【Cell导读】2025年9-10月刊论文导读

期刊介绍：

Cell是Cell Press细胞出版社旗下的旗舰刊，创办于1974年，由Elsevier公司出版发行。这是一本多学科期刊，包括但不限于细胞生物学、分子生物学、神经科学、免疫学、病毒学和微生物学、癌症、人类遗传学、系统生物学、信号传导和疾病机制和疾病治疗。该期刊为双周刊，最新影响因子为45.5。

SEP 18 2025 丨Volume 188丨Issue 19

2025年9月18日此期共发表Previews 1篇，Articles 12篇，Resources 4篇。

1. A multi-adjuvant personal neoantigen vaccine generates potent immunity in melanoma

多佐剂个性化新抗原疫苗在黑色素瘤中产生强大免疫应答

麻省理工学院与哈佛大学布罗德研究所

Personalized neoantigen-targeting vaccines have demonstrated great promise; however, improved immunogenicity is still needed. Since antigen availability and effective T cell priming are critical for maximal immunogenicity, we tested a synthetic long peptide vaccine formulated with Montanide, poly-ICLC, and locally administered ipilimumab in addition to systemic nivolumab in 10 patients with melanoma. These personalized vaccines generated de novo ex vivo T cell responses against the majority of immunizing neoepitopes in all 9 fully vaccinated patients and ex vivo CD8+ T cell responses in 6 of 9. Vaccination induced hundreds of circulating and intratumoral T cell receptor (TCR) clonotypes that were distinct from those arising after PD-1 inhibition. By linking the vaccine neoantigen specificity of T cell clonotypes with single-cell phenotypes in tumors, we demonstrate remodeling of the intratumoral T cell repertoire following vaccination. These observations show that multi-pronged immune adjuvanticity can boost T cell responses to neoantigen-targeting vaccines.

个性化新抗原靶向疫苗在肿瘤治疗领域已展现出显著潜力，然而其免疫原性仍有提升空间，这一问题也成为当前研究需重点突破的方向。鉴于抗原的可及性与高效的 T 细胞激活是实现最大化免疫原性的核心前提，研究者在10名黑色素瘤患者中测试了一种合成的长肽疫苗，该疫苗与Montanide、聚ICLC以及局部注射的伊匹木单抗和全身性的纳武利尤单抗联合使用。研究结果显示，在完成全部疫苗接种流程的 9 例患者中，该个性化疫苗可针对多数免疫新表位诱导产生新的体外 T 细胞反应，且其中 6 例患者进一步出现体外 CD8+ T 细胞反应，初步验证了联合方案的免疫激活效果。进一步探索发现，疫苗接种可诱导产生数百种循环及肿瘤内 TCR克隆型，且这些克隆型与PD-1抑制剂治疗后出现的克隆型存在明显差异。通过将疫苗新抗原特异性相关的 T 细胞克隆型与肿瘤组织中的单细胞表型进行关联分析，最终证实：疫苗接种能够驱动肿瘤内 T 细胞库发生重塑，为后续深入解析疫苗介导的抗肿瘤免疫机制提供了关键依据。

2. Deconstructing the intercellular interactome in vascular dementia with focal ischemia for therapeutic applications

解构局灶性缺血性血管性痴呆中的细胞间互作组并探索其治疗应用

美国加州大学洛杉矶分校大卫·盖芬医学院

Vascular dementia (VaD), the second-leading cause of dementia, is primarily a white matter ischemic disease with no direct therapies. Cell-cell interactions within lesion sites dictate disease progression or repair. To elucidate key intercellular pathways, we employ a VaD mouse model with focal ischemia replicating many elements of the complex pathophysiology of human VaD combined with transcriptomic and functional analyses. By integrating cell-type-specific mouse VaD transcriptomes and human VaD single-nucleus RNA sequencing (snRNA-seq) data plus a custom ligand-receptor database (4,053 human and 2,032 mouse pairs), conserved dysregulated intercellular pathways in both species are identified. We demonstrate that two intercellular signaling systems, Serpine2-Lrp1 and CD39-A3AR, are disrupted in VaD. Reduced Serpine2 expression enhances oligodendrocyte progenitor cell (OPC) differentiation, promoting repair, while an A3AR-specific agonist—currently in clinical trials for psoriasis—restores tissue integrity and behavioral function in the VaD model. This study reveals intercellular signaling targets and provides a foundation for developing innovative therapies for VaD.

血管性痴呆（VaD）是痴呆的第二大原因，主要是一种白质缺血性疾病，无直接治疗方法。已有研究表明，病变区域内不同细胞类型间的相互作用，是决定疾病走向进展或启动自我修复过程的关键调控环节。为阐明核心细胞间通路，研究者构建含局部缺血的 VaD 小鼠模型（可模拟人类 VaD 多个病理生理要素），结合转录组学与功能分析，通过整合细胞类型特异性小鼠 VaD 转录组、人类 VaD 单核 RNA 测序（snRNA-seq）数据，以及定制配体-受体数据库（人类 4053 对、小鼠 2032 对），识别出两种物种中保守且失调的细胞间通路。研究证实，Serpine2-Lrp1 和 CD39-A3AR 两大信号系统在 VaD 中功能受损：Serpine2 表达减少可促进寡突胶质细胞前体细胞（OPC）分化，助力组织修复；而已进入银屑病临床试验的 A3AR 特异性激动剂，能恢复 VaD 模型的组织完整性与行为功能。本研究明确了 VaD 的细胞间信号传导靶点，为开发创新疗法奠定了基础。

