防御的功能作用。通过TME中存在的不同免疫细胞，如肿瘤相关巨噬细胞、肿瘤浸润中性粒细胞、髓源性抑制细胞、t细胞、自然杀伤细胞、树突状细胞和b细胞，进一步探讨了TME在铁凋亡调节中的关系，这些免疫细胞以促进和抗肿瘤的方式修饰TME。随后，本文还讨论了免疫-代谢环境在铁下垂调控中的趋同作用，并最终提出了这一背景下的研究空白，为更好地理解免疫-代谢环境在驱动铁下垂耐药中的作用提供了重要的探索问题，以促进抗癌治疗的进展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

期刊介绍： Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.