Clinical and Translational Medicine最新文献_第4页

Alterations of the immune microenvironment with age predicts patient prognosis of gastrointestinal tract tumours 随着年龄的增长，免疫微环境的改变可以预测胃肠道肿瘤患者的预后。

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine

Pub Date : 2026-01-07 DOI: 10.1002/ctm2.70592

Fangzhen Li, Jingjing Chen, Junjie Wang, Qiuhong Zhu, Cuiying Chu, Zhiwen Zhang, Yuting Deng, Liang Zhang, Xu Lu, Wei Wang, Huipeng Wang, Dongxue Li, Aili Zhang, Hai-bo Wu, Wenchao Zhou

<p>Dear Editor:</p><p>Because aging plays critical roles in immune response and tumour development, alterations of the tumour immune microenvironment with age may be predictive of prognosis. Hence, we analysed single-cell RNA-seq (scRNA-seq) data of gastrointestinal (GI) tract tumours to search for immune cells enriched in elderly patients, and thereby raised an immune index with potential clinical values.</p><p>We initially constructed a single-cell atlas using scRNA-seq datasets from Gene Expression Omnibus (GEO) for gastric cancer (GC) , colorectal carcinoma (CRC) and oesophageal carcinoma (OSCA), which contained 115 samples and 419 000 cells (Figure S1A,B and Table S1). The lymphoid and myeloid cells were reclustered to subpopulations (Figures S1C–G and S2A,B; Figure 1A,B), and their biased distributions in older (>60 years) and younger (≤60 years) patients were evaluated by the ratio of observed to expected cell numbers (Ro/e) analysis<span><sup>1</sup></span> (Figure 1C). For each subpopulation showing preference for older patients, the top 100 differentially expressed genes were employed to score patients from TCGA datasets via ssGSEA.<span><sup>2</sup></span> The following Kaplan–Meier analysis revealed several subpopulations that were inversely correlated to survival (Figure 1D and Table S2). Further analysis of the differentially expressed genes of these subpopulations discovered multiple commonly enriched pathways (Figure S2C–F). Moreover, among these subpopulations, the CD8T_C2 and Proli_T_C1 had high expression of T cell exhaustion markers (Figure S2G), although this may not necessarily stand for a canonical exhaustion state. Taken together, several immune subpopulations are enriched in older GI tract tumour patients and may affect prognosis.</p><p>We analysed the potential communications between immune subpopulations with CellChat,<span><sup>3, 4</sup></span> and evaluated strength of intercellular signalling pathway with IMPORTANCE (Figure S3A,B). Among the immune subpopulations with enrichment in older patients and correlation to prognosis, nine subpopulations demonstrated markedly altered signalling in older relative to younger patients (ΔIMPORTANCE > 10) (Figure 2A) and had intensive interactions (Figure S3C). Therefore, the nine subpopulations may constitute an elderly enriched immune meta-cluster (EIM). Deconvolution analysis of spatial transcriptomic data for GC tumours defined distinctive distribution patterns of immune subpopulations, and the pattern with preference for older patients contained several EIM component subpopulations (Figure 2B–D and Figure S3D). The spatial co-enrichment of EIM component subpopulations were observed by multiple methods (Figure S3D,E). Moreover, GI tract tumour patients in TCGA were scored for EIM followed by Kaplan–Meier analysis, which revealed an inverse correlation between EIM and survival (Figure 2E and Figure S3F). Meanwhile, pathway enrichment network analysis of the signature gen

