撰文丨王聪 编辑丨王多鱼 排版丨水成文 在老年人群中，愈合过程中细胞行为失调会影响损伤后的组织再生。在再生过程的早期阶段， 促炎性巨噬细胞 会导致免疫失衡，而在后期阶段， 衰老干细胞 会 降低再生能力。 | | 2025 年 10 月 | 1 日，浙江大学医学院附属邵逸夫医院 | | 方向前 | / | 赵玥绮 | 团 | | --- | --- | --- | --- | --- | --- | --- | --- | | 队联合浙江大学化学系 | | 唐睿康 / | 刘昭明 | 团队 | | （浙江大学医学院 | | | 附属邵逸夫医院 | | 梁凯裕 | 、浙江中医药大学附属杭州市中医院 | | | 赵澜 | | | 为共同第一作者） | ，在 | Nature 子刊 | Nature Nanotechnology | | 上发表了题为： | | | | | | Spatiotemporal-adaptive nanotherapeutics promote post-injury regeneration in ageing through metabolic modulation | | | | 的 ...

Core Viewpoint - The research identifies a metabolic vulnerability in glioblastoma, revealing that the tumor relies on "stealing" serine from its environment for rapid growth, which can be targeted for treatment [4][8]. Group 1: Research Findings - Glioblastoma is the most common and aggressive primary malignant brain tumor in adults, with standard treatments including surgery, radiotherapy, and temozolomide chemotherapy, but it often recurs, leading to a high mortality rate within 1-2 years post-diagnosis [3]. - The study published in Nature highlights that glioblastoma tumors can utilize serine from their surroundings instead of synthesizing it, presenting a critical metabolic weakness [4][8]. - By feeding glioblastoma mouse models a diet lacking serine, researchers observed a slowdown in tumor growth and spread, extending survival time [4][8]. Group 2: Metabolic Mechanism - The research team analyzed samples from eight glioblastoma patients and found that tumors utilize glucose from the environment to synthesize essential components like DNA, facilitating aggressive growth [6][7]. - In healthy brain tissue, glucose is metabolized for the tricarboxylic acid (TCA) cycle and converted into serine, while glioblastoma bypasses serine synthesis by "stealing" it, allowing glucose to be redirected for synthesizing nucleotides necessary for cancer cell proliferation [7][8]. Group 3: Clinical Implications - The study suggests that the reliance on serine presents a targetable metabolic vulnerability, and the team plans to conduct clinical trials on a serine-restricted diet for patients, which, while not curative, could provide additional time for some patients [8].

Core Viewpoint - The study highlights the role of C19orf12 as a mitochondrial metabolic regulator in non-small cell lung cancer (NSCLC), indicating that elevated expression levels may serve as a biomarker for improved response to metformin treatment [10]. Group 1: Research Findings - C19orf12 is highly expressed in NSCLC and is associated with poor prognosis [7]. - C19orf12 regulates mitochondrial function and drives glucose metabolic reprogramming [7]. - C19orf12 interacts with LRPPRC protein, downregulating the expression of mitochondrial electron transport chain complexes I and IV [7]. - High levels of C19orf12 inhibit mitochondrial respiration and reduce glucose flux through the tricarboxylic acid (TCA) cycle [5][6]. Group 2: Implications for Treatment - C19orf12 enhances the sensitivity of NSCLC cells to the antitumor effects of metformin [6]. - The study suggests that C19orf12 expression levels could predict the response to metformin treatment in NSCLC patients [10].

Core Viewpoint - The study reveals that RIOK1 phase separation restricts PTEN translation via stress granules, promoting tumor growth in hepatocellular carcinoma (HCC) [4][12]. Group 1: Mechanism of Drug Resistance - RIOK1 phase separation mediates the formation of stress granules under TKI treatment stress, recruiting IGF2BP1 and G3BP1 to form dynamic stress granules [11]. - Stress granules selectively encapsulate PTEN mRNA, inhibiting its translation into PTEN protein, leading to the inactivation of the PTEN/PI3K/AKT pathway [11]. - The loss of PTEN activates the pentose phosphate pathway (PPP), increasing NADPH production and antioxidant capacity, helping cancer cells eliminate TKI-induced reactive oxygen species (ROS) [11]. Group 2: Key Findings and Clinical Relevance - The NRF2-RIOK1 regulatory axis is activated by oxidative stress (e.g., TKI treatment), upregulating RIOK1 expression and enhancing cancer cell adaptability through a positive feedback loop [11]. - The study establishes a causal chain linking stress granules, metabolic reprogramming, and TKI treatment resistance in HCC [12]. Group 3: Research Significance and Translational Directions - Targeting RIOK1 phase separation may disrupt the cancer cell's "stress buffering system," providing a new direction to improve TKI efficacy [12]. - Combination therapy of TKI and Chidamide may synergistically enhance anti-tumor effects [13]. - RIOK1 expression levels or the dynamics of stress granules could serve as predictive biomarkers for TKI efficacy, guiding personalized treatment [13].