3. Fibroblast bioelectric signaling drives hair growth

成纤维细胞生物电信号驱动毛发生长

中国北京国家生物科学研究所

清华大学多学科生物医学研究所

Hair loss affects millions globally, significantly impacting quality of life and psychological well-being. Despite its prevalence, effective strategies for promoting human hair growth remain elusive. By investigating congenital generalized hypertrichosis terminalis (CGHT), a rare genetic disorder characterized by excessive hair growth, we discover that chromatin deletions or an inverted duplication disrupt the topologically associating domain (TAD), leading to the upregulation of the potassium channel KCNJ2 in dermal fibroblasts. Mouse genetics demonstrate that KCNJ2-mediated membrane hyperpolarization in dermal fibroblasts promotes hair growth by enhancing fibroblasts Wnt signaling responses, involving a reduction in intracellular calcium levels. Notably, fibroblast membrane potential oscillates during the normal hair cycle, with hyperpolarization specifically associated with the growth phase. Inducing fibroblast membrane depolarization delays the growth phase, while KCNJ2-mediated hyperpolarization rescues hair loss in aging and androgenetic alopecia models. These results uncover a previously unrecognized role of fibroblast bioelectricity in tissue regeneration, offering novel therapeutic avenues for hair loss treatment.

脱发影响全球数百万人口，显著影响生活质量与心理健康。尽管脱发现象普遍，但促进人类毛发生长的有效策略仍然有限。研究者通过聚焦先天性全身性终毛型多毛症（CGHT）—— 一种以过度毛发生长为典型特征的罕见遗传性疾病，发现染色质缺失或倒位重复会破坏拓扑相关结构域（TAD），进而导致皮肤成纤维细胞中钾通道 KCNJ2 表达上调。小鼠遗传学实验证实，成纤维细胞中 KCNJ2 介导的膜超极化，可通过增强细胞对 Wnt 信号的响应来促进毛发生长，这一过程与细胞内钙水平降低密切相关。在正常毛发生长周期中，成纤维细胞膜电位会发生周期性振荡，其中超极化状态与毛发的生长阶段高度相关：诱导成纤维细胞膜去极化会延迟生长阶段启动，而 KCNJ2 介导的超极化则能在衰老及雄激素性脱发模型中有效挽救毛发损失。该研究揭示了成纤维细胞生物电在组织再生中此前未被发现的关键作用，为脱发治疗提供了全新的作用靶点与治疗方向。

4.Procr+ chondroprogenitors sense mechanical stimuli to govern articular cartilage maintenance and regeneration

Procr+软骨祖细胞感知机械刺激以调控关节软骨的维持和再生

上海东方医院国家心血管疾病重点实验室与医学创新中心

同济大学生命科学技术学院

Protein C receptor+ (Procr+) cells were identified as stem or progenitor cells in multiple adult tissues. However, whether mechanical stimuli fine-tune their activation and differentiation remain unknown. Here, we found rare Procr+ cells in the superficial layer of tibial articular cartilage and meniscus, which keep replenishing chondrocytes in postnatal knee joints. Mechanical stimulation by forced running significantly increased the frequency of Procr+ cells, whereas mechanical unloading by tail suspension showed opposite effects. Osteoarthritis (OA) activated Procr+ cells to repair cartilage erosion, whereas genetic ablation of Procr+ cells accelerated OA progression. Pharmacological or genetic inhibition of the mechanosensor Piezo1 significantly blunted cartilage regeneration by Procr+ cells and exacerbated OA. In contrast, intra-articular administration of a Piezo1 agonist ameliorated OA symptoms. Purified mouse or human Procr+ superficial cells robustly repair articular cartilage after expansion and in vivo transplantation. Together, we discovered a mechanosensitive chondroprogenitor population indispensable for articular cartilage maintenance and regeneration.

蛋白C受体+（Procr+）细胞被鉴定为多种成年组织中的干细胞或祖细胞。然而，机械刺激是否微调它们的激活和分化尚不清楚。研究者在胫骨关节软骨和半月板的表层中发现了稀有的Procr+细胞，这些细胞在出生后的膝关节中不断补充软骨细胞。实验证实，强制跑步带来的机械刺激能显著提高 Procr⁺细胞的出现频率，而尾部悬挂造成的无机械刺激状态则产生相反效应。骨关节炎（OA）发生时，Procr⁺细胞会被激活以修复软骨侵蚀损伤，若通过遗传手段消融 Procr⁺细胞，会加速 OA 病程进展。进一步机制研究显示，采用药物或遗传方法抑制机械感应器 Piezo1，会显著削弱 Procr⁺细胞的软骨再生能力并加重 OA 症状；相反，关节内注射 Piezo1 激动剂则可改善 OA 相关症状。此外，纯化后的鼠源或人源 Procr⁺表层细胞，经体外扩增后进行体内移植，能够高效修复损伤的关节软骨。综上所述，研究者发现了一种对关节软骨维持和再生不可或缺的机械敏感性软骨祖细胞群。

OCT 02 2025 丨Volume 188丨Issue 20

2025年10月02日此期共发表Previews  1篇，Review 1篇，Short Articles    1篇，Articles 17篇

高度保守的β冠状病毒序列被人类 T 细胞广泛识别

美国加利福尼亚州拉荷亚免疫学研究所

The COVID-19 pandemic highlighted the critical need for vaccine strategies capable of addressing emerging viral threats. Betacoronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS), and SARS-CoV-2, present significant pandemic risks due to their zoonotic potential and genetic diversity. T cell-mediated immunity has demonstrated durable responses and strong cross-reactivity, offering a promising avenue for achieving broad immunity within a viral family. In this study, we combined comprehensive epitope mapping with sequence conservation analyses to identify conserved T cell epitope regions (CTERs), which constitute 12% of the complete SARS-CoV-2 proteome. We showed that SARS-CoV-2 CTER-specific T cells cross-reactively recognize sequences from multiple Betacoronavirus subgenera. Importantly, incorporating CTERs from non-spike proteins significantly enhanced T cell cross-reactivity potential and human leukocyte antigen (HLA) coverage compared with T cells targeting only spike proteins. Our findings lay the groundwork for a multi-antigen vaccine strategy that includes non-spike proteins to expand cross-reactive immunity across a broader spectrum of Betacoronaviruses.