亲爱的编辑：由于衰老在免疫反应和肿瘤发展中起着关键作用，肿瘤免疫微环境随年龄的变化可能预示预后。因此，我们分析了胃肠道肿瘤的单细胞RNA-seq （scRNA-seq）数据，以寻找老年患者中富集的免疫细胞，从而提出一种具有潜在临床价值的免疫指标。我们最初使用来自Gene Expression Omnibus （GEO）的scRNA-seq数据集构建了胃癌（GC）、结直肠癌（CRC）和食管癌（OSCA）的单细胞图谱，其中包含115个样本和419000个细胞（图S1A、B和表S1）。淋巴细胞和髓细胞重新聚集成亚群（图S1C-G和S2A，B；图1A，B），并通过观察到的细胞数与预期细胞数的比值（Ro/e）分析来评估它们在老年（60岁）和年轻（≤60岁）患者中的偏态分布（图1C）。对于表现出老年患者偏好的每个亚群，通过ssgsea使用前100个差异表达基因对TCGA数据集中的患者进行评分接下来的Kaplan-Meier分析揭示了几个与生存率呈负相关的亚群（图1D和表S2）。对这些亚群差异表达基因的进一步分析发现了多个共同富集的途径（图S2C-F）。此外，在这些亚群中，CD8T_C2和Proli_T_C1具有T细胞衰竭标志物的高表达（图S2G），尽管这可能不一定代表典型的衰竭状态。综上所述，几个免疫亚群在老年胃肠道肿瘤患者中富集，并可能影响预后。我们通过CellChat、3、4分析了免疫亚群之间的潜在通信，并通过IMPORTANCE评估了细胞间信号通路的强度（图S3A，B）。在老年患者中富集并与预后相关的免疫亚群中，有9个亚群在老年患者中表现出相对于年轻患者明显改变的信号传导（ΔIMPORTANCE > 10）（图2A），并具有强烈的相互作用（图S3C）。因此，这9个亚群可能构成一个老年人免疫富集元群（EIM）。GC肿瘤空间转录组数据的反褶积分析定义了免疫亚群的独特分布模式，老年患者偏好的模式包含几个EIM成分亚群（图2B-D和图S3D）。通过多种方法观察EIM成分亚群的空间共富集（图S3D，E）。此外，对TCGA的胃肠道肿瘤患者进行EIM评分，并进行Kaplan-Meier分析，结果显示EIM与生存率呈负相关（图2E和图S3F）。同时，EIM特征基因的通路富集网络分析表明它们参与免疫调节（图S3G）。然后对胃肠道肿瘤切片进行EIM分子标记染色。较大比例的CD8+ T细胞和CD14+/CD16+单核细胞属于EIM，相对于年轻患者，老年患者的肿瘤中检测到更多的CD8、CD14和CD16的免疫荧光信号（图2F、G）。此外，尽管EIM淋巴样亚群在T细胞衰竭标志物上得分很高（图S2G），但在老年患者的肿瘤中观察到PD1表达升高（图S4A，B）。这些潜在的EIM标记物的双重染色显示相同的趋势（图S4C-F）。因此，老年患者胃肠道肿瘤中EIM含量丰富，且与预后呈负相关。我们应用了一个由四个分类器组成的机器学习框架，并测试了EIM是否可以对TCGA和GEO数据集的老年患者进行分类。5,6数据集对每个免疫亚群的每个分类器进行分类，得到曲线下的面积值作为结果。采用特定数据集曲线值下面积最大的分类器（图3A）。当涉及到老年患者的分类时，EIM优于任何亚群，并且优于CellAge7的衰老相关基因特征（图3B，C和图S5A-C）。我们利用OSCA和CRC肿瘤的scRNA-seq数据来探索EIM在新辅助抗pd1免疫治疗应答中的作用（图S6A，B）。使用scRNA-seq图谱对细胞类型进行注释后，将包括年龄组和治疗结果在内的信息分配给细胞（图3D和图S6C-E）。不同分布的Ro/e分析显示，相对于不完全病理反应或主要病理反应的老年OSCA患者，完全病理反应的老年OSCA患者大多数EIM成分亚群下降（图3E）。与此一致的是，不完全病理反应患者的EIM评分高于主要病理反应或完全病理反应患者（图3F）。在对新辅助免疫治疗有反应或无反应的老年结直肠癌患者中也获得了类似的结果（图S7A-C）。在接受化疗的老年结直肠癌患者中，EIM评分越高生存率越差（图3G和图S7D）。综上所述，EIM能够预测老年胃肠道肿瘤患者的衰老状态和对治疗的反应。我们试图通过整合10种机器学习算法来识别简洁的基因集，从而获得基于EIM的预后指数8（图4A）。我们发现RSF+Ridge模型在所有队列中获得了卓越的表现，并对高/低风险患者进行了分层（图4A，B）。值得注意的是，我们基于eim的模型在GC和OSCA中的表现优于几种经典的预后特征（图4C）。我们使用基于EIM的RSF+Ridge机器学习模型中的69个顶级特征基因生成EIM指数（表S3），并将患者分为高组和低组。有趣的是，尽管TCGA队列中的年轻患者总体上EIM指数较低，但有一小部分患者属于EIM指数较高的组，且预后较差（图S7E）。相同的切点将大多数老年患者分层为高EIM指数组，生存率较差（图S7E）。然而，对于所有患者，EIM指数均为阴性预测预后（图4D）。事实上，相对于实足年龄的EIM指数与预后的相关性更强（图4E）。我们利用每个样本的前3000个高度可变基因，通过主成分分析进一步评估肿瘤的转录特征（图4F）。令人惊讶的是，在主成分分析中，EIM指数而不是实足年龄将患者分为不同的组（图4F）。此外，EIM指数水平较高的患者，无论其实际年龄如何，其已知衰老标志物（如衰老相关分泌表型（SASP））的表达也较高（图4G）。因此，EIM指数不仅能预测预后，还能反映实足年龄以外的衰老状态。人们刚刚开始利用单细胞分析来研究与年龄有关的免疫特征本研究通过对老年和年轻患者胃肠道肿瘤免疫景观的scRNA-seq分析，我们发现EIM在老年人中富集，与患者生存呈负相关，从而提高了EIM指数，具有潜在的预后价值。我们的研究结果表明，可以量化老年患者肿瘤免疫微环境的变化，以预测肿瘤的发展，尽管这种变化的原因需要进一步研究。J.C.和J.W.对这项工作贡献相同。w.z.、h.w.、A.Z.和d.l.提出了工作假设和科学概念。w.z., f.l., j.c.和J.W.设计了实验，分析了数据并准备了手稿。F.L.和J.C.进行了实验并整理了数据。D.L.和X.L.提供了手术标本。所有作者协助实验，帮助准备稿件，并提供科学意见。作者声明无利益冲突。所有参与者均获得书面知情同意，相关实验经中国科大大学第一附属医院医学研究伦理委员会批准，许可证号：2023 ky454。中国科技大学第一附属医院医学研究伦理委员会免除了使用公开人类患者测序数据的伦理审批。所有的测序数据都是公开的。详细信息请参见支持信息。本研究中使用的代码可根据要求提供。

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Single-molecule electrical protein fingerprinting in solid-state nanopores 固态纳米孔中的单分子电蛋白指纹图谱。

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine

Pub Date : 2026-01-07 DOI: 10.1002/ctm2.70589

Neeraj Soni, Amit Meller

<p>Proteins play a central role in virtually all biological processes and serve as critical indicators of health and disease. Despite their importance, protein-based diagnostics remain far less developed than nucleic acid-based approaches. A major limitation is the insufficient sensitivity of current proteomic technologies, which typically require either enzymatic digestion of proteins into peptides or their immobilisation on surfaces for affinity-based detection.<span><sup>1</sup></span> These strategies inherently discard information encoded in full-length proteins and rely heavily on the availability and performance of high-quality antibodies.</p><p>Soni et al.<span><sup>2</sup></span> report a fundamentally different approach for antibody-free, full-length protein fingerprinting based on solid-state nanopores. A nanopore is a nanometre-scale aperture in a thin insulating membrane that separates two electrolyte reservoirs. When a biopolymer translocates through the pore under an applied electric field, it transiently modulates the ionic current, producing a signal that reflects the molecule's physical and chemical properties.<span><sup>3</sup></span> This principle underpins nanopore-based DNA sequencing, in which variations in ionic current are used to infer the nucleotide sequence of individual DNA molecules. The success of nanopore DNA sequencing is attributable to several intrinsic features of DNA: a uniformly charged backbone, the closely related chemical structures of its four nucleotides and the availability of enzymes that regulate DNA motion through the pore. Extending this framework to proteins, however, is substantially more challenging because of the immense diversity in protein size, charge distribution and three-dimensional structure. Additionally, unlike DNA, proteins cannot be amplified, imposing stringent requirements on the sensor's limit of detection (LoD).</p><p>To overcome key barriers such as single-file translocation and limited temporal resolution,<span><sup>4</sup></span> Soni et al.<span><sup>2</sup></span> introduce a chemo-selective labelling strategy (Figure 1). Proteins are denatured and site-specifically conjugated at cysteine residues with short single-stranded DNA oligonucleotides (5- or 10-mers) using click chemistry. Remarkably, proteins labelled with a 5-mer oligonucleotide exhibit a distinctive stick–slip translocation mechanism, characterised by prolonged transient binding within the nanopore at the oligonucleotide–cysteine junction. This behaviour is absent in unconjugated proteins and results in an approximately 20-fold slowing of translocation dynamics. Molecular dynamics simulations corroborate the mechanistic origin of these interactions. This controlled slowdown enables the generation of time-resolved ionic current pulses, which serve as proxies for the positions of cysteine residues along the protein backbone. These pulse patterns constitute protein-specific fingerprints. Using only a few tens of tr

