Core Viewpoint - Tumor immunotherapy, particularly immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 pathway, shows promise in treating advanced cancers but is limited by insufficient response rates. Recent findings suggest that Gasdermin D-mediated pyroptosis can trigger a robust systemic immune response, with only 15% of pyroptotic tumor cells capable of eliminating the entire tumor, presenting a new strategy for enhancing anti-tumor immunity [2][3][10]. Summary by Sections Research Development - A new self-luminous photodynamic therapy system, CC@PDC, has been developed to efficiently activate pyroptosis and stimulate anti-tumor immunity. This system, when used in conjunction with anti-PD-L1 antibodies, demonstrates superior anti-tumor and immune effects, offering a novel strategy for cancer treatment [3][10]. Mechanism and Composition - The CC@PDC system is designed with efficient resonance energy transfer, effective generation of singlet oxygen (1 O₂), and strong pyroptosis induction capabilities. It consists of amphiphilic porphyrin lipids, camptothecin derivatives, and a targeted assembly that encapsulates oleic acid-modified calcium peroxide and a specific compound to enhance its efficacy in acidic tumor microenvironments [7][10]. Key Findings - The study highlights that the camptothecin-enhanced self-luminous photodynamic chemotherapy can synergistically induce tumor cell pyroptosis and, when combined with anti-PD-L1 antibodies, significantly enhances the anti-tumor immune response, providing a promising new approach for cancer therapy [10][11].

撰文丨 编辑丨王多鱼 排版丨水成文 严重的呼吸道病毒感染会导致肺泡上皮细胞广泛受损，并引发强烈的免疫反应。免疫微环境如何与肺干细 胞/祖细胞相互作用并影响肺泡再生，目前尚不清楚。 2025 年 12 月 23 日，上海科技大学生命科学与技术学院 席莹 教 授团队 （ 陆甜甜 、 刘莉 、 王萍 为论 文 共同第一作者 ） 联合上海交通大学医学院附属 第六人民医院 任涛 教授、广州医科大学/广州实验室 赵 金存 教授，在 Cell Stem Cell 期刊 发表 了 题为： Dysplastic epithelial repair promotes the tissue- residence of lymphocytes to inhibit alveolar regeneration post viral infection 的研究论文。 该研究首次揭示了肺组织中异常修复的 KRT5 基底样细胞 对 T 细胞 组织驻留 的促进作用，同时发现流感 病毒清除后持续存在的 T 细胞会 抑制气道 Club 细胞介导的 肺泡 再生 。该研究 深化了对严重病毒感染后 肺修复 再生 障碍的机制认识， 也为促进感染后肺泡再生 ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 脑转移 （ Brain metastasis ） 是 肺癌 患者死亡的主要原因。大脑独特的微环境在 脑转移瘤 （BM） 的发生和发展中发挥着关键作用，然而，其中肿瘤与微环 境相互作用的分子机制仍知之甚少。 2025 年 12 月 24 日，中国医学科学院肿瘤医院 王洁 教授团队在 Signal Transduction and Targeted Therap 期刊发表了题为： Lipocalin-2 drives brain metastatic progression through reciprocal tumor-microenvironment interactions in lung cancer 的研究论文。 该研究发现， LCN2 通过肺癌中肿瘤-微环境的相互作用，驱动脑转移进展。 这一发现突显了 LCN2 在驱动脑转移中的核心作用，并提出了脑转移性肺癌的一种 潜在治疗靶点。 论文链接 ： https://www.nature.com/articles/s41392-025-02514-2 总的来说，这一发现突显了 LCN2 在驱动脑转移中的核心作用，并提 ...

胚胎植入是指发育至囊胚阶段的胚胎通过与母体子宫内膜发生定位、附着并最终入侵内膜基质的过程，是 成功妊娠的第一步。胚胎植入失败，严重影响女性健康及出生人口数量。因此,对胚胎植入的研究至关重 要。然而，胚胎植入发生于子宫内，无法直接研究。因此,迫切需要在体外建立人胚胎植入模型，还原真实 的胚胎植入过程及植入后胚胎发育。 2025 年 12 月 23 日，中国科学院动物研究所 于乐谦 研究员、 王红梅 研究员、得克萨斯大学西南医学中 心 吴军 教授、中国农业大学 魏育蕾 教授、北京妇产医院 杨晓葵 教授团队合作 （ 李谦 、 元杨 、 赵文 涛 、 李圆君 、 修雨 、 韩米 为论文共同第一作者 ） ，在国际顶尖学术期刊 Cell 上发表了题为： A 3D In Vitro Model for Studying Human Implantation and Implantation Failure 的研究论文。 该研究基于 微流控芯片 技术建立了 3D 人类胚胎植入模型 （人工/自然囊胚植入人工子宫） ，实现了 首 次在实验室精准复刻人类胚胎植入过程 ，为研究人类胚胎植入的细胞和分子机制提供了重要模型，也为治 疗 ...