新冠疫情的爆发凸显了开发可应对新兴病毒威胁的疫苗策略的迫切性。以严重急性呼吸综合征冠状病毒（SARS-CoV）、中东呼吸综合征冠状病毒（MERS-CoV）及新型冠状病毒（SARS-CoV-2）为代表的β冠状病毒，凭借其显著的人畜共患病潜力与遗传多样性，持续构成重大大流行风险。而 T 细胞介导的免疫反应已被证实具有持久性与强交叉反应性，为实现对冠状病毒家族的广泛免疫提供了极具前景的研究方向。本研究通过整合表位映射技术与序列保守性分析，成功识别出 SARS-CoV-2 的保守 T 细胞表位区域（CTER），该区域占其完整蛋白质组的 12%。研究证实，针对 SARS-CoV-2 特异性 CTER 的 T 细胞，能够交叉反应识别来自多个β冠状病毒亚属的同源序列。尤为重要的是，与仅靶向刺突蛋白的 T 细胞免疫策略相比，纳入非刺突蛋白的 CTER 可显著提升 T 细胞的交叉反应潜能，并扩大人类白细胞抗原（HLA）的覆盖范围。综上，本研究为开发包含非刺突蛋白的多抗原疫苗策略奠定了基础，该策略旨在拓展免疫保护谱，实现对更广泛β 冠状病毒的跨物种交叉防护。

2.Immunometabolic defects of CD8+ T cells disrupt gut barrier integrity in people with HIV

CD8+ T 细胞的免疫代谢缺陷会破坏HIV感染者的肠道屏障完整性

哈佛大学、麻省理工学院、麻省总医院联合Ragon Institute

A hallmark of HIV infection is disruption of intestinal barrier integrity that persists in people with HIV (PWH) despite treatment with antiretroviral therapy (ART). This disruption is central to HIV disease progression, yet the causes remain incompletely understood. We report a mechanism by which immunometabolic defects in colon-resident CD8+ T cells in PWH lead to intestinal epithelial apoptosis and disruption of intestinal barrier integrity. We show that in PWH, these cells downregulate the lipid sensor peroxisome proliferator-activated receptor-γ (PPARγ), which results in reduced intracellular lipid droplets, impaired fatty acid oxidation, and acquisition of lipids by CD8+ T cells from intestinal epithelial cells, which then contributes to epithelial cell death. Our findings indicate that HIV-associated immunometabolic dysregulation of colon CD8+ T cells leads to loss of intestinal epithelial homeostasis. These results identify potential strategies to reduce comorbidities in PWH and other disorders with disrupted intestinal barrier integrity.

肠道屏障完整性破坏是 HIV 感染的标志性特征之一，即便在接受抗逆转录病毒治疗（ART）后，这一问题在 HIV 感染者（PWH）中仍持续存在。该屏障损伤是 HIV 疾病进展的核心驱动因素，但目前其具体成因尚未被完全阐明。研究者通过探索，揭示了 PWH 结肠常驻 CD8+ T 细胞的免疫代谢缺陷，是导致肠道上皮细胞凋亡及肠道屏障完整性破坏的关键机制。研究证实，PWH 体内的这类 CD8+ T 细胞会下调脂质传感器过氧化物酶体增殖激活受体-γ（PPARγ）的表达，进而引发一系列连锁反应：细胞内脂滴储备减少、脂肪酸氧化过程受损，同时促使 CD8+ T 细胞从肠道上皮细胞中夺取脂质，最终导致上皮细胞死亡。这一发现表明，与 HIV 感染相关的结肠 CD8+ T 细胞免疫代谢失调，是造成肠道上皮稳态失衡的重要原因。综上，该研究明确了 HIV 感染后肠道屏障损伤的关键分子与细胞机制，为制定针对性策略以减少 PWH 的共病风险，以及为其他肠道屏障完整性受损相关疾病的干预提供了潜在靶点与理论依据。

3.Exercise-induced microbiota metabolite enhances CD8 T cell antitumor immunity promoting immunotherapy efficacy

运动诱导的微生物群代谢物增强 CD8+ T 细胞抗肿瘤免疫，促进免疫治疗疗效

匹兹堡大学医学院免疫学系

Exercise improves immune checkpoint inhibitor (ICI) efficacy in cancers such as melanoma; however, the mechanisms through which exercise mediates this antitumor effect remain obscure. Here, we identify that the gut microbiota plays a critical role in how exercise improves ICI efficacy in preclinical melanoma. Our study demonstrates that exercise stimulates microbial one-carbon metabolism, increasing levels of the metabolite formate, which subsequently enhances cytotoxic CD8 T cell (Tc1)-mediated ICI efficacy. We further establish that microbiota-derived formate is both sufficient and required to enhance Tc1 cell fate in vitro and promote tumor antigen-specific Tc1 immunity in vivo. Mechanistically, we identify the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) as a crucial mediator of formate-driven Tc1 function enhancement in vitro and a key player in the exercise-mediated antitumor effect in vivo. Finally, we uncover human microbiota-derived formate as a potential biomarker of enhanced Tc1-mediated antitumor immunity, supporting its functional role in melanoma suppression.