蛋白质在几乎所有的生物过程中发挥着核心作用，是健康和疾病的关键指标。尽管它们很重要，但基于蛋白质的诊断方法仍然远不如基于核酸的方法发达。一个主要的限制是当前蛋白质组学技术的灵敏度不足，通常需要将蛋白质酶切成肽或将其固定在表面以进行基于亲和力的检测这些策略固有地丢弃了全长蛋白编码的信息，严重依赖于高质量抗体的可用性和性能。Soni等人2报道了一种完全不同的基于固态纳米孔的无抗体全长蛋白质指纹识别方法。纳米孔是隔离两个电解质储层的薄绝缘膜上的纳米级孔径。当生物聚合物在外加电场作用下通过孔移位时，它会短暂地调节离子电流，产生反映分子物理和化学性质的信号这一原理支撑了基于纳米孔的DNA测序，其中离子电流的变化被用来推断单个DNA分子的核苷酸序列。纳米孔DNA测序的成功归功于DNA的几个内在特征：一个均匀带电的主链，其四个核苷酸的密切相关的化学结构，以及调节DNA通过纳米孔运动的酶的可用性。然而，由于蛋白质大小、电荷分布和三维结构的巨大差异，将这一框架扩展到蛋白质上更具挑战性。此外，与DNA不同，蛋白质不能被扩增，这对传感器的检测限（LoD）提出了严格的要求。为了克服单文件易位和有限的时间分辨率等关键障碍，Soni等人引入了一种化学选择性标记策略（图1）。蛋白质变性和位点特异性结合在半胱氨酸残基与短单链DNA寡核苷酸（5-或10-mers）使用点击化学。值得注意的是，用5-聚寡核苷酸标记的蛋白质表现出独特的粘滑易位机制，其特征是在寡核苷酸-半胱氨酸连接处的纳米孔内长时间的瞬时结合。这种行为在非偶联蛋白中不存在，导致易位动力学减慢约20倍。分子动力学模拟证实了这些相互作用的机制起源。这种受控的减速可以产生时间分辨的离子电流脉冲，作为沿蛋白质主干的半胱氨酸残基位置的代理。这些脉冲模式构成了蛋白质特异性指纹。仅使用几十个易位事件，动态时间扭曲分析产生共识信号图，成功地在六种不同的蛋白质中实现。使用血管内皮生长因子的两种亚型进一步证明了这种方法的临床相关性。传统的纳米孔指标“阻断电流”和“停留时间”显示同种异构体之间完全重叠，使得区分不可行。相比之下，导电脉冲的数量和时间安排为同工异构体水平的分化提供了一个强大的特征，即使只有几个拷贝的蛋白质被纳米孔采样。此外，机器学习辅助分类甚至可以在复杂的混合物中准确识别目标蛋白质。除了指纹识别之外，由于增加了负电荷，寡核苷酸偶联极大地增强了蛋白质向纳米孔的传递。这对于临床样品尤其重要，因为临床样品中许多蛋白质生物标志物的内源性浓度极低，并且与核酸不同，无法扩增。Soni等人2证明了寡核苷酸共轭后捕获率增加了10倍，这直接转化为纳米孔LoD的数量级提升。新兴的用于全长蛋白质分析的生物纳米孔方法，无论是酶引导的还是无酶的，已经取得了更高的分辨率，但往往是以牺牲传递效率为代价的相比之下，目前的工作在提高纳米孔的LoD的同时获得了高灵敏度，而不依赖于酶马达。总之，这些结果建立了一个可扩展的、无抗体的纳米孔平台，能够在超低浓度下识别全长蛋白。这一策略标志着向临床可翻译的蛋白质组学诊断迈出了重要的一步，为直接从复杂的生物样品中检测高度敏感、标记最小化和信息丰富的蛋白质提供了一条途径。作者声明无利益冲突。

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引用次数: 0

Baseline multi-omics signatures could predict therapeutic response to neoadjuvant anti-PD-1 immunochemotherapy in non-small-cell lung cancer 基线多组学特征可以预测非小细胞肺癌患者对新辅助抗pd -1免疫化疗的治疗反应。

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine

Pub Date : 2026-01-07 DOI: 10.1002/ctm2.70579

Ailing Cao, Yaobin Lin, Shaoxing Guan, Youhao Chen, Wenyu Zhai, Yuheng Zhou, Shoucheng Feng, Yanping Guan, Yiyu Zhang, Min Huang, Xueding Wang, Hao Long

Background

Neoadjuvant anti-programmed cell death 1 (PD-1) immunochemotherapy has shown promising efficiency in the treatment of early-stage non-small-cell lung cancer (NSCLC), but it has not consistently yielded durable responses. Biomarkers for the prediction of efficacy are warranted.

Methods

We performed shotgun metagenomic and plasma/faecal metabolomic studies in 44 NSCLC patients who underwent neoadjuvant tislelizumab plus platinum-based doublet chemotherapy. Samples were collected at baseline and before surgical resection, and the major pathologic response (MPR) was evaluated.

Results

MPR patients showed a significantly higher gut-microbial alpha diversity, an enrichment of Ruminococcaceae, Lachnospiraceae and Clostridiales species, and an increased plasma level of tryptophan metabolites at baseline. On the contrary, non-MPR patients were characterized by enrichment of Prevotella species in faecal samples and higher plasma levels of linoleic acid metabolites. A high predictive accuracy was achieved using a small panel of differential microbial (Clostridium sp. M62/1 and Eisenbergiella tayi) or metabolomic features (linoleic acid, oxindole-3-acetic acid and quinolinic acid) with AUCs > .85.

Conclusions

The baseline characteristics of the gut microbiota and plasma metabolites could provide early predictions of the response to neoadjuvant anti-PD-1 immunochemotherapy.

Trial registration

NCT05244837.

Key points

Baseline metagenomic and metabolomic signatures were significantly associated with the major pathologic response of neoadjuvant anti-PD-1 immunochemotherapy.
Integrated microbial model (consists of Clostridium sp. M62/1 and Eisenbergiella tayi) and metabolomic model (consists of linoleic acid, oxindole-3-acetic acid and quinolinic acid) could provide early predictions of the response.

