撰文丨王聪 编辑丨王多鱼 排版丨水成文 在癌症治疗领域， 免疫疗法 革命性地改变了众多患者的命运。然而，为什么有些患者对免疫治疗响应良好，而另一些却效果不佳？科学家们一直在寻找答案。 2026 年 1 月 5 日， 上海交通大学医学院附属胸科医院 王佳谊 研究员、德州大学西南医学中心 唐道林 教授、法国索邦大学 Guido Kroemer 、广州医科大学附 属第三医院 柳娇 研究员等，在国际顶尖学术期刊 Cell 上发表了题为： E xtracellular GPX4 impairs antitumor immunity via dendritic ZP3 receptors 的研究论 文。 该研究发现了一条抑制铁死亡免疫原性的调控轴。在 铁死亡 过程中，癌细胞释放 GPX4 蛋白，该蛋白与 树突状细胞 （DC） 表面的 ZP3 受体结合，激活 cAMP-PRKA 信号级联反应，抑制糖酵解，损害树突状细胞的成熟和活化，最终导致 T 细胞启动缺陷。而破坏 GPX4-ZP3 的相互作用可恢复树突状细胞的代谢 活性并增强抗肿瘤免疫。在临床前模型中，阻断该通路可改善癌症免疫监视，并与化疗、免疫化疗或放疗联用时增强细胞 ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 结直肠癌 （CRC） 在全球癌症死亡率中排名第三，其发病率和死亡率一直居高不下。人口老龄化、西式饮食，再加上肥胖和缺乏运动等已知风险因素，导致结直 肠癌的发病率不断上升。尽管近年来在检测方法和治疗手段方面取得了显著进展，包括内镜和手术局部切除、局部消融治疗、靶向治疗和免疫干预等，但结直肠 癌患者的长期预后仍然不佳，尤其是在晚期或转移性病例中。因此，深入研究结直肠癌的分子过程，发现新的治疗靶点和预后生物标志物，对于改善患者的临床 结局至关重要。 2025 年 12 月 26 日 ， 湖南省肿瘤医院/ 中南大学湘雅医学院附属肿瘤医院 袁霞 、 中南大学基础医学院 周艳宏 等， 在 Signal Transduction and Targeted Therapy 期刊发表了题为 ： Inhibin beta A drives colorectal cancer progression through macrophage M2 polarization and mitochondria-dependent ferroptosis suppression 的研究论文。 该研究表 ...

Core Viewpoint - Ferroptosis is a newly discovered iron-dependent form of programmed cell death that plays a significant role in the development of various diseases, including cancer, and represents a promising new strategy for cancer treatment by inducing lipid peroxidation [1][6]. Group 1: Research Findings - The study published in Molecular Cell highlights that PRDX6 is a key regulatory factor of GPX4, which helps resist ferroptosis, and targeting PRDX6 can enhance the anti-tumor effects mediated by ferroptosis [2][6]. - The research team identified that PRDX6 influences the localization and function of GPX4, thereby contributing to the resistance against ferroptosis [3][6]. - PRDX6 has phospholipase A2 activity, catalyzing the conversion of peroxidized phospholipids into lysolipids and oxidized fatty acids, which is crucial for its interaction with GPX4 [4][6]. Group 2: Implications for Cancer Treatment - Combining PRDX6 inhibition with ferroptosis inducers can increase lipid peroxidation and effectively suppress tumor growth in mouse models of liver and ovarian cancer, including patient-derived models [4][6]. - High expression of PRDX6 is associated with shorter progression-free survival in various human cancer types, indicating its potential as a therapeutic target [4][6].

Core Viewpoint - Triple-negative breast cancer (TNBC) is characterized by high invasiveness and poor prognosis due to the lack of specific treatment targets and high rates of postoperative recurrence and metastasis. Current treatments primarily involve surgical resection followed by chemotherapy, but inherent chemotherapy resistance necessitates new effective treatment strategies. The study introduces a promising approach using nanozyme-based therapy for postoperative adjuvant treatment of TNBC [1][4][7]. Group 1: Research Background - TNBC is the most aggressive subtype of breast cancer, with high recurrence and mortality rates. It lacks expression of estrogen receptors, progesterone receptors, and HER2, leading to a lack of precise treatment targets. The main treatment methods are surgical resection and postoperative chemotherapy, but challenges such as residual metastatic lesions and chemotherapy resistance contribute to high recurrence and metastasis rates [4][5]. - Recent studies indicate that immune checkpoint blockade (ICB) therapy shows potential in TNBC treatment due to the high density of tumor-infiltrating lymphocytes. However, resistance to immune checkpoint inhibitors and low immune response limit treatment efficacy, highlighting the need for enhanced antitumor immunity [4][5]. Group 2: Study Findings - The research combines iron-based unit point nanozymes (MFCA) with a responsive hydrogel delivery system to address two key challenges in TNBC treatment: eliminating residual tumor satellite lesions and inhibiting postoperative metastasis. This hydrogel composite can be directly injected into the surgical cavity for sustained release of MFCA, inducing ferroptosis in TNBC cells and enhancing immunogenicity [2][6]. - The study developed a biodegradable unit point nanozyme-loaded hydrogel that effectively inhibits postoperative metastasis and systemic recurrence in TNBC, providing a direct, efficient, and safe adjuvant treatment method to improve patient prognosis [7].