运动已被证实可提升黑色素瘤等癌症中免疫检查点抑制剂（ICI）的治疗效果，但运动介导该抗肿瘤效应的具体分子与细胞机制，目前仍不明确。研究者通过实验揭示，肠道微生物群在运动增强临床前黑色素瘤模型的 ICI 疗效中发挥关键调控作用。研究表明，运动能够刺激肠道微生物的单碳代谢通路，显著提高代谢物甲酸的水平，进而增强细胞毒性 CD8+ T 细胞（Tc1）介导的抗肿瘤免疫，最终提升 ICI 治疗效果。进一步验证显示，微生物群来源的甲酸对于该效应既是充分条件也是必要条件 —— 体外实验中可直接增强 Tc1 细胞的分化命运，体内实验中能有效促进肿瘤抗原特异性 Tc1 细胞免疫应答。机制层面，研究明确转录因子核因子红细胞2相关因子2（Nrf2）是核心介导者：体外实验证实其参与甲酸驱动的 Tc1 细胞功能增强过程，体内实验也验证其在运动介导的抗肿瘤效应中发挥关键作用。此外，研究者发现人类肠道微生物群来源的甲酸，可作为增强 Tc1 细胞介导抗肿瘤免疫的潜在生物标志物，这一结果进一步支持了甲酸在黑色素瘤抑制中的功能性作用。

4.Glucose restriction shapes pre-metastatic innate immune landscapes in the lung through exosomal TRAIL

葡萄糖限制通过外泌体TRAIL重塑肺部转移前先天免疫景观

中山大学生命科学院药物功能基因重点实验室、中山大学生物科学院基因功能调控重点实验室

Targeting glucose metabolism has emerged as a promising strategy for inhibiting tumor growth. However, we herein uncover an unexpected paradox: while glucose deprivation through a low-carbohydrate diet or impaired in situ metabolism suppresses primary tumor growth, it simultaneously promotes lung metastasis by depleting natural killer (NK) cells via lung macrophages. Mechanistically, glucose deprivation induces endoplasmic reticulum (ER) stress, activating HMG-CoA reductase degradation protein 1 (HRD1) to catalyze K63-linked ubiquitination of TRAIL, which is then packaged into exosomes via the endosomal sorting complex required for transport (ESCRT) complex. These exosomal TRAIL molecules polarize PVR+ macrophages, triggering NK cell exhaustion and establishing a pre-metastatic niche. Notably, TIGIT blockade not only prevents metastasis induced by glucose deprivation but also enhances its anti-tumor effects. Clinically, low glucose metabolism correlates with higher 2-year postoperative recurrence across 15 cancer types. Furthermore, plasma exosomal TRAIL outperforms traditional markers, such as α-fetoprotein (AFP) and tumor size, in predicting early postoperative lung metastasis, revealing both the risks and therapeutic potential of targeting glucose metabolism.

靶向葡萄糖代谢已成为抑制肿瘤生长的潜在有效策略，为癌症治疗提供了新的研究方向。然而，研究者发现了一个生物学悖论：通过低碳水化合物饮食或原位代谢受损导致的葡萄糖缺乏，虽能有效抑制原发肿瘤生长，却会通过肺巨噬细胞介导的自然杀伤细胞（NK）消耗，反而促进肺转移的发生。研究表明，葡萄糖剥夺会诱发内质网（ER）应激，进而激活 HMG-CoA 还原酶降解蛋白1（HRD1）。HRD1 可催化 TRAIL 分子发生 K63 连接泛素化修饰，随后这些泛素化的 TRAIL 会通过运输所需的内体分选复合物（ESCRT）被包装进外泌体。外泌体中的 TRAIL 分子会极化 PVR + 巨噬细胞，触发 NK 细胞耗竭并构建转移前生态位，最终促进肺转移。临床数据显示，低葡萄糖代谢状态与 15 种癌症患者术后 2 年复发率升高显著相关。此外，血浆外泌体 TRAIL 在预测早期癌症患者术后肺转移方面，表现优于甲胎蛋白（AFP）、肿瘤大小等传统标志物，这一发现既揭示了靶向葡萄糖代谢策略潜在的转移风险，也明确了其临床治疗潜力与优化方向。

5.Tumor transcriptome-wide expression classifiers predict treatment sensitivity in advanced prostate cancers

肿瘤转录组范围的表达分类器预测晚期前列腺癌的治疗敏感性

伦敦大学学院癌症研究所

伦敦大学学院医院

Advanced prostate cancers respond to hormone therapy but outcomes vary and no predictive tests exist for informed treatment selection. To identify novel biomarker-treatment pairings, we examined associations between biological pathways and 14-year survival outcomes of patients randomized in practice-changing phase 3 trials (testing docetaxel or abiraterone). We included transcriptome-wide expression signatures and immunohistochemistry markers (Ki-67 and PTEN) on prostate tumors from 1,523 patients (832 metastatic). Tumor androgen receptor signaling is associated with longer survival, whereas increased proliferation predicted shorter survival. In a pre-specified analysis, the previously identified decipher RNA signature was both prognostic and predicted survival benefit from docetaxel for metastatic cancers (biomarker-docetaxel interaction p = 0.039). Additionally, transcriptome-based classification of PTEN inactivation identified tumors more likely to have PTEN protein loss (p = 4 × 10−37) and metabolically perturbed metastatic cancers that had shorter survival with hormone therapies (p < 0.001) but exhibited docetaxel sensitivity (biomarker-docetaxel interaction p = 0.002). Transcriptome classifiers predict docetaxel benefit and could be clinically implemented for improved patient management.