Core Viewpoint - The study identifies AKR1B1 as a key regulatory enzyme in metabolic reprogramming and a potential biomarker and therapeutic target for hepatocellular carcinoma (HCC), suggesting that targeting AKR1B1 can reverse systemic therapy resistance in HCC [3][7]. Group 1: Research Findings - HCC is a major subtype of liver cancer and a leading cause of cancer-related deaths globally, with high incidence and mortality rates [2]. - The research team established HCC cell lines with multidrug resistance characteristics, observing enhanced metabolic activity in these cells [5]. - Multi-omics analysis revealed that glucose-lipid and glutathione metabolic pathways are overactive, playing critical roles in supporting tumor cell proliferation and survival [5]. Group 2: Mechanism of Resistance - The study constructed a metabolic reprogramming map for resistant HCC cells, identifying AKR1B1 as a key regulatory factor that maintains resistance by modulating energy metabolism and enhancing stress tolerance [5]. - The expression level of AKR1B1 is closely related to drug resistance and poor prognosis in HCC patients, highlighting its predictive value [5]. Group 3: Therapeutic Implications - The combination of Epalrestat, a clinically approved AKR1B1 inhibitor, with standard therapy (Lenvatinib) significantly alleviated resistance in HCC [7]. - The findings provide new insights into the mechanisms of resistance in HCC and lay the theoretical foundation for developing new predictive biomarkers and therapeutic strategies to overcome resistance [7].

Core Viewpoint - The study reveals that RIOK1 phase separation restricts PTEN translation via stress granules, promoting tumor growth in hepatocellular carcinoma (HCC) [2][3][6]. Group 1: Research Findings - RIOK1 is highly expressed in HCC and is associated with poor prognosis, activated by NRF2 under various stress conditions [6]. - RIOK1 facilitates liquid-liquid phase separation (LLPS) by incorporating IGF2BP1 and G3BP1 into stress granules, which sequester PTEN mRNA, reducing its translation [6]. - This process activates the pentose phosphate pathway, helping cells cope with stress and protecting them from the effects of tyrosine kinase inhibitors (TKIs) [6]. Group 2: Implications for Treatment - The small molecule Chidamide, a selective histone deacetylase inhibitor, can downregulate RIOK1 and enhance the efficacy of TKIs [6]. - RIOK1-positive stress granules were found in tumors of HCC patients resistant to Donafenib, indicating a potential target for overcoming drug resistance [6][7]. Group 3: Broader Context - The findings connect the dynamic changes of stress granules and metabolic reprogramming to the progression of HCC, suggesting potential strategies to improve TKI efficacy [7]. - A related article in Nature Cancer discusses how cancer cells form stress granules to adapt to stress and survive, highlighting the role of RIOK1-mediated phase separation in drug resistance [8].

Core Viewpoint - The study highlights the role of metabolic reprogramming in promoting immune suppression in hepatocellular carcinoma (HCC), which is crucial for developing targeted and effective anti-tumor strategies [2][3]. Group 1: Research Findings - The research integrates multi-omics data, including metabolomics, transcriptomics, and single-cell sequencing, to elucidate how tumor cells produce and actively export N1-acetylspermidine (N1-Ac-Spd), leading to immune suppression [3][4]. - N1-Ac-Spd accumulates in HCC tissues and increases in paired plasma compared to non-tumor liver tissues, promoting tumor progression and weakening the efficacy of immune checkpoint blockade (ICB) therapy in preclinical models [4][6]. - Inflammatory macrophages enhance the expression of SAT1 in HCC cells, which increases the export of N1-Ac-Spd through the polyamine transporter SLC3A2, creating an immunosuppressive tumor microenvironment [5][6]. Group 2: Mechanistic Insights - N1-Ac-Spd activates SRC signaling in a charge-dependent manner, leading to the polarization of CCL1+ macrophages and recruitment of regulatory T cells, which diminishes the effectiveness of ICB therapy [5][6]. - Blocking the synthesis of N1-Ac-Spd or targeting SLC3A2, SAT1, or CCL1 can significantly enhance the anti-tumor effects of ICB therapy [5][6]. Group 3: Implications for Treatment - The findings reveal mechanisms by which metabolic reprogramming fosters an immunosuppressive tumor microenvironment, providing theoretical foundations and potential intervention targets for enhancing HCC treatment [6][9].

Core Viewpoint - CAR-T cell therapy has shown remarkable efficacy in treating hematological cancers, but its effectiveness in solid tumors remains limited due to the challenging tumor microenvironment (TME) [1][2] Group 1: Research Findings - The study reveals that Foxp3 enhances the long-term efficacy of CAR-T cells through metabolic reprogramming, providing a survival advantage in solid tumor environments [2][7] - CAR-T Foxp3 cells exhibit a distinct metabolic reprogramming profile compared to conventional CAR-T cells, characterized by decreased aerobic glycolysis and oxidative phosphorylation, alongside increased lipid metabolism [5][9] - The interaction between Foxp3 and Drp1 drives the metabolic transition in CAR-T Foxp3 cells, which do not acquire the immunosuppressive functions typical of Treg cells [5][9] Group 2: Implications for Cancer Treatment - The findings establish a new strategy based on metabolic reprogramming to enhance CAR-T cell adaptability in harsh tumor microenvironments while maintaining therapeutic efficacy [9] - CAR-T Foxp3 cells demonstrate lower levels of exhaustion markers and exhibit stronger anti-tumor efficacy compared to traditional CAR-T cells [9][6]