背景：新辅助抗程序性细胞死亡1 （PD-1）免疫化疗在治疗早期非小细胞肺癌（NSCLC）中显示出有希望的效果，但它并没有始终产生持久的反应。预测疗效的生物标志物是必要的。方法：我们对44例接受新辅助tislelizumab加铂类双重化疗的NSCLC患者进行了散弹枪宏基因组学和血浆/粪便代谢组学研究。在基线和手术切除前收集样本，并评估主要病理反应（MPR）。结果：MPR患者显示出更高的肠道微生物多样性，瘤胃球菌科、毛螺科和梭菌属物种丰富，血浆色氨酸代谢物水平在基线时升高。相反，非mpr患者的特点是粪便样品中普氏菌种类丰富，血浆中亚油酸代谢物水平较高。利用一小组差异微生物（Clostridium sp. M62/1和Eisenbergiella tayi）或代谢组学特征（亚油酸、氧吲哚-3-乙酸和喹啉酸）获得了较高的预测准确性，auc为0.85。结论：肠道菌群和血浆代谢物的基线特征可以提供对新辅助抗pd -1免疫化疗反应的早期预测。试验注册：NCT05244837。关键点：基线宏基因组和代谢组学特征与新辅助抗pd -1免疫化疗的主要病理反应显著相关。综合微生物模型（包括Clostridium sp. M62/1和Eisenbergiella tayi）和代谢组学模型（包括亚油酸、氧吲哚-3-乙酸和喹啉酸）可以提供早期预测。

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引用次数: 0

Multi-omics analysis identifies PUS7 as an immune modulator driving NETs-mediated macrophage polarization in pancreatic cancer 多组学分析发现，PUS7是驱动nets介导的胰腺癌巨噬细胞极化的免疫调节剂。

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine

Pub Date : 2026-01-06 DOI: 10.1002/ctm2.70581

Jike Fang, Shiye Ruan, Yajie Wang, Yue Chen, Fuxin Huang, Zhongyan Zhang, Chuanzhao Zhang, Baohua Hou, Shanzhou Huang

Pseudouridine synthases (PUS) have been implicated in various cancers, yet their roles in pancreatic cancer immunity remain unclear. Through integrative multi-omics analyses combining genomics, transcriptomics, and clinical datasets, we evaluated associations between PUS family genes and oncogenic features, including tumour microenvironment scores, immune infiltration, cancer stemness, and prognosis. Among them, PUS7 and PUS3 showed the strongest correlations with tumour-promoting phenotypes, with high PUS7 expression in PDAC predicting poor overall survival. Functional assays revealed that PUS7 overexpression markedly enhanced PDAC cell proliferation, migration, and invasion. Transcriptomic profiling demonstrated that PUS7 promotes neutrophil extracellular traps formation, identifying it as a key regulator of NET-mediated immune modulation. Single-cell RNA sequencing of orthotopic mouse models showed PUS7 overexpression reduced macrophage infiltration and skewed macrophage polarization towards the M2 phenotype while suppressing M1 polarization. We found that PUS7 reshapes the PDAC immune landscape primarily by inducing NETs, which drive macrophage polarization from M1 to M2, fostering immune suppression and tumour progression. The PUS7–NET–M2/M1 axis thus represents a novel mechanism of PDAC pathogenesis and a potential therapeutic target in this lethal malignancy.

Highlights

PUS7 enhances pancreatic ductal adenocarcinoma progression by modulating the tumour immune microenvironment.
PUS7 induces neutrophil extracellular trap formation within pancreatic tumours.
NETs reprogram tumour-associated macrophages from an M1 to an M2 phenotype, promoting immune suppression.

假尿嘧啶合成酶（PUS）与多种癌症有关，但其在胰腺癌免疫中的作用尚不清楚。通过结合基因组学、转录组学和临床数据集的综合多组学分析，我们评估了PUS家族基因与肿瘤微环境评分、免疫浸润、肿瘤干性和预后等致癌特征之间的关系。其中，PUS7和PUS3与促瘤表型相关性最强，PDAC中PUS7的高表达预示着较差的总生存期。功能分析显示，PUS7过表达可显著增强PDAC细胞的增殖、迁移和侵袭。转录组学分析表明，PUS7促进中性粒细胞胞外陷阱的形成，确定它是net介导的免疫调节的关键调节剂。原位小鼠模型的单细胞RNA测序显示，PUS7过表达减少巨噬细胞浸润，巨噬细胞向M2表型倾斜极化，同时抑制M1极化。我们发现PUS7主要通过诱导NETs重塑PDAC免疫景观，NETs驱动巨噬细胞从M1向M2极化，促进免疫抑制和肿瘤进展。因此，PUS7-NET-M2/M1轴代表了一种新的PDAC发病机制和这种致命恶性肿瘤的潜在治疗靶点。重点：PUS7通过调节肿瘤免疫微环境促进胰腺导管腺癌的进展。PUS7诱导胰腺肿瘤内中性粒细胞胞外陷阱的形成。NETs将肿瘤相关巨噬细胞从M1表型重编程为M2表型，促进免疫抑制。

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引用次数: 0

Stimulator of interferon genes (STING)-activating nanomedicines: Translating innate immune modulation into effective therapy for triple-negative breast cancer 干扰素基因刺激剂(STING)-激活纳米药物：将先天免疫调节转化为三阴性乳腺癌的有效治疗。

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine

Pub Date : 2026-01-05 DOI: 10.1002/ctm2.70580

Harshita Singhai, Taha Alqahtani, Humood Al Shmrany, Garima Gupta, Umesh Kumar Patil, Amirhossein Sahebkar, Prashant Kesharwani

Triple-negative breast cancer (TNBC), marked by profound immunosuppressive complexity, poses a critical challenge in therapy due to the absence of hormone receptors in its phenotype, making it unavailable for conventional therapies. The stimulator of interferon genes (STING) pathway is emerging as critical pathway translating the immunogenic ‘cold’ TNBC tumour into ‘hot’ one, thereby improving the responsiveness to immune checkpoint blockade (ICB). However, the clinical translation is still hindered by insufficient cytosolic delivery, rapid systemic degradation and tumour microenvironment-induced metabolic inactivation. This review outlines the recent advances in STING-mediated nanoparticle delivery with special emphasis on biomimetic, Trojan horse logic gate, manganese-based and redox-responsive stimuli delivery systems. Mechanistically, it integrates immune activation by ferroptosis, cuproptosis and mitochondrial DNA disruption. They synergise the amplification of type 1 interferon with dendritic cell maturation, potentiating antitumour immunogenesis. Notably, the combination with ICBs will further amplify the therapeutic potential of nanoparticles. Convergence of immunology and targeted therapies with nanoparticles opens new array for TNBC treatment. The review visualizes the clinical translation of mind maps into clinical reality, activating the innate immunity.

Highlights

STING activation converts immunologically cold TNBC into ICB-responsive hot tumors.
Nanoparticles overcome poor delivery, degradation, and TME-driven STING inactivation.
Biomimetic and stimuli-responsive systems enhance type I IFN and DC maturation.
Synergy with ICBs boosts innate immunity and antitumor immunogenesis.