晚期前列腺癌患者对激素治疗存在应答，但个体治疗结局差异显著，目前尚无有效的预测性检测手段为临床治疗方案的知情选择提供支撑。为识别新的生物标志物-治疗配对策略，研究者针对一项Ⅲ期临床试验（对比多西他赛与阿比特龙治疗效果）中随机分组的患者，探索了生物通路与 14 年生存结局之间的关联性。该研究纳入 1523 名患者（其中 832 例为转移性前列腺癌），系统分析了其肿瘤组织的全转录组表达特征及免疫组化标志物（Ki-67 和 PTEN）。研究结果显示，肿瘤雄激素受体信号活性与患者更长生存期显著相关，而肿瘤增殖水平升高则预测患者生存期缩短。在预先指定的分析中，此前已被识别的 Decipher RNA 特征不仅具有独立预后价值，还可预测转移性前列腺癌患者接受多西他赛治疗的生存获益。此外，基于转录组数据构建的 PTEN 失活分类模型，能够准确识别出更易发生 PTEN 蛋白缺失的肿瘤；这类伴随代谢扰动的转移性前列腺癌患者，对激素治疗的应答较差且生存期较短，但对多西他赛治疗表现出显著敏感性。综上，该研究提出的转录组分类器可有效预测患者从多西他赛治疗中的获益情况，有望应用于临床实践以优化晚期前列腺癌患者的治疗管理。

6.Comprehensive human proteome profiles across a 50-year lifespan reveal aging trajectories and signatures

涵盖50年生命周期的全面人类蛋白质组图谱揭示了衰老轨迹和特征

中国科学院动物学研究所器官再生与重建国家重点实验室

Proteins are the cornerstone of life. However, the proteomic blueprint of aging across human tissues remains uncharted. Here, we present a comprehensive proteomic and histological analysis of 516 samples from 13 human tissues spanning five decades. This dynamic atlas reveals widespread transcriptome-proteome decoupling and proteostasis decline, characterized by amyloid accumulation. Based on aging-associated protein changes, we developed tissue-specific proteomic age clocks and characterized organ-level aging trajectories. Temporal analysis revealed an aging inflection around age 50, with blood vessels being a tissue that ages early and is markedly susceptible to aging. We further defined a plasma proteomic signature of aging that matches its tissue origins and identified candidate senoproteins, including GAS6, driving vascular and systemic aging. Together, our findings lay the groundwork for a systems-level understanding of human aging through the lens of proteins.

蛋白质作为生命活动的核心物质基础，其在人类组织衰老过程中的动态变化规律尚未被系统阐明，完整的衰老相关蛋白质组蓝图仍有待构建。本研究通过对覆盖五十年年龄跨度的 13 种人体组织、共计 516 个样本，开展了全面的蛋白质组学分析与组织学表征。该动态蛋白质组图谱揭示了衰老过程中广泛存在的转录组-蛋白质组表达脱耦现象，以及以淀粉样蛋白积累为典型特征的蛋白质稳态失衡。基于衰老相关的蛋白质表达变化模式，研究团队成功构建了组织特异性蛋白质组年龄时钟，并系统描绘了不同器官的衰老轨迹特征。时间序列分析表明，人体衰老相关趋势约在50岁左右开始显现，其中血管组织属于早期衰老且衰老敏感性极高的组织类型。此外，研究还明确了与组织起源特征相符的血浆蛋白质组表达谱，并鉴定出包括 GAS6 在内的候选蛋白，这类蛋白被证实可调控血管衰老进程并参与全身衰老的调控。综上，本研究的系列成果为从蛋白质组层面系统解析人类衰老的分子机制，奠定了坚实的理论与数据基础。

OCT  16 2025 丨Volume 188丨Issue 21

2025年10月16日此期共发表Leading Edge 1篇，Short Articles 1篇，Articles 13篇，Resources 1篇。

1.Prevalent mesenchymal drift in aging and disease is reversed by partial reprogramming

衰老和疾病中的普遍间充质漂移可通过部分重编程逆转

美国加利福尼亚州圣地亚哥阿尔托斯实验室

美国加利福尼亚州拉荷亚索尔克生物研究所

The loss of cellular and tissue identity is a hallmark of aging and numerous diseases, but the underlying mechanisms are not well understood. Our analysis of gene expression data from over 40 human tissues and 20 diseases reveals a pervasive upregulation of mesenchymal genes across multiple cell types, along with an altered composition of stromal cell populations, denoting a “mesenchymal drift” (MD). Increased MD correlates with disease progression, reduced patient survival, and an elevated mortality risk, whereas suppression of key MD transcription factors leads to epigenetic rejuvenation. Notably, Yamanaka factor-induced partial reprogramming can markedly reduce MD before dedifferentiation and gain of pluripotency, rejuvenating the aging transcriptome at the cellular and tissue levels. These findings provide mechanistic insight into the underlying beneficial effects of partial reprogramming and offer a framework for developing interventions to reverse age-related diseases using the partial reprogramming approach.

细胞与组织身份特征的丧失是衰老进程及多种疾病发生发展的核心标志，但其潜在的分子调控机制尚未被完全阐明。研究者通过系统分析 40 余种人类组织及 20 类疾病的基因表达数据，发现了一种普遍存在的分子表型变化——“间充质漂移”（MD）：间充质相关基因在多种细胞类型中出现广谱性上调，同时基质细胞群的组成特征发生显著改变。进一步关联分析显示，MD 程度的增加与疾病进展进程密切相关，且与患者生存期缩短、死亡风险升高呈正相关；而抑制关键的 MD 转录因子，可诱导细胞发生表观遗传层面的 “回春” 效应。值得关注的是，山中因子介导的部分重编程策略，能在细胞发生退分化及获得多能性之前，显著降低 MD 水平，使衰老相关的转录组特征在细胞与组织层面均得到有效逆转。这些发现不仅为部分重编程的潜在生物学益处提供了机制性解释，更为开发基于部分重编程技术、用于逆转年龄相关疾病的干预策略，奠定了重要的理论框架。

2.Design of soluble Notch agonists that drive T cell development and boost immunity