Core Viewpoint - The study highlights that tolerance to ferroptosis enhances lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation, suggesting a potential therapeutic target for asthma through the modulation of antioxidant systems [1][6]. Group 1: Key Findings - Pathogenic ILC2 in allergic airway inflammation relies on cysteine for metabolic adaptation and survival [3]. - Cysteine uptake promotes the synthesis of glutathione (GSH), which works in conjunction with the upregulation of GPX4 and TXNRD1 to enhance resistance to ferroptosis by combating lipid peroxidation and reactive oxygen species (ROS) [3]. - The adaptive changes accelerate lipid acquisition and metabolism, promoting the expansion of ILC2 and Th2 cells [3]. Group 2: Implications - The study indicates that the antioxidant and ferroptosis resistance pathways enable lipid metabolism in ILC2 and Th2 cells [4]. - GPX4 and TXNRD1 are crucial in promoting pathogenic type 2 immune responses [4]. - The redox balance system represents a targetable metabolic vulnerability in airway inflammation [4].

编辑丨王多鱼 排版丨水成文 撰文丨王聪 多细胞生物在发育过程中，存在着多种预定的、受到精确控制的细胞程序性死亡，例如细胞凋亡 （Apoptosis） 、 程序性坏死 （Necroptosis） 、 细胞焦亡 （Pyroptosis） ，以及铁死亡 （Ferroptosis） 等。 其中， 铁死亡 （Ferroptosis） 是于 2012 年发现的一种铁依赖性的新型细胞程序性死亡方式，由过度堆积的过氧化脂质 诱导发生，其形态特征，作用方式以及 分子机制与其他程序性死亡方式截然不同。 与此同时，细胞中也有多个对抗铁死亡的途径 （尤其是癌细胞） ——例如 GPX4 所介导的通过谷胱甘肽 （GSH） 特异性催化过氧化脂质来抑制铁死亡。 实际上，在 "铁死亡"这一术语被提出之前，德国 亥姆霍兹慕尼黑研究中心 Marcus Conrad 教授团队就已揭示了 GPX4 通过阻止细胞和小鼠中无限制的磷脂过氧 化，调控一种新的非凋亡细胞死亡类型。 2025 年 12 月 4 日， Marcus Conrad 教授团队在国际顶尖学术期刊 Cell 发表了题为： A fin-loop-like structure in GPX4 ...

Core Viewpoint - Ferroptosis is emerging as a promising anti-tumor therapy driven by the oxidation of polyunsaturated fatty acids in cell membranes, leading to lipid peroxidation and cell death, while also releasing damage-associated molecular patterns (DAMPs) that enhance T cell activation [1][4]. Summary by Sections Ferroptosis Mechanism and Challenges - Ferroptosis induces cell death through increased intracellular iron, reduced glutathione synthesis, and elevated reactive oxygen species (ROS) levels. However, the upregulation of PD-L1 in tumor cells can inhibit cytotoxic T cell recognition, leading to immune suppression [1][5]. Research Development - A team from Shenyang Pharmaceutical University and Shenzhen University developed a fluorinated prodrug-engineered nano-remodeler that combines a PD-L1 inhibitor (JQ1) and a ferroptosis inducer (sorafenib) to enhance oxygen supply in hypoxic tumors, significantly improving the efficacy of ferroptosis and anti-tumor immunogenicity [2][6]. Nano-remodeler Characteristics - The engineered nano-remodeler (FJSO NA) has high oxygen solubility and releases oxygen in low-pressure environments, alleviating hypoxia in solid tumors, downregulating PD-L1 expression, and enhancing ferroptosis induction and anti-tumor immune responses [6][8]. Efficacy and Safety - The study demonstrated that the nano-remodeler effectively inhibited tumor growth in various models without significant toxicity, indicating a promising direction for enhancing ferroptosis-based immunotherapy by addressing the hypoxic tumor microenvironment [8].