三阴性乳腺癌（TNBC）具有严重的免疫抑制复杂性，由于其表型中缺乏激素受体，使其无法用于常规治疗，因此对治疗构成了重大挑战。干扰素基因刺激因子（STING）途径正在成为将免疫原性“冷”TNBC肿瘤转化为“热”TNBC肿瘤的关键途径，从而提高对免疫检查点阻断（ICB）的反应性。然而，临床翻译仍然受到细胞质递送不足、快速全身降解和肿瘤微环境诱导的代谢失活的阻碍。本文综述了sting介导的纳米颗粒递送系统的最新进展，重点介绍了仿生、特洛伊木马逻辑门、锰基和氧化还原反应刺激递送系统。机制上，它整合了铁下垂、铜下垂和线粒体DNA破坏的免疫激活。它们协同1型干扰素的扩增与树突状细胞成熟，增强抗肿瘤免疫发生。值得注意的是，与ICBs的结合将进一步扩大纳米颗粒的治疗潜力。纳米颗粒的免疫学和靶向治疗的融合为TNBC治疗开辟了新的阵列。该综述将思维导图的临床翻译可视化为临床现实，激活先天免疫。重点：STING激活可将免疫冷TNBC转化为icb反应性热肿瘤。纳米颗粒克服了递送不良、降解和tme驱动的STING失活。仿生和刺激反应系统促进I型IFN和DC成熟。与ICBs协同作用增强先天免疫和抗肿瘤免疫发生。

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引用次数: 0

HBx hijacks the miR-19a-3p/BAMBI/TGF-β1 axis to impair the anti-tumour activity of CD4+ T cells in diffuse large B-cell lymphoma HBx劫持miR-19a-3p/BAMBI/TGF-β1轴，损害弥漫性大b细胞淋巴瘤中CD4+ T细胞的抗肿瘤活性。

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine

Pub Date : 2026-01-05 DOI: 10.1002/ctm2.70578

Xuecong Guo, Jianguo Li, Xiaofei Bai, Yinghui Huang, Xu Xu, Jiabang Yang, Zhenghao Sun, Wangcheng Zhu, Xudong Guo, Jie Chen, Jiuhong Kang

<div> <section> <h3> Background</h3> <p>Hepatitis B virus (HBV) is clinically associated with poor prognosis in diffuse large B-cell lymphoma (DLBCL), while cellular communication in the tumour microenvironment (TME) is recognized as a critical driver of tumour progression. Nevertheless, whether HBV infection mediates DLBCL cell-immune cell crosstalk remains undefined, with the precise mechanisms and associated key molecules remaining elusive.</p> </section> <section> <h3> Methods</h3> <p>SsGSEA, Cox regression (univariate/multivariate), WGCNA, and Kaplan–Meier analyses identified prognostic immune subsets and miRNAs in HBV<sup>+</sup> DLBCL. Dual luciferase assay, qRT-PCR, western blot, ChIP, Co-IP, flow cytometry, enzyme-linked immunosorbent assay, immunohistochemistry, and murine models were employed together to evaluate CD4<sup>+</sup> T cell dysfunction in vitro and in vivo. ScRNA-seq analyses encompassed clustering, pseudotemporal trajectory, and ligand–receptor networks to decode TME dynamics.</p> </section> <section> <h3> Results</h3> <p>TME profiling identified diminished CD4⁺ T cell infiltration as an independent predictor of poor survival in HBV⁺ DLBCL. Mechanistically, HBx-mediated down-regulation of miR-19a-3p activated the BAMBI/Wnt signalling pathway, thereby enhancing TGF-β1 secretion and suppressing the anti-tumour activity of CD4<sup>+</sup> T cells. Single-cell analysis revealed that BAMBI<sup>high</sup> DLBCL cells engage CD4<sup>+</sup> T cells via TGFB1-TGFBR2 pair, with TGFBR2 enriched in exhausted subsets of CD4<sup>+</sup> T cells and shaping their dysfunctional fate. Therapeutic restoration of miR-19a-3p or blockade of TGF-β reinforced the CD4⁺ T cell anti-tumour activity and restrained the progression of HBx-overexpressing DLBCL in vivo.</p> </section> <section> <h3> Conclusions</h3> <p>HBx promoted TGF-β1 hypersecretion via miR-19a-3p repression-mediated Wnt/β-catenin activation, directly driving CD4<sup>+</sup> T cell depletion and functional exhaustion in DLBCL. Our work provided important insights into the immune determinants of poor prognosis in HBV<sup>+</sup> DLBCL, highlighting the pivotal role of CD4<sup>+</sup> T cell dysfunction in driving disease progression and adverse clinical outcomes.</p> </section> <section> <h3> Highlights</h3> <div> <ol> <li> <p>Reduced CD4<sup>+</sup> T cell enrichment in the TME predicted poor surviva

背景：乙型肝炎病毒（HBV）在临床上与弥漫性大B细胞淋巴瘤（DLBCL）的不良预后相关，而肿瘤微环境中的细胞通讯（TME）被认为是肿瘤进展的关键驱动因素。然而，HBV感染是否介导DLBCL细胞-免疫细胞串扰仍然不明确，确切的机制和相关的关键分子仍然难以捉摸。方法：SsGSEA、Cox回归（单因素/多因素）、WGCNA和Kaplan-Meier分析确定了HBV+ DLBCL的预后免疫亚群和mirna。采用双荧光素酶法、qRT-PCR法、western blot法、ChIP法、Co-IP法、流式细胞术、酶联免疫吸附法、免疫组织化学法、小鼠模型等方法评价CD4+ T细胞在体外和体内的功能障碍。ScRNA-seq分析包括聚类、伪时间轨迹和配体-受体网络来解码TME动力学。结果：TME分析发现CD4 + T细胞浸润减少是HBV + DLBCL患者生存不良的独立预测因子。机制上，hbx介导的miR-19a-3p下调激活BAMBI/Wnt信号通路，从而增强TGF-β1分泌，抑制CD4+ T细胞的抗肿瘤活性。单细胞分析显示，BAMBIhigh DLBCL细胞通过TGFB1-TGFBR2对参与CD4+ T细胞，TGFBR2富集于CD4+ T细胞的衰竭亚群中，并形成其功能失调的命运。治疗性恢复miR-19a-3p或阻断TGF-β增强了CD4 + T细胞的抗肿瘤活性，抑制了体内hbx过表达的DLBCL的进展。结论：HBx通过miR-19a-3p抑制介导的Wnt/β-catenin激活促进TGF-β1高分泌，直接驱动DLBCL中CD4+ T细胞耗竭和功能耗竭。我们的工作为HBV+ DLBCL不良预后的免疫决定因素提供了重要的见解，强调了CD4+ T细胞功能障碍在驱动疾病进展和不良临床结果中的关键作用。重点：TME中CD4+ T细胞富集降低预示着HBV+ DLBCL患者的低生存率。HBx下调miR-19a-3p激活bambi介导的Wnt信号，放大TGF-β1分泌，抑制CD4 + T细胞的抗肿瘤活性。TGF-B1/TGFBR2对介导HBV+ DLBCL-CD4+ T细胞通讯。靶向TGF-β或miR-19a-3p可改善CD4+ T细胞免疫抑制HBV+ DLBCL进展。