设计可溶性Notch 激动剂以推动 T 细胞发育并增强免疫力

波士顿儿童医院

哈佛医学院布拉瓦特尼克研究所

The rational design of receptor agonists to control cell signaling is an emerging strategy for developing disease therapeutics. Creating a soluble cytokine-like agonist for the Notch receptor, which regulates cell fate in embryonic and adult development, is challenging, as receptor activation requires a mechanical force that is usually mediated by cell-associated transmembrane ligands. Here, we exploit computationally designed protein complexes with precise valencies and geometries to generate soluble cytokine-like Notch agonists. These molecules promote cell-cell bridging, cluster Notch receptors at cell synapses, and activate receptor signaling. We show that these agonists drive T cell differentiation from cord blood progenitors and human induced pluripotent stem cells (iPSCs) and in bioreactor production of T cells in liquid suspension. When delivered intravenously in mice, they stimulate cytokine production, expansion of antigen-specific CD4+ T cells, and antibody class switching. These de-novo-designed ligands can be broadly applied to optimize in vitro cell differentiation and advance immunotherapy development.

通过合理设计受体激动剂调控细胞信号传导，已成为疾病治疗药物开发的新兴策略。Notch 受体在胚胎发育及成年个体的细胞命运调控中发挥关键作用，但为其设计可溶性细胞因子样激动剂面临显著挑战——该受体的激活依赖机械力刺激，而这种机械力通常由细胞表面相关的跨膜配体介导。为突破这一技术瓶颈，研究者利用计算机辅助设计技术，构建了具有精确价态与几何结构的蛋白复合物，成功开发出可溶性细胞因子样 Notch 激动剂。这类设计分子能够促进细胞间桥接形成，在细胞突触处实现 Notch 受体的聚集，进而高效激活受体下游信号传导通路。功能验证表明，该激动剂可有效驱动脐带血祖细胞及人类诱导多能干细胞（iPSCs）向 T 细胞定向分化，且适用于悬浮生物反应器中的 T 细胞规模化生产。在体内实验中，通过静脉注射给药后，该激动剂能够刺激小鼠体内细胞因子产生，促进抗原特异性 CD4+ T 细胞扩增，并诱导抗体类别转换。综上，这类从头设计的 Notch 配体为体外细胞定向分化体系的优化提供了全新工具，同时为免疫治疗领域的技术发展与应用推进奠定了重要基础。

3.Identification of gut microbial bile acid metabolic enzymes via an AI-assisted pipeline

通过 AI 辅助流程鉴定肠道微生物胆汁酸代谢酶

北京大学医学免疫学国家重点实验室

北京大学第三医院

北京大学化学与分子工程学院

The modifications of bile acids (BAs) are fundamental to their role in host physiology and pathology. Identifying their synthetases is crucial for uncovering the diversity of BAs and developing targeted interventions, yet it remains a significant challenge. To address this hurdle, we developed an artificial intelligence (AI)-assisted workflow, bile acid enzyme announcer unit tool (BEAUT), which predicted over 600,000 candidate BA metabolic enzymes that we compiled into the human generalized microbial BA metabolic enzyme (HGBME) database (https://beaut.bjmu.edu.cn). We identified a series of uncharacterized BA enzymes, including monoacid acylated BA hydrolase (MABH) and 3-acetoDCA synthetase (ADS). Notably, ADS can produce an unreported skeleton BA, 3-acetoDCA, with a carbon-carbon bond extension. After determining its bacterial source and catalytic mechanism, we found that 3-acetoDCA is widely distributed among populations and regulates the microbial interactions in the gut. In conclusion, our work offers alternative insights into the relationship between microbial BAs and the host from an enzymatic perspective.

胆汁酸（BAs）的修饰作用是其在宿主生理与病理过程中发挥功能的基础。明确胆汁酸合成酶的身份，对于揭示胆汁酸的多样性及开发靶向干预手段至关重要，但这一课题至今仍面临巨大挑战。为攻克这一难题，研究者开发了一套人工智能辅助工作流程——胆汁酸酶播报单元工具（BEAUT），该工具预测出超过 60 万个候选胆汁酸代谢酶，并将其整合至人类广义微生物胆汁酸代谢酶（HGBME）数据库（https://beaut.bjmu.edu.cn）中。通过该工具，研究者鉴定出一系列未被表征的胆汁酸酶，包括单酸酰化胆汁酸水解酶（MABH）和 3-乙酰去氧胆酸合成酶（ADS）。值得关注的是，ADS 能够合成一种全新骨架的胆汁酸——3-乙酰去氧胆酸（3-acetoDCA），该合成过程伴随碳 - 碳键的延伸。在明确其细菌来源及催化机制后，我们发现 3-乙酰去氧胆酸在人群中广泛分布，且对肠道微生物间的相互作用具有调控作用。综上，本研究从酶学视角为解析微生物胆汁酸与宿主的关联提供了新的思路。

4.Vagal blockade of the brain-liver axis deters cancer-associated cachexia

迷走神经阻断大脑-肝脏轴可阻止癌症相关的恶病质

美国加利福尼亚州洛杉矶寺崎生物医学创新研究所

美国德克萨斯大学 MD 安德森癌症中心

以色列雷霍沃特魏茨曼科学研究所

Cancer-associated cachexia (CAC) is a multifactorial and currently incurable syndrome responsible for nearly one-third of cancer-related deaths. It contributes to therapy resistance and increases mortality among affected patients. In this study, we show that cancer-induced systemic inflammation alters vagal tone in CAC mouse models. This vagal dysregulation disrupts the brain-liver vagal axis, leading to a reprogramming of hepatic protein metabolism through the depletion of HNF4α, a key transcriptional regulator of liver function. The loss of HNF4α disrupts hepatic metabolism and promotes systemic inflammation, resulting in cachectic phenotypes. Interventions targeting the right cervical vagus nerve surgically, chemically, electrically, or through a non-invasive transcutaneous device attenuate CAC progression, alleviate its clinical manifestations, and synergize with chemotherapy to improve overall health and survival in mice.

