【Nature Cancer】2025年5月-2025年6月论文导读
期刊介绍：
《Nature Cancer》是一本癌症领域的期刊，将帮助广大研究人员了解生命、物理、应用和社会科学领域与癌症相关的最新、最重要的进展。该期刊主要感兴趣的领域包括基础性临床前研究，从而进一步了解肿瘤发生、传播和进展的机制;旨在通过专注于开发和提供可用于诊断和治疗癌症的新方法，并将这些知识转化为临床的工作;可为癌症诊断、治疗和预防提供信息的临床研究;以及可用于理解癌症对全球社会影响的新方法。在行业领域中学术影响力很大，属于国际一流期刊，最新影响因子为28.5。
在2025年5月-6月，Nature Cancer共发33篇文章，其中包括17篇Article，5篇News & Views，6篇Research Briefing，5篇Review Article.
1.A peptide vaccine targeting the CMV antigen pp65 in children and young adults with recurrent high-grade glioma and medulloblastoma: a phase 1 trial
靶向CMV pp65抗原的肽疫苗在复发性高级别胶质瘤和髓母细胞瘤儿童及青少年患者中的Ⅰ期临床试验
杜克大学神经外科，美国
The human cytomegalovirus (CMV) antigen pp65 is expressed in high-grade glioma (HGG) and medulloblastoma but not in the adjacent brain. This single-arm phase 1 trial (NCT03299309) assessed the safety and immunogenicity of a peptide vaccine (PEP-CMV) targeting pp65 in individuals (3–35 years old) with recurrent HGG or medulloblastoma. Thirty-six individuals with HGG received PEP-CMV. The mean age was 22.75 ± 9.34 years. The primary outcome, percentage of unacceptable toxicity, was met. The maximum-grade adverse events (AE) related to PEP-CMV were 17 grade 1 AEs, 15 grade 2 AEs, 1 grade 3 AE (pyramidal tract syndrome) and 1 grade 4 AE (cerebral edema). As a secondary outcome, in 21 individuals with evaluable data, T cell reactivity, measured as change in baseline interferon-γ pp65 enzyme-linked immunospot assay reactivity, had an estimated increase of 46 spots (95% confidence interval (95% CI): 8, 194) after treatment with PEP-CMV. As exploratory endpoints, the median progression-free survival was 2.5 months (95% CI: 2.2, 3.2), and median overall survival was 6.5 months (95% CI: 4.6, 8.4). PEP-CMV is well tolerated and elicits an antigen-specific immune response in individuals with multiply recurrent HGG. Only two individuals with medulloblastoma were enrolled, showing one grade 3 encephalopathy possibly related to PEP-CMV, while neither had postvaccine immune assessments due to progression-free survival and overall survival less than 2 months.
人巨细胞病毒（CMV）抗原pp65在高级别胶质瘤（HGG）及髓母细胞瘤中特异性表达，但不存在于邻近脑组织中。本单臂I期临床试验（NCT03299309）评估了靶向pp65的多肽疫苗（PEP-CMV）在复发性HGG或髓母细胞瘤患者（3~35岁）中的安全性与免疫原性。共有36例HGG患者接受了PEP-CMV治疗，平均年龄为22.75±9.34岁。试验的主要终点（不可接受毒性反应发生率）达到了预设标准。与PEP-CMV相关的不良事件（AE）包括：17例1级不良事件、15例2级AE、1例3级AE（锥体束综合征）及1例4级AE（脑水肿）。作为次要终点，在21例可评估患者中，通过干扰素-γ pp65酶联免疫斑点检测（ELISpot）测量的T细胞反应性显示，治疗后基线值估计增加46个点（95%置信区间[95%CI]:8-194）。探索性终点显示：中位无进展生存期为2.5个月（95%CI:2.2-3.2），中位总生存期为6.5个月（95%CI:4.6-8.4）。研究证实PEP-CMV耐受性良好，并在多次复发的HGG患者中诱导抗原特异性免疫应答。仅有两名髓母细胞瘤患者入组，1例出现可能与疫苗相关的3级脑病，但两者均因无进展生存期和总生存期不足2个月而未能完成疫苗接种后的免疫评估。
2.Long-acting IL-2 release from pressure-fused biomineral tablets promotes antitumor immune response
基于高压融合生物矿物片剂的长效IL-2释放系统促进抗肿瘤免疫应答
浙江大学药学院，先进药物递送系统国家重点实验室，中国
Long-acting controlled drug release formulations are highly desired for potentiating efficacy and reducing administration frequency. Here we present a kinetically controllable long-term interleukin-2 (IL-2) release platform by the fusion and boundary elimination of calcium carbonate and calcium phosphate amorphous phases. Unlike mixtures, a group of hybrid biominerals with the chemical formula Ca(CO3)x(PO4)2(1−x)/3 (CaCPs, 0 < x < 1) was fabricated under high pressure (2 GPa), and the CaCPs showed crystallization-driven release behaviors to optimize the in vivo fate of IL-2. Ca(CO3)1/2(PO4)1/3 dynamically remodeled immunosuppressive tumor microenvironments, preferentially activated cytotoxic and memory T cells by improving IL-2 redistribution and achieved weeks-long IL-2 retention in tumors with high tolerance and biosafety. In a melanoma model in female mice, Ca(CO3)1/2(PO4)1/3 revealed superior antitumor effects to inhibit local tumor recurrence, hinder the growth of distant untreated tumors and maintain long-term T cell responses against the rechallenged metastatic tumors.