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引用次数: 0

Targeting neutrophil-driven immunosuppression: A strategy to overcome immune checkpoint inhibitor resistance 靶向中性粒细胞驱动的免疫抑制：一种克服免疫检查点抑制剂耐药性的策略。

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine

Pub Date : 2026-01-05 DOI: 10.1002/ctm2.70582

Ying Ning, Ke Lei, Xinyan Gao, Yan Kong, Yuping Shan, Tian Tian, Zhumei Cui, He Ren

Immune checkpoint blockade (ICB) has revolutionized tumour therapy by relieving immunosuppression and restoring effector T cell cytotoxicity. However, its clinical utility is constrained by low response rates and acquired resistance. Tumour-associated neutrophils (TANs), key players in tumour immunoregulation, have emerged as critical mediators of ICB responsiveness and resistance, highlighting the therapeutic potential of combining TAN-targeted strategies with immune checkpoint inhibitors (ICIs). This review systematically synthesizes current knowledge of neutrophils in ICB resistance from several dimensions: (1) clinical indicators of neutrophils, such as the neutrophil-to-lymphocyte ratio (NLR) and tissue TANs abundance, as predictors of ICI response and patients prognosis; (2) multifaceted TAN-involved resistance mechanisms, including direct T cell inhibition, antigen presentation impairment, function modulation of other immune cells, promotion of tumour angiogenesis, and elevation of tumour mutation burden (TMB); (3) combination therapeutic strategies targeting TAN generation/ exhaustion, recruitment, phenotypic polarization, activation, proangiogenic functions, and neutrophil extracellular traps (NETs), along with progress in related clinical trials. Combinatorial approaches integrating TAN-targeted therapies with ICIs hold substantial promise for overcoming resistance by reshaping the immune microenvironment. Elucidating neutrophil-mediated resistance mechanisms and optimizing combination strategies will pave the way for precision tumour immunotherapy.

Key points

TANs drive ICI resistance via antitumour immune remodelling, angiogenesis promotion, and elevation of tumour mutation burden
Neutrophil biomarkers (e.g., NLR, TAN abundance) show strong predictive value for ICI response and prognosis.
Targeting TAN recruitment, polarization, function and NETosis represents a promising strategy to overcome ICI resistance.
Numerous clinical trials are evaluating combination therapies targeting neutrophils to enhance immunotherapy efficacy.

免疫检查点阻断（ICB）通过缓解免疫抑制和恢复效应T细胞毒性，彻底改变了肿瘤治疗。然而，其临床应用受到低有效率和获得性耐药的限制。肿瘤相关中性粒细胞（TANs）是肿瘤免疫调节中的关键角色，已成为ICB反应性和耐药性的关键介质，突出了将tan靶向策略与免疫检查点抑制剂（ICIs）联合使用的治疗潜力。本文从几个方面系统地综合了中性粒细胞在ICB耐药中的现有知识：(1)中性粒细胞的临床指标，如中性粒细胞与淋巴细胞比率（NLR）和组织TANs丰度，作为ICI反应和患者预后的预测因子；(2)与鞣质相关的多重耐药机制，包括直接T细胞抑制、抗原呈递损伤、其他免疫细胞的功能调节、促进肿瘤血管生成和肿瘤突变负荷（TMB）的升高；(3)针对TAN生成/耗竭、募集、表型极化、激活、促血管生成功能和中性粒细胞胞外陷阱（NETs）的联合治疗策略，以及相关临床试验的进展。将tan靶向治疗与ICIs相结合的组合方法通过重塑免疫微环境来克服耐药性具有很大的希望。阐明中性粒细胞介导的耐药机制和优化联合策略将为精确的肿瘤免疫治疗铺平道路。重点：TANs通过抗肿瘤免疫重塑、促进血管生成和肿瘤突变负荷升高驱动ICI耐药，中性粒细胞生物标志物（如NLR、TAN丰富度）对ICI反应和预后具有很强的预测价值。靶向TAN的招募、极化、功能和NETosis是克服ICI耐药性的一种有前景的策略。许多临床试验正在评估针对中性粒细胞的联合治疗以提高免疫治疗效果。

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引用次数: 0

MUC4 mutations promote a thrombotic phenotype in patients with paroxysmal nocturnal haemoglobinuria by increasing the deposition of terminal complement MUC4突变通过增加终末补体的沉积促进阵发性夜间血红蛋白尿患者的血栓表型。

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine

Pub Date : 2026-01-05 DOI: 10.1002/ctm2.70567

Yingying Chen, Mengting Che, Chaomeng Wang, Qiaoyi Bronte Zhang, Weixin Chen, Hui Liu, Chunyan Liu, Guang Sheng Ling, Rong Fu

<div> <section> <h3> Background</h3> <p>Thrombosis is a common complication in paroxysmal nocturnal haemoglobinuria (PNH) patients, but primary prevention remains controversial. Identifying high-risk individuals could enable risk-stratified prophylactic anticoagulation strategies.</p> </section> <section> <h3> Methods</h3> <p>We analyzed clinical data from PNH patients with or without thrombosis, including <i>MUC4</i> mutation status and serum complement C5b-9 levels. Complement deposition assays and a murine lower limb deep vein thrombosis model were used to investigate the role of <i>MUC4</i> mutation in thrombotic risk and explore the underlying mechanism involving terminal complement activation in PNH patients. Therapeutic interventions with low molecular weight heparin (LMWH) were tested in vivo.</p> </section> <section> <h3> Results</h3> <p>We found that PNH patients with <i>MUC4</i> mutations have a higher incidence of thrombotic events (TEs) and <i>MUC4</i> mutation is an independent risk factor for TE in PNH patients. Additionally, PNH patients with acute thrombosis had elevated serum complement C5b-9 levels, and complement deposition experiments further confirmed the abnormal activation and excessive deposition of C5b-9 as the basis for the thrombotic tendency in PNH patients. By constructing a mouse model of lower limb deep vein thrombosis, we confirmed the thrombotic tendency in a PNH mouse model and that MUC4 deficiency further promoted the thrombotic phenotype of the mice. Moreover, we found that MUC4 knockdown promoted the deposition of C5b-9 on the cell surface, indicating that a lack of MUC4 expression facilitates the deposition of C5b-9. Finally, in vivo drug administration experiments demonstrated that prophylactic anticoagulation with LMWH significantly reduced both the incidence of thrombosis and thrombus length in murine models.</p> </section> <section> <h3> Conclusion</h3> <p><i>MUC4</i> mutations promote the thrombotic phenotype in PNH patients by increasing the deposition of terminal complement. In PNH patients with concomitant MUC4 mutations, the risk of TEs is further elevated. The potential role of early complement inhibitor therapy in reducing this heightened thrombotic risk, as well as the value of prophylactic LMWH therapy as a potential option for patients who are unable to receive complement inhibitor treatment, warrants further study and prospective validation.</p> </section> <section> <h3> Key points</h3> <div>