Core Viewpoint - The research highlights the importance of the interaction between the embryo and the endometrium during the early stages of pregnancy, revealing that the endometrium actively regulates the implantation process rather than being a passive recipient [2][5]. Group 1: Research Findings - A 3D co-culture system was developed to allow human embryos to interact with endometrial tissue, significantly improving embryo survival rates and providing insights into early pregnancy mechanisms [2][5]. - The study found that trophoblast cells began to invade the endometrial organoid by day 7, and key developmental milestones were observed that were not seen in previous culture systems without maternal tissue [5][8]. - The endometrium was shown to initiate the invasion program of extravillous trophoblasts (EVT) three days earlier than previously recorded, indicating a proactive role in the implantation process [8]. Group 2: Molecular Mechanisms - The research identified that EVT cells, crucial for placental invasion, appeared significantly earlier in the co-culture system, with molecular signals activating key invasion genes [8][9]. - The study demonstrated that human chorionic gonadotropin (hCG) is essential for successful implantation, with blocking its function leading to a drastic decrease in embryo adhesion and development [9][10]. - The embryo was observed to exchange materials with the mother through vesicle transport, mimicking in vivo dynamics within the co-culture environment [10].

Core Viewpoint - The article discusses the potential for reversing advanced Alzheimer's disease through the restoration of NAD+ homeostasis, challenging the long-held belief that the disease is irreversible [2][10]. Group 1: Alzheimer's Disease Overview - Over 50 million people worldwide are currently affected by Alzheimer's disease, with projections indicating this number will exceed 150 million by 2050 [1]. - Current treatments primarily target beta-amyloid proteins or provide symptomatic relief, with limited effectiveness [1]. Group 2: Research Breakthroughs - A study published by researchers at Case Western Reserve University demonstrated that the drug P7C3-A20 can restore NAD+ homeostasis, successfully reversing advanced Alzheimer's disease in mice [2][10]. - The research indicates that even late-stage Alzheimer's may be reversible by enhancing the brain's resilience [2][10]. Group 3: Mechanism of Action - NAD+ is a crucial molecule for cellular energy metabolism, involved in energy production, DNA repair, and antioxidant defense [5]. - The study found that NAD+ levels significantly decline as Alzheimer's disease progresses, correlating directly with the severity of the disease [5]. Group 4: Effects of P7C3-A20 - P7C3-A20 treatment not only halted disease progression in late-stage Alzheimer's mouse models but also achieved comprehensive reversal of cognitive deficits [7]. - Post-treatment, animals showed normal performance in memory and learning tests, reduced tau protein phosphorylation, decreased blood-brain barrier damage, and diminished oxidative stress [8]. Group 5: Human Brain Evidence - Analysis of human brain samples revealed a close relationship between NAD+ homeostasis imbalance and the severity of Alzheimer's disease [9]. - Individuals with Alzheimer's pathology but normal cognition (NDAN) exhibited maintained NAD+ homeostasis, suggesting a protective mechanism [9]. Group 6: Future Directions - The study's breakthroughs include the first demonstration that late-stage Alzheimer's-like pathology can be reversed, the identification of NAD+ homeostasis as a central mechanism in disease progression, and the discovery of potential therapeutic targets in the human brain [10][14]. - Future plans involve preclinical safety and efficacy assessments to lay the groundwork for human clinical trials, potentially offering a new treatment direction for Alzheimer's disease [14].

Core Viewpoint - The study published in Cell highlights that chronic metabolic stress from high-fat diets not only leads to fatty liver but also induces profound changes in liver stem cells, which can promote tumorigenesis [1][2]. Group 1: Research Findings - Chronic stress forces liver cells to choose between survival and maintaining organ function, leading to early adaptive changes that can "pre-program" future tumor development [3][4]. - The research utilized a high-fat diet mouse model to simulate human metabolic dysfunction related to fatty liver disease, tracking changes in liver cells through multi-omics analysis [5]. - Chronic metabolic stress activates two core programs in liver cells: an upregulation program that promotes cell survival and regeneration while downregulating liver-specific functions, leading to decreased liver function [6]. Group 2: Key Mechanisms - The decline of the ketogenesis rate-limiting enzyme HMGCS2 is crucial, as its knockout in liver cells under high-fat diet stress exacerbates stress responses and significantly increases tumor incidence [8]. - The transcription factors SOX4 and RELB play a central role in promoting liver cell dedifferentiation and proliferation under stress, with high expression levels in patients with metabolic dysfunction-associated fatty liver disease (MASLD) indicating poor prognosis [10]. Group 3: Clinical Implications - The study reveals a "memory effect" of chronic stress and suggests monitoring the expression of genes like HMGCS2 and SOX4 as early risk markers for liver cancer [14]. - Targeting metabolic pathways, such as ketogenesis, or transcription factors like SOX4 may block precancerous states, providing potential intervention strategies [15]. - Overall, the adaptation of the liver to chronic metabolic stress enhances short-term cell survival but sacrifices long-term liver function, emphasizing the importance of healthy diets and metabolic stress control in preventing liver cancer [17].

