编辑丨王多鱼 排版丨水成文 近年来， 以 肥 胖 和 2 型糖尿病 为代表的 内分泌代谢系统疾病已成为严重威胁 人类 健康的重大公共卫生 问题。《 柳叶刀 》的一项研究指出， 2022 年全球肥胖人口已突破 10 亿，占全球总人口的八分之一，且 这一趋势仍在持续上升。肥胖不仅显著增加个体罹患心血管疾病、癌症等多种重大疾病的风险，也给公共 卫生体系带来了沉重负担。 2 型糖尿病在全球范围内 也 呈持续攀升趋势。国际糖尿病联盟 （ IDF ） 数据 显示， 2021 年全球 20–79 岁的成年人中约有 5.89 亿人患糖尿病，占全球成人总数约 10.5% ，预计到 2045 年患者将增至约 7.8 亿人，占比超过 12% ，这意味着几乎每 9 名成年人中就有 1 人受累，其中大 部分为 2 型糖尿病。 随着全球老龄化、城市化、久坐生活方式以及高热量饮食的普及，未来几十年， 2 型糖尿病的患病率还将 持续上升，并将带来更大的心血管、肾脏、神经及眼底疾病负担 。 内分泌代谢系统疾病迫切需要依托大规 模人群遗传学获取高质量证据，识别可用于预防、早筛与精准干预的新分子靶点。 2025 年 10 月 10 日 ，昌平实验 ...

Core Insights - The article discusses a study revealing that both gender (male) and smoking are significant risk factors for bladder cancer, influencing the selection and accumulation of specific somatic mutations in normal bladder tissue long before cancer develops [3][9]. Group 1: Molecular Basis of Gender Differences - The study found that male bladder tissue accumulates significantly more driver mutations in key genes (RBM10, CDKN1A, ARID1A) compared to females, indicating a stronger survival or proliferation advantage for cells with these harmful mutations [7]. - This accumulation of "latent" harmful cell clones in males explains the higher risk of bladder cancer in men [7]. Group 2: Impact of Smoking and Aging - The research identified that TERT promoter mutations, common drivers of bladder cancer, can promote the expansion of clones in normal bladder tissue, showing a strong positive correlation with age and smoking history [7]. - Smoking and aging processes directly enhance the growth of potentially carcinogenic clones in normal tissue, significantly increasing cancer risk [7]. Group 3: Research Methodology - The study utilized ultra-deep double-strand DNA sequencing (approximately 5000× depth) to analyze 79 normal bladder samples from 45 individuals, identifying thousands of clone-driving mutations across 16 genes [8]. - This "Natural Saturation Mutagenesis" approach allows for a more accurate reflection of human biology compared to traditional cell line or animal model experiments, providing insights into precancerous lesions in various tissues [8]. Group 4: Implications for Cancer Risk and Prevention - The findings challenge the traditional dichotomy of "health" and "disease," showing that cancer risk factors like male gender and smoking begin shaping normal tissue cell clone landscapes years before cancer onset [9]. - The study offers new molecular targets and theoretical foundations for high-risk population screening and early intervention for bladder cancer [9].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 2025 年 10 月 6 日， 2025 年诺贝尔生理学或医学奖揭晓，授予了 Mary Brunkow 、 Fred Ramsdell 、 坂口志文 ， 他们发现并定义了 调节性 T 细胞 （Treg 细胞） ， 揭示了其在防止免疫系统攻击自身组织中 所发挥的作用，开创了 Treg 细胞介导的外周免疫耐受这一新领域。 除他们三人外， Alexander Rudensky 也对 Treg 作出了重要贡献，2017 年， 坂口志文 、 Fred Ramsdell 和 Alexander Rudensky 就因在 Treg 领域的 贡献获得了 克拉福德奖 。 2025 年 10 月 8 日， 耶鲁大学 胡玮 、 纪念·斯隆凯特琳癌症中心 Alexander Rudensky 等人在 Nature 子刊 Nature Immunology 上发表了题为 ： Temporal and context-dependent requirements for the transcription factor Foxp3 expression in regulatory T cells ...

2025 年 10 月 10 日，同济大学附属上海市肺科医院 戈宝学 、 杨华 、 季哲 及中国医学科学院北京协和医学院 孙义成 研究员作为共同通讯作者 （ 程红玉 、 李沈芝 、 刘红洁 、 闫玫漪 、 王晶香 为共同第一作者） ，在 Nature 子刊 Nature Microbiology 上发表题为： Mycobacterium tuberculosis -derived linoleic acid increases regulatory T cell function to promote bacterial survival within macrophages 的研究论文。 该研究首次揭示了 结核杆菌 通过分泌代谢产物 亚油酸 ，上调 Treg 细胞 的 CTLA-4 表达来抑制宿主抗结核免疫的新机制，为开发抗结核新型疫苗和药物提供了 全新靶点和策略。 撰文丨王聪 编辑丨王多鱼 排版丨水成文 2025 年 10 月 6 日， 2025 年诺贝尔生理学或医学奖揭晓，授予了 Mary Brunkow 、 Fred Ramsdell 、 坂口志文 ， 他们发现并定义了 调节性 T 细胞 （Treg ...