背景：血栓形成是阵发性夜间血红蛋白尿（PNH）患者的常见并发症，但初级预防仍有争议。识别高危人群可以实现风险分层的预防性抗凝策略。方法：我们分析伴有或不伴有血栓形成的PNH患者的临床资料，包括MUC4突变状态和血清补体C5b-9水平。通过补体沉积法和小鼠下肢深静脉血栓形成模型，研究MUC4突变在PNH患者血栓形成风险中的作用，并探讨终末补体激活的潜在机制。低分子肝素（LMWH）治疗干预在体内进行了测试。结果：我们发现伴有MUC4突变的PNH患者血栓形成事件（TEs）发生率较高，MUC4突变是PNH患者TE的独立危险因素。此外，PNH合并急性血栓患者血清补体C5b-9水平升高，补体沉积实验进一步证实了C5b-9的异常活化和过度沉积是PNH患者血栓形成倾向的基础。通过构建小鼠下肢深静脉血栓形成模型，我们证实了PNH小鼠模型的血栓形成倾向，MUC4缺乏进一步促进了小鼠的血栓表型。此外，我们发现MUC4敲低促进了C5b-9在细胞表面的沉积，表明MUC4表达缺失促进了C5b-9的沉积。最后，体内给药实验表明，在小鼠模型中，低分子肝素预防性抗凝可显著降低血栓发生率和血栓长度。结论：MUC4突变通过增加终末补体沉积促进PNH患者的血栓表型。在伴有MUC4突变的PNH患者中，te的风险进一步升高。早期补体抑制剂治疗在降低这种升高的血栓形成风险方面的潜在作用，以及预防性低分子肝素治疗作为无法接受补体抑制剂治疗的患者的潜在选择的价值，值得进一步研究和前瞻性验证。关键点：MUC4基因突变增加PNH患者异常活化的终末补体的沉积，从而促进PNH患者的血栓表型。因此，并发MUC4突变的PNH患者血栓形成的风险进一步升高。在伴有MUC4突变的PNH患者中，早期补体抑制剂治疗在降低血栓形成风险方面的潜在作用，以及预防性低分子肝素治疗作为无法接受补体抑制剂治疗的潜在替代方案的价值，可能需要进一步的研究和前瞻性验证。

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引用次数: 0

Feedback regulation between histone H3 lysine 18 lactylation and TROP2-mediated glycolysis drives metastatic progression of colorectal cancer 组蛋白H3赖氨酸18乳酸化和trop2介导的糖酵解之间的反馈调节驱动结直肠癌的转移进展。

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine

Pub Date : 2026-01-03 DOI: 10.1002/ctm2.70562

Weifeng Wang, Yuxiang Deng, Weihao Li, Ruowei Wang, Chi Zhou, Yanbo Xu, Jiahua He, Le' en Liao, Jin Lan, Long Yu, Da Kang, Weili Zhang, Qingjian Ou, Zhizhong Pan, Yujing Fang, Peirong Ding, Junzhong Lin, Jianhong Peng

<div> <section> <h3> Background</h3> <p>TROP2, a critical cell surface oncogenic signal transducer, is increasingly linked to refractory metastatic colorectal cancer (CRC) and other solid tumours. Robust lactate accumulation within metastatic niches correlates with pathological metastatic progression. Anti-TROP2 antibody-drug conjugates (ADCs) are clinically available but show limited efficacy in advanced metastatic CRC. Elucidating how TROP2 signalling orchestrates molecular and cellular programs enabling CRC metastatic progression would help improve metastasis therapies.</p> </section> <section> <h3> Methods</h3> <p>Tissue microarray, immunohistochemistry, and western blotting delineated TROP2's pathological role in CRC liver metastasis (CRLM). Metabolomics characterised TROP2-mediated metabolic effect. Western blot detected TROP2 responsive lactylation sites. Cell-derived xenograft (CDX), intra-splenic injection models, and patient-derived xenografts (PDX) validated TROP2 or TROP2-induced H3K18 lactylation (H3K18la) in CRLM pathogenesis and Acriflavine therapeutic response. Genome-wide H3K18la profiling was performed by ChIP-seq.</p> </section> <section> <h3> Results</h3> <p>Here, we identify a self-reinforcing positive feedback loop between H3K18la and TROP2 in CRC cells that drives CRC metastatic progression. We show that TROP2 is elevated during CRC metastatic process, with high TROP2 levels in liver metastases predicting increased post-therapy recurrence in two distinct cohorts. We find that H3K18la levels are upregulated in CRC cells in response to TROP2 expression level. TROP2 promotes robust lactate production via the YBX1-HIF-1α signal axis. Targeting glycolytic flux decreases H3K18 lactylation and curbs TROP2-driven CRLM colonisation and progression. Mechanistically, ChIP-seq detection reveals H3K18la deposition at a set of pro-metastatic gene promoters, promoting their expression. Crucially, TROP2-induced H3K18la is found in turn sustaining TROP2 expression, forming a positive feedback loop that further accelerated metastatic progression. Pharmacologic HIF-1α inhibition with acriflavine, an old FDA-approved agent, suppresses TROP2-high CRLM progression in multiple pre-clinical models.</p> </section> <section> <h3> Conclusions</h3> <p>Collectively, we establish H3K18la as a crucial epigenetic driver of TROP2-mediated CRLM progression and propose that disrupting the H3K18la–TROP2 feedback loop offers a novel therapeutic strategy against CRC metastasis.</p> </section> <section>