癌症相关恶病质（CAC）是一种多因素介导的难治性综合征，其发生率较高，约占癌症相关死亡病例的三分之一。该综合征不仅会加剧肿瘤对治疗的抵抗性，还会显著增加患者的死亡风险，目前尚无有效治愈手段。本研究通过 CAC 小鼠模型系统探究其发病机制，发现癌症诱发的全身性炎症会导致迷走神经张力异常改变。这种迷走神经功能紊乱进一步破坏了脑-肝迷走神经调控轴，通过耗竭肝脏功能关键转录调控因子 HNF4α，引发肝脏蛋白质代谢重编程。HNF4α的表达缺失会直接导致肝脏代谢稳态失衡，并进一步加剧全身性炎症反应，最终促使恶病质表型形成。针对这一机制，研究团队采用多种干预方式（包括外科手术、化学干预、电刺激或非侵入性经皮装置）靶向调控右颈迷走神经，结果显示这些干预措施能够有效减缓 CAC 进展、缓解相关临床症状，且与化疗联合使用时具有协同效应，可显著改善模型小鼠的整体健康状况及生存率。

OCT  30 2025 丨Volume 188丨Issue 22

2025年10月30日此期共发表Leading Edge 2篇，Short Article 1篇，Articles 14篇，Resources 2篇。

1. Multiscale proteomic modeling reveals protein networks driving Alzheimer’s disease pathogenesis

多尺度蛋白质组学建模揭示了驱动阿尔茨海默病发病机制的蛋白质网络

伊坎医学院西奈山分校

The molecular mechanisms underlying the pathogenesis of Alzheimer’s disease (AD), the most common form of dementia, remain poorly understood. Proteomics offers a crucial approach to elucidating AD pathogenesis, as alterations in protein expression are more directly linked to phenotypic outcomes than changes at the genetic or transcriptomic level. In this study, we develop multiscale proteomic network models for AD by integrating large-scale matched proteomic and genetic data from brain regions vulnerable to the disease. These models reveal detailed protein interaction structures and identify putative key driver proteins (KDPs) involved in AD progression. Notably, the network analysis uncovers an AD-associated subnetwork that captures glia-neuron interactions. AHNAK, a top KDP in this glia-neuron network, is experimentally validated in human induced pluripotent stem cell (iPSC)-based models of AD. This systematic identification of dysregulated protein regulatory networks and KDPs lays down a foundation for developing innovative therapeutic strategies for AD.

阿尔茨海默病（AD）作为最常见的痴呆类型，其发病的分子机制尚未被充分阐明。蛋白质组学技术为解析 AD 发病机制提供了关键研究手段 —— 相较于遗传或转录组层面的变化，蛋白质表达的动态改变与疾病表型结局的关联更为直接，能更精准反映病理生理过程。本研究通过整合 AD 易感脑区的大规模配对的蛋白质组数据与遗传数据，成功构建了多尺度的 AD 蛋白质组网络模型。该系列模型清晰揭示了 AD 相关蛋白质间的详细相互作用结构，并精准识别出参与 AD 病理进展的关键驱动蛋白（KDP）。进一步的网络分析发现了一个与 AD 病理密切相关的子网络，该子网络可有效捕捉胶质细胞与神经元之间的相互作用模式。其中，AHNAK 被证实是该胶质 - 神经元网络中核心的领先 KDP，且这一结论已在基于人类诱导多能干细胞（iPSC）的 AD 模型中得到实验验证。综上，本研究通过系统性策略识别出 AD 中失调的蛋白质调控网络及关键驱动蛋白，为深入理解 AD 发病的分子机制提供了重要支撑，也为开发 AD 创新治疗策略奠定了坚实基础。

2.IL-25-induced memory type 2 innate lymphoid cells enforce mucosal immunity

IL-25 诱导的记忆型 2 型先天淋巴细胞增强黏膜免疫

加利福尼亚大学旧金山分校

霍华德·休斯医学研究所

Adaptation of intestinal helminths to vertebrates involved the evolution of strategies to attenuate host tissue damage to support parasite reproduction and dissemination of offspring to the environment. Helminths initiate the IL-25-mediated tuft cell-type 2 innate lymphoid cell (ILC2) circuit that enhances barrier protection of the host, although viable parasites can target and limit this pathway. We used IL-25 alone to create small intestinal adaptation, marked by anatomic and immunologic changes that persisted months after induction. Adaptation was associated with heightened resistance to barrier pathogens, including in the lung, and was enforced by transcriptionally and epigenetically modified effector-memory ILC2s distinct from those described by innate “training”; epithelial stem cells remained unaltered. Despite requiring IL-25 for induction, effector-memory ILC2s maintained an activated state in the absence of multiple alarmins and supported mucosal resilience while avoiding adverse sensitization to chronic inflammation, revealing a pathway for deploying innate immune cells to coordinate a distributed mucosal defense.