Core Viewpoint - The article discusses the challenges and advancements in developing targeted therapies for T-cell cancers, particularly focusing on antibody-drug conjugates (ADCs) that target TRBC2 and TRBC1, which may provide new treatment options for patients with limited survival rates [1][3][6]. Group 1: T-cell Cancer Overview - T-cell leukemia and lymphoma, collectively known as T-cell cancer, see approximately 100,000 new patients globally each year [1]. - The 5-year survival rate for adult patients with relapsed T-cell cancer ranges from 7% to 38%, highlighting the limited treatment options available compared to B-cell cancers [1]. Group 2: Antibody-Drug Conjugates (ADCs) - ADCs are a novel class of targeted drugs composed of antibodies, cytotoxic agents, and linkers, designed to selectively deliver cytotoxic molecules to tumor cells while sparing healthy cells [1]. - While ADCs have shown significant success in treating solid tumors and hematologic malignancies, developing ADCs for T-cell cancers poses unique challenges due to the need to selectively target malignant T-cells without harming normal T-cells [1]. Group 3: Research Developments - A study published by Suman Paul’s team at Johns Hopkins University developed a TRBC2-targeting ADC for T-cell cancer treatment, demonstrating specific cytotoxic effects on TRBC2-positive cancer cells in vitro and in mouse models [2][6]. - The research indicates that targeting TRBC2 could provide a promising and ready-to-use treatment option for T-cell cancer patients [6]. Group 4: TRBC1-targeting ADCs - Another study from the same team confirmed that CAR-T cells targeting TRBC1 could inadvertently kill normal TRBC1+ T-cells, leading to poor treatment responses [7]. - To address this issue, the team developed a TRBC1-targeting ADC that effectively treats T-cell cancer in vitro and in mouse models, suggesting it may offer an optimal targeting strategy for TRBC1 [8].

Core Viewpoint - The research highlights the significant role of gut microbiota in promoting maternal-fetal immune tolerance, which is crucial for preventing miscarriage. It establishes a connection between gut health and pregnancy outcomes, providing new insights for miscarriage prevention [2][17]. Group 1: Changes During Pregnancy - Gut permeability in pregnant mice increases with gestational age, allowing substances to enter the bloodstream more easily. The composition of gut microbiota also changes dynamically, with certain bacteria like Bacteroidetes and Clostridia increasing in number [5]. - The absence or disruption of gut microbiota in germ-free or antibiotic-treated mice leads to a significantly higher rate of miscarriage, indicating that gut microbiota is essential for successful pregnancy [5]. Group 2: Immune Imbalance and Miscarriage - Analysis of immune cells reveals severe immune imbalance at the maternal-fetal interface in mice lacking gut microbiota. Specifically, excessive IFN-γ is identified as a key factor leading to miscarriage [7]. - The study identifies two critical pathways through which gut microbiota influences immune responses: the role of myeloid-derived suppressor cells (MDSCs) in inhibiting IFN-γ production and the presence of RORγt+ regulatory T cells that help maintain immune balance [10]. Group 3: Metabolites and Immune Regulation - Tryptophan metabolites, particularly indole compounds, are found to be abundant in the plasma and amniotic fluid of normally pregnant mice. These metabolites activate the aryl hydrocarbon receptor (AhR), promoting the differentiation of RORγt+ Tregs and the functional maturation of MDSCs [12]. - Supplementation with indole-3-carbinol (I3C), an AhR agonist, restores normal miscarriage rates in germ-free mice, demonstrating the potential for dietary interventions to influence pregnancy outcomes [12]. Group 4: Human Relevance - The research extends beyond mouse models, analyzing human datasets that show reduced MDSC numbers and function, decreased RORγt+ Treg proportions, and lower levels of tryptophan metabolites in the endometrium of patients with recurrent miscarriage [14][15]. - These findings suggest that the gut-placenta immune signaling axis is also significant in human pregnancies, reinforcing the importance of gut health for pregnancy outcomes [17].

Core Viewpoint - The article discusses the potential of enhancing hydrogen sulfide (H₂S) generation through natural compounds, specifically diallyl sulfides (DAS), to promote healthspan and lifespan in mammals, particularly male mice [5][8]. Group 1: H₂S Generation Mechanisms - H₂S is generated through both non-enzymatic and enzymatic mechanisms, with the non-enzymatic pathway involving sulfur donors such as cysteine and homocysteine [1]. - Natural sulfur compounds, particularly those found in garlic, are highlighted for their ability to release H₂S in the body, making them significant for research on H₂S's physiological functions [1]. Group 2: Research Findings - A study published in Cell Metabolism indicates that enhanced non-enzymatic H₂S generation can extend lifespan and healthspan in male mice [3]. - The research shows that DAS not only prolongs the lifespan of wild-type male mice but also improves key health indicators throughout their life, including glucose regulation, motor function, and cognitive abilities [6]. - Observations at the histological and molecular levels revealed reduced liver lipid droplet volume and decreased activity in mTOR and immune-related pathways, alongside increased levels of protein persulfidation [6]. Group 3: Implications for Human Health - In human studies, higher levels of protein persulfidation in individuals with multiple pathological conditions are associated with enhanced muscle strength and reduced triglyceride levels, supporting the physiological relevance of this modification [6].