背景：TROP2是一种关键的细胞表面致癌信号传感器，越来越多地与难治性转移性结直肠癌（CRC）和其他实体肿瘤联系在一起。转移性壁龛内乳酸积累与病理性转移进展相关。抗trop2抗体-药物偶联物（adc）临床可用，但对晚期转移性结直肠癌的疗效有限。阐明TROP2信号如何协调分子和细胞程序，使CRC转移进展将有助于改善转移治疗。方法：组织芯片、免疫组化和western blotting检测TROP2在结直肠癌肝转移（CRLM）中的病理作用。代谢组学表征了trop2介导的代谢作用。Western blot检测TROP2反应性乳酸化位点。细胞来源的异种移植物（CDX）、脾内注射模型和患者来源的异种移植物（PDX）验证了TROP2或TROP2诱导的H3K18乳酸化（H3K18la）在CRLM发病机制和吖黄酮治疗反应中的作用。通过ChIP-seq进行全基因组H3K18la分析。结果：在这里，我们确定了CRC细胞中H3K18la和TROP2之间的自我强化的正反馈回路，该回路驱动CRC转移进展。我们发现，在结直肠癌转移过程中，TROP2升高，在两个不同的队列中，肝转移的高TROP2水平预示着治疗后复发的增加。我们发现H3K18la水平在CRC细胞中响应TROP2表达水平而上调。TROP2通过YBX1-HIF-1α信号轴促进乳酸生成。靶向糖酵解通量降低H3K18乳酸化，抑制trop2驱动的CRLM定植和进展。在机制上，ChIP-seq检测显示H3K18la沉积在一组促转移基因启动子上，促进其表达。至关重要的是，发现TROP2诱导的H3K18la反过来维持TROP2的表达，形成一个正反馈循环，进一步加速转移进展。在多种临床前模型中，用一种fda批准的老药物吖啶黄碱抑制HIF-1α可抑制trop2高水平的CRLM进展。结论：总的来说，我们确定H3K18la是trop2介导的CRLM进展的关键表观遗传驱动因素，并提出破坏H3K18la- trop2反馈回路提供了一种新的治疗CRC转移的策略。重点：H3K18la在CRC细胞中特异性增加，响应TROP2信号并驱动TROP2介导的CRLM进展。全基因组分析显示，H3K18la沉积在转移促进基因的启动子处，驱动其在高TROP2 CRC中的表达。乳酸通过H3K18la维持CRC细胞中TROP2的表达，吖黄碱通过靶向H3K18la/TROP2反馈回路抑制TROP2驱动的CRLM。

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引用次数: 0

Roll with the punches: Fibroblast growth factor 10 alleviates pyroptosis of alveolar epithelial cells in different immune niches 顺势而为：成纤维细胞生长因子10减轻不同免疫龛中肺泡上皮细胞的焦亡。

IF 6.8 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine

Pub Date : 2026-01-02 DOI: 10.1002/ctm2.70569

Tianchang Wei, Xiaoyan Chen, Jian Xu, Weiqi Mao, Zhenlin Yang, Yuhan Wang, Yufan Li, Wenting Jin, Cuicui Chen, Cuiping Zhang, Yuanlin Song

<div> <section> <h3> Background</h3> <p>Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by high mortality with no specific treatments. Fibroblast growth factor 10 (FGF10) is recognized for its tissue repair and anti-inflammatory roles in injured lungs; however, its clinical relevance and mechanistic role in ARDS remain unclear.</p> </section> <section> <h3> Methods</h3> <p>Serum FGF10 levels were measured in patients with ARDS and analyzed for associations with clinical outcomes. An LPS-induced mouse model of acute lung injury (ALI) was used to evaluate the effects of FGF10 treatment in vivo. Single-cell RNA sequencing of lineage-traced alveolar epithelial cells (AECs) was performed to identify transcriptional changes following FGF10 administration. In vitro co-culture systems involving macrophages or neutrophils with AECs were established to investigate immune cell-specific mechanisms.</p> </section> <section> <h3> Results</h3> <p>We found that serum FGF10 levels were significantly reduced in ARDS patients, and this reduction correlated with poor prognosis. Moreover, FGF10 treatment alleviated lung inflammation by decreasing inflammatory cell infiltration and pro-inflammatory cytokine release in mice. Leveraging single-cell RNA sequencing of lineage tracing alveolar epithelial cells (AECs), we identified that the mRNA expression of <i>Ripk1</i>, <i>Casp8</i>, and <i>Casp3</i> were decreased after FGF10 treatment. In in vitro co-culture experiments, we noticed that FGF10 did not inhibit macrophage pyroptosis. Instead, FGF10 effectively blocked the downstream RIPK1/caspase-8/caspase-3/gasdermin E (GSDME) signaling pathway in AECs. Additionally, FGF10 suppressed AMP-activated protein kinase (AMPK) activation by modulating ATP production, thereby preventing RIPK1 cleavage.</p> </section> <section> <h3> Conclusion</h3> <p>FGF10 alleviates acute lung injury by inhibiting AMPK-RIPK1/caspase-8/caspase-3/GSDME-mediated pyroptosis in AECs primed by distinct immune cell populations, supporting its potential as a therapeutic strategy for ARDS.</p> </section> <section> <h3> Key points</h3> <div> <ul> <li>Our study reveals a marked decrease of serum FGF10 levels in ARDS patients, correlating with P/F ratio, hospitalisation days and mortality rates.</li> <li>We clarify how FGF10 prevents AECs' pyroptosis triggered by di

背景：急性呼吸窘迫综合征（ARDS）是一种危及生命的疾病，其特点是死亡率高，无特异性治疗。成纤维细胞生长因子10 （FGF10）在肺损伤中具有组织修复和抗炎作用；然而，其在ARDS中的临床相关性和机制作用尚不清楚。方法：检测ARDS患者血清FGF10水平，并分析其与临床结局的关系。采用lps诱导的小鼠急性肺损伤（ALI）模型，在体内评价FGF10的治疗效果。对谱系追踪的肺泡上皮细胞（AECs）进行单细胞RNA测序，以确定FGF10给药后的转录变化。建立了巨噬细胞或中性粒细胞与aec体外共培养系统，以研究免疫细胞特异性机制。结果：我们发现ARDS患者血清FGF10水平显著降低，且这种降低与预后不良相关。此外，FGF10治疗通过降低小鼠炎症细胞浸润和促炎细胞因子释放来减轻肺部炎症。利用对肺泡上皮细胞（AECs）进行谱系追踪的单细胞RNA测序，我们发现FGF10处理后，Ripk1、Casp8和Casp3的mRNA表达降低。在体外共培养实验中，我们注意到FGF10没有抑制巨噬细胞的焦亡。相反，FGF10在aec中有效阻断了下游RIPK1/caspase-8/caspase-3/gasdermin E （GSDME）信号通路。此外，FGF10通过调节ATP的产生抑制amp活化蛋白激酶（AMPK）的激活，从而阻止RIPK1的裂解。结论：FGF10通过抑制AMPK-RIPK1/caspase-8/caspase-3/ gsdme介导的AECs焦亡，减轻急性肺损伤，支持其作为ARDS治疗策略的潜力。重点：我们的研究显示ARDS患者血清FGF10水平显著下降，与P/F比、住院天数和死亡率相关。我们阐明了FGF10如何以不同的方式阻止不同免疫细胞浸润引发的aec焦亡。FGF10恢复ATP水平，通过AMPK减弱RIPK1磷酸化，破坏aec的焦亡。

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