肠道蠕虫对脊椎动物的适应，涉及一系列策略的进化——这些策略可减轻宿主组织损伤，从而为寄生虫的繁殖及后代向外界扩散提供支持。蠕虫会启动由 IL-25 介导的簇细胞-2型固有淋巴样细胞（ILC2）信号通路，该通路能增强宿主的屏障保护功能，不过存活的寄生虫可靶向并限制这一通路。本研究单独利用 IL-25 构建了小肠适应性模型，其特征为诱导后持续数月的解剖结构与免疫功能改变。这种适应性与宿主对屏障病原体（包括肺部病原体）的抵抗力增强相关，且由转录组和表观遗传修饰的效应记忆型 ILC2 所维持——这类细胞与固有免疫 “训练” 所描述的细胞存在差异，而上皮干细胞未发生改变。值得注意的是，尽管诱导过程依赖 IL-25，但效应记忆型 ILC2 在缺乏多种警报素的情况下仍能维持激活状态，在支持黏膜韧性的同时，避免了对慢性炎症的不良致敏，这一发现揭示了一条通过调动固有免疫细胞来协调分布式黏膜防御的通路。

3.Glycan shielding enables TCR-sufficient allogeneic CAR-T therapy

糖基屏蔽实现TCR 保留的异体 CAR-T 治疗

北京大学生物医学先锋创新中心

常平实验室

南开大学医学院

Despite the success of autologous chimeric antigen receptor (CAR)-T cell therapy, achieving persistence and avoiding rejection in allogeneic settings remains challenging. We showed that signal peptide peptidase-like 3 (SPPL3) deletion enabled glycan-mediated immune evasion in primary T cells. SPPL3 deletion modified glycan profiles on T cells, restricted ligand accessibility, and reduced allogeneic immunity without compromising the functionality of anti-CD19 CAR molecules. In a phase I clinical trial, SPPL3-null, T cell receptor (TCR)-deficient anti-CD19 allogeneic CAR-T cells reached the safety primary endpoint, with grade 3 or higher cytokine release syndrome (CRS) observed in 3 out of 9 patients with relapsed/refractory B cell non-Hodgkin lymphoma (B-NHL) (ClinicalTrials.gov: NCT06014073). Reverse translational research highlighted the pivotal role of TCR in sustaining T cell persistence. We therefore evaluated the safety of SPPL3-null, TCR-sufficient CAR-T therapy on three patients with lymphoma or leukemia for compassionate care and observed no clinical signs of graft-versus-host disease. Our findings suggest glycan shielding by SPPL3 deletion is a promising direction for optimizing universal CAR-T therapies.

尽管自体嵌合抗原受体 T 细胞（CAR-T）疗法在临床应用中成效显著，但在异体 CAR-T 细胞治疗领域，如何实现细胞的持久体内存续并有效规避免疫排斥反应，仍是当前亟待解决的关键难题。研究者探索发现，敲除信号肽肽酶样 3（SPPL3）基因，可借助糖链调控途径介导 T 细胞的免疫逃逸效应。具体而言，SPPL3 缺失能够显著重塑 T 细胞表面的糖链表达谱，通过限制免疫相关配体的可及性，在降低同种异体免疫原性的同时，不损害抗CD19 CAR分子功能。在Ⅰ期临床试验中该细胞疗法成功达到预设的主要安全终点：9 例复发/难治性 B 细胞非霍奇金淋巴瘤（B-NHL）患者中，有 3 例出现≥3 级的细胞因子释放综合征。

反向转化研究证实，TCR 对于维持 T 细胞在体内的持久存续具有至关重要的作用。基于此发现，研究者在同情用药框架下，对 3 例淋巴瘤或白血病患者采用了 SPPL3 缺失但保留 TCR 的 CAR-T 细胞治疗方案，治疗后未观察到移植物抗宿主病（GVHD）的临床征象。

4.Tumors hijack macrophages for iron supply to promote bone metastasis and anemia

肿瘤劫持巨噬细胞获取铁供应以促进骨转移与贫血

普林斯顿大学分子生物学系

路德维希癌症研究所

新泽西州罗格斯癌症研究所

Bone marrow is both a primary site for hematopoiesis and a fertile niche for metastasis. The mechanism of the common occurrence of anemia among patients with bone metastasis remains poorly understood. Here, we show that a specialized population of VCAM1+CD163+CCR3+ macrophages, normally essential for erythropoiesis by transporting iron to erythroblasts, are highly enriched in the bone metastatic niche in mouse models. Tumor cells hijack these macrophages for iron supply, reducing iron availability for erythroblasts, impairing erythropoiesis, and contributing to anemia. Increased iron supply enables tumor cells to produce hemoglobin in response to hypoxia, mimicking erythroblasts. We identify macrophages with similar iron-transporting features in human bone metastases and show that elevated HBB expression correlates with increased risk of bone metastasis. These findings establish iron-transporting macrophages as an essential component of the metastatic bone niche, revealing a critical interplay between immune cells, metal metabolism, and tumor cell plasticity in driving metastasis and anemia.

骨髓作为机体核心造血中枢，同时也是肿瘤转移的重要靶器官与 “沃土”。骨转移患者常伴随贫血症状，但其潜在病理机制长期未被阐明。本研究通过骨转移小鼠模型研究发现，模型中一群特异性表达 VCAM1⁺CD163⁺CCR3⁺表型的巨噬细胞显著富集；该类巨噬细胞在生理状态下主要负责向成红细胞转运铁元素，为红细胞生成提供关键物质支持。而肿瘤细胞通过 “劫持” 该群巨噬细胞获取铁源，直接减少了成红细胞可利用的铁含量，进而抑制红系造血过程，最终导致贫血的发生。与此同时，在骨转移灶的缺氧微环境中，肿瘤细胞利用额外获取的铁元素合成血红蛋白，表现出类似成红细胞的生物学特征。为验证该机制的临床相关性，研究者在人类骨转移标本中成功鉴定出具有同等铁转运功能的巨噬细胞亚群，并发现血红蛋白β链（HBB）高表达与患者骨转移风险升高存在显著关联。综上，该研究明确铁转运巨噬细胞是骨转移微环境中的关键功能组分，首次揭示了免疫细胞、金属代谢与肿瘤细胞表型可塑性之间的核心互作网络，该互作网络在驱动肿瘤转移进程与贫血发生中发挥关键调控作用，为理解骨转移相关贫血的发病机制提供了全新视角。