Core Insights - Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation, gaining attention for its potential in cancer therapy [2][6] - Despite extensive research on the biological mechanisms of ferroptosis, its anti-tumor effects are significantly limited due to challenges in the precise delivery of ferroptosis inducers to tumor tissues [2][4] Group 1: Biological Mechanisms and Challenges - Cancer remains a major global health challenge and a leading cause of death, with traditional therapies like chemotherapy and radiotherapy facing inherent limitations such as drug resistance and reduced efficacy in hypoxic tumor microenvironments [6] - Ferroptosis, first reported in 2012, offers a promising opportunity to overcome clinical bottlenecks faced by traditional cancer therapies, with its therapeutic effects validated in various cancer types including pancreatic ductal adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, and triple-negative breast cancer [6][7] - The need to enhance the delivery efficiency of ferroptosis inducers to tumor tissues is a critical theme, as several inducers have shown effectiveness in preclinical models but failed to improve patient survival in clinical trials [7][9] Group 2: Nanotechnology and Delivery Systems - Recent advancements in nanotechnology provide new perspectives for the innovation of tumor ferroptosis, particularly through the development of nanodrug delivery systems (NDDS) that can regulate multiple molecular pathways and enhance tumor-specific delivery [4][8] - Multifunctional nanomaterials can serve as nanocarriers for the synergistic delivery of various therapeutic agents, overcoming ferroptosis resistance in cancer cells and effectively targeting multiple molecular pathways [8][9] - NDDS can be designed to respond to tumor-specific stimuli, allowing for spatiotemporal controlled release of ferroptosis inducers, thereby minimizing off-target damage and enhancing therapeutic efficacy [8][9] Group 3: Future Directions - The review establishes a connection between the biology of ferroptosis and nanomaterial science, elucidating how functional nanoplatforms can enhance ferroptosis by modulating dysfunctional organelles and improving the delivery efficiency of inducers [9][27] - The current limitations of ferroptosis in clinical applications and the future development directions based on nanotechnology are summarized, indicating a significant potential for improving clinical outcomes and patient quality of life through enhanced ferroptosis cancer therapies [9][27]

Core Viewpoint - The in vivo CAR-T field has rapidly evolved over three years, marked by significant acquisitions and clinical advancements, culminating in major deals such as AbbVie’s $2.1 billion acquisition of Capstan Therapeutics and BMS’s $1.5 billion acquisition of Orbital Therapeutics [3][4]. Group 1: Acquisitions and Market Activity - AbbVie announced the acquisition of Capstan Therapeutics for $2.1 billion in cash, highlighting the growing interest in in vivo CAR-T therapies [3]. - BMS acquired Orbital Therapeutics for $1.5 billion, expanding its portfolio into the in vivo CAR-T cell therapy space [4]. - These acquisitions reflect a broader trend of increasing investment and collaboration in the CAR-T sector, indicating a robust market outlook [3][4]. Group 2: Technological Advancements - BMS's acquisition of Orbital enhances its cell therapy research platform, focusing on a potential best-in-class therapy aimed at autoimmune diseases [6]. - The therapy OTX-201, developed by Orbital, is in the pre-IND research stage and is expected to enter clinical trials in the first half of 2026 [6]. - OTX-201 utilizes optimized circular RNA (circRNA) to generate CAR-T cells in vivo, targeting CD19 to treat B-cell driven autoimmune diseases [7]. Group 3: Research and Development Focus - Orbital Therapeutics aims to develop next-generation RNA drugs that reprogram cells to treat diseases at their source, offering a simpler and safer alternative to current CAR-T therapies [10]. - The company’s platform integrates circRNA, linear RNA, targeted delivery systems, and AI-driven design to create durable and programmable therapies [10]. - In addition to autoimmune diseases, Orbital is also exploring in vivo CAR-T therapies for cancer and developing next-generation mRNA vaccines [12].

Core Insights - Immune therapy has fundamentally changed the clinical approach to tumor treatment, particularly with PD-1/PD-L1 immune checkpoint inhibitors, which have received continuous FDA approvals for both monotherapy and combination therapy. However, the clinical benefits in advanced tumor patients remain limited due to low somatic mutation rates, few infiltrating lymphocytes, and low PD-L1 expression levels, indicating these tumors are "cold tumors" [2] - Various immune cytokines such as IL-2, IL-7, IL-12, and IL-15 have been identified to regulate T cell proliferation, survival, and function, with the potential to convert "cold tumors" into "hot tumors" and enhance anti-tumor responses when used in conjunction with immune checkpoint inhibitors. Nonetheless, their clinical application faces challenges including technical difficulties, safety concerns, and insufficient efficacy observed in advanced tumors [2] Group 1 - The recent study published in Cell Reports Medicine demonstrates the local delivery of IL-15 and anti-PD-L1 nanobody via in vitro transcribed circILNb, which activates robust anti-tumor immunity in "cold tumors" that are unresponsive to conventional immunotherapy [3][4] - The research team engineered a circCV-B3 vector to achieve scarless circular RNA (circRNA) engineering, allowing circILNb to co-encode IL-15 and anti-PD-L1 nanobody. This circILNb is purified through a biotin-avidin purification system and encapsulated in lipid nanoparticles (LNP) for intratumoral injection, leading to in situ protein expression and activation of existing CD8+ T cells and NK cells for local tumor control [6][8] Group 2 - The study highlights the potential of the circCV-B3 vector and BAPS as circRNA engineering methods, confirming that circILNb can serve as a non-protein therapeutic strategy for tumor immunotherapy [8]