Core Viewpoint - Ferroptosis is a newly discovered iron-dependent form of programmed cell death that plays a significant role in cancer and other diseases, with potential implications for immunotherapy and radiotherapy [1][2]. Group 1: Ferroptosis Mechanism and Importance - Ferroptosis is characterized by the accumulation of peroxidized lipids and is distinct from other forms of cell death [1]. - Key defense mechanisms against ferroptosis include GPX4, which inhibits ferroptosis by catalyzing peroxidized lipids, and FSP1, which promotes cancer cell resistance to ferroptosis through the antioxidant form of coenzyme Q10 [1]. Group 2: Research Findings on Lung Cancer - A study published on November 5, 2025, demonstrated that targeting FSP1 triggers ferroptosis in lung cancer, indicating that lung cancer is highly sensitive to ferroptosis [4][6]. - The research showed that the knockout of the FSP1 gene in tumors led to increased lipid peroxidation and significant tumor suppression, highlighting the protective role of FSP1 in vivo [6][7]. - FSP1 expression is prognostic for disease progression and survival in lung adenocarcinoma patients, suggesting its potential as a therapeutic target [7][9]. Group 3: FSP1 in Melanoma - Another study indicated that FSP1 targeting in the lymph node environment could effectively inhibit the progression of metastatic melanoma [10][16]. - The research found that metastatic melanoma cells showed decreased expression of GCLC and reduced levels of GSH in the hypoxic lymphatic microenvironment, leading to increased reliance on FSP1 [13][16]. - Selective FSP1 inhibitors demonstrated significant efficacy in suppressing melanoma growth in lymph nodes, emphasizing the specific dependency of melanoma cells on FSP1 in that microenvironment [13][16].

Core Viewpoint - Systemic treatment is the best option for patients with unresectable or advanced hepatocellular carcinoma (HCC), but its efficacy is limited by drug resistance [2][3]. Group 1: Research Findings - Ferroptosis is a unique form of regulated cell death that plays a crucial role in the systemic treatment of HCC [3]. - A study published in Nature Cancer reveals that SCRN1 confers resistance to ferroptosis in HCC by stabilizing GPX4 through STK38-mediated phosphorylation, providing potential therapeutic targets and strategies for HCC treatment [4][8]. - The research team found that high expression of SCRN1 is closely related to ferroptosis resistance and poor prognosis in HCC [7]. Group 2: Mechanism of Action - SCRN1 enhances the interaction between STK38 and GPX4, promoting the phosphorylation of GPX4 at the S45 site, which impairs HSC70's recognition of GPX4 and reduces its degradation via chaperone-mediated autophagy, thereby alleviating lipid peroxidation and ferroptosis [7][8].

Core Viewpoint - The article discusses the emerging focus on metabolic cell death as a new frontier in cancer therapy, highlighting the significance of ferroptosis, cuproptosis, and disulfidptosis as potential therapeutic targets against cancer cells that evade traditional cell death pathways [3][4][5]. Group 1: Metabolic Cell Death Mechanisms - Metabolic cell death is characterized by the collapse of metabolic homeostasis, leading to irreversible cell death due to nutrient deprivation or the accumulation of harmful metabolites [3]. - Ferroptosis, discovered in 2012, is an iron-dependent cell death mechanism that results from uncontrolled lipid peroxidation, leading to membrane damage [8]. - Cuproptosis, identified in 2022, is a copper-dependent cell death mechanism where excess copper ions induce protein toxicity by binding to fatty acylated proteins in mitochondria [14]. - Disulfidptosis, proposed in 2023, occurs when cystine accumulation leads to the collapse of the actin cytoskeleton under conditions of glucose deprivation or NADPH depletion [19]. Group 2: Cancer Treatment Implications - Targeting metabolic cell death pathways presents a unique opportunity to exploit cancer cells' vulnerabilities, particularly through the mechanisms of ferroptosis, cuproptosis, and disulfidptosis [5][26]. - The interplay between these pathways suggests that combined interventions could enhance therapeutic efficacy and overcome drug resistance in cancer treatment [24][26]. - Establishing verifiable biomarker systems is crucial for advancing clinical applications and achieving precise patient stratification and treatment [26].