撰文丨王聪 编辑丨王多鱼 排版丨水成文 生理学中的一个基本问题是了解组织如何适应并改变其细胞构成以响应饮食信号。哺乳动物的小肠由快速更新的 LGR5 + 肠道干细胞 （ISC） 维持，这些细胞会对诸如禁食方案和致肥胖饮食等宏量营养素的变化作出反应，然而，在稳态和损伤期间，特定氨 基酸如何控制肠道干细胞的功能，目前仍不清楚。 放疗和化疗等癌症治疗，以及炎症性肠病，都会导致肠道损伤。然而，长期以来，肠道损伤修复的复杂动态一直 困扰着研究人员，能够刺激 肠道内壁的肠道干细胞再生的干预措施，寥寥无几。 2025 年 10 月 1 日，麻省理工学院 Ömer H. Yilmaz 团队 （博士后 迟方涛 为第一作者） ，在国际顶尖学术期刊 Nature 上发表了题为： Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22 的研究论文。 饮食来源的半胱氨酸 能够增强肠道损伤后肠道干细胞介导的肠 道再生。 该研究证实，饮食中的 半胱氨酸 ，通过 刺激 CD8+ T 细胞分泌 IL-22 ，增强肠道损伤后肠道干细胞介导的损伤修复和 ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 胰腺癌 （Pancreatic Cancer） ，是一种恶性程度很高，诊断和治疗都很困难的消化道恶性肿瘤，其中 胰腺导管腺癌 （PDAC） 占全部胰腺癌的 95% 以上。 胰腺癌早期的确诊率不高，发现时往往已是晚期，由于生存率低、预后差，胰腺癌也被称为" 癌中之王 "。 2025 年 10 月 9 日， 浙江大学医学院附属第一医院 梁廷波 教授团队在 Cell 子刊 Cancer Cell 上发表了题为： Neoadjuvant nab-paclitaxel plus gemcitabine followed by modified FOLFIRINOX for resectable pancreatic cancer: A randomized phase 3 trial 的研究论文。 这项随机 3 期临床试验， 在 324 例可切除的 胰腺癌 患者中，评估了 序贯新辅助治疗方案 与 直接手术方案 的疗效对比，结果显示，这种 新辅助白蛋白结合型 紫杉醇联合吉西他滨序贯改良 FOLFIRINOX 方案 ， 可显著 改善无事件生存期 ，且 安全性可控 ，为可切除的胰腺癌患 ...

Core Viewpoint - The research led by José C.R. Silva and Chen Chuanxin at Guangzhou National Laboratory presents a significant advancement in human post-implantation embryo modeling through the activation of the STAT3 signaling pathway, achieving high-fidelity models that address previous limitations in efficiency and accuracy [3][4][10]. Summary by Sections Research Background - The study addresses the inefficiencies and limited fidelity of current systems in simulating the post-implantation stage of human embryo development [3][6]. Key Findings - **STAT3 Mediated Pluripotent Stem Cell Reprogramming**: A specialized medium (SAM) enhances STAT3 activity, allowing pluripotent stem cells (PSCs) to be reprogrammed into various early cell lineages within 60 hours, including hypoblast, trophectoderm, naive epiblast, and extraembryonic mesoderm [7]. - **Efficient 3D Self-Organizing Model Construction**: Cells treated with SAM for 60-120 hours can be cultured in 3D, resulting in a significant increase in efficiency to 52.41% ± 8.92% for developing post-implantation embryo-like structures, surpassing current mainstream methods [8]. - **High Simulation of Natural Embryo Development**: The structures formed on day 6 closely resemble Carnegie stages 5-7 (CS5-CS7) human embryos, exhibiting features such as bilaminar disc structure, amniotic cavity formation, mesenchymal cell distribution, chorionic cavity, and trophoblast cell differentiation [8]. - **Successful Formation of Primitive Streak**: The CS6/7 stage embryo-like structures demonstrate key developmental events, including the correct formation and localization of the primitive streak, epithelial-mesenchymal transition (EMT), and differentiation of mesoderm and definitive endoderm [8]. - **Molecular Level Validation**: Single-cell transcriptome analysis shows that the model aligns closely with real CS6/7 human embryo data at the molecular level, confirming its biological relevance and research application value [8]. Implications - The STAT3 activation-induced model represents a breakthrough in overcoming existing efficiency bottlenecks (over 50% generation rate) and provides a more accurate in vitro platform for studying early human embryonic development mechanisms, congenital disease modeling, and drug toxicity testing [10]. This advancement marks a transition from "morphological simulation" to "functional simulation" in embryo modeling, opening new pathways for research in developmental biology and regenerative medicine [10].