长效可控药物递送系统对增强疗效和减少给药频率具有重要价值。本研究通过融合碳酸钙与磷酸钙的无定形态相并消除界面差异，开发了一种动力学可控的长期白细胞介素-2（IL-2）释放平台。区别于简单混合物，本研究在2Gpa高压下合成了一组新型杂化生物矿物（化学式Ca(CO3)x(PO4)2(1−x)/3，简写CaCPs，0<x<1），该材料通过结晶驱动释放机制精准调控IL-2的体内代谢过程。其中Ca(CO3)1/2(PO4)1/3组分可以动态重塑免疫抑制性肿瘤微环境，通过改善IL-2重分布优先激活细胞毒性T细胞和记忆T细胞，并在肿瘤部位实现长达数周的IL-2维持（具有高耐受性与生物安全性）。在雌性小鼠黑色素瘤模型中，Ca(CO3)1/2(PO4)1/3显示出优异的抗肿瘤效果：抑制局部肿瘤复发、遏制未经治疗的远端肿瘤生长，并维持T细胞对二次转移肿瘤的长期免疫应答。
3.Development and validation of an autonomous artificial intelligence agent for clinical decision-making in oncology
肿瘤学临床决策自主人工智能代理系统的开发与验证
海德堡大学医院国家肿瘤疾病中心, 德国
Clinical decision-making in oncology is complex, requiring the integration of multimodal data and multidomain expertise. We developed and evaluated an autonomous clinical artificial intelligence (AI) agent leveraging GPT-4 with multimodal precision oncology tools to support personalized clinical decision-making. The system incorporates vision transformers for detecting microsatellite instability and KRAS and BRAF mutations from histopathology slides, MedSAM for radiological image segmentation and web-based search tools such as OncoKB, PubMed and Google. Evaluated on 20 realistic multimodal patient cases, the AI agent autonomously used appropriate tools with 87.5% accuracy, reached correct clinical conclusions in 91.0% of cases and accurately cited relevant oncology guidelines 75.5% of the time. Compared to GPT-4 alone, the integrated AI agent drastically improved decision-making accuracy from 30.3% to 87.2%. These findings demonstrate that integrating language models with precision oncology and search tools substantially enhances clinical accuracy, establishing a robust foundation for deploying AI-driven personalized oncology support systems.
肿瘤学临床决策具有高度复杂性，需整合多模态数据与多领域专业知识。研究开发并评估了一款基于GPT-4框架、结合多模态精准肿瘤学工具的自主临床人工智能（AI）代理系统，用于支持个性化临床决策。该系统整合了视觉转换器（用于从病理切片中检测微卫星不稳定性和KRAS/BRAF突变）、医学影像分割模型MedSAM（用于放射影像分割）以及OncoKB、PubMed和Google等网络检索工具。在对20例真实多模态患者病例的评估中，该AI代理系统自主调用工具的准确率达87.5%，得出正确临床结论的比例为91.0%，并能在75.5%的情况下准确引用肿瘤学指南。相较于单独使用GPT-4，整合式AI代理将决策准确率从30.3%显著提升至87.2%。研究证明，将大语言模型与精准肿瘤学工具及检索系统深度结合，可大幅提升临床准确性，为AI驱动的个性化肿瘤诊疗系统奠定坚实基础。
4.crossNN is an explainable framework for cross-platform DNA methylation-based classification of tumors
crossNN：一种支持跨平台的DNA甲基化肿瘤分类可解释性框架
柏林夏里特医学院实验神经病学系，德国
DNA methylation-based classification of (brain) tumors has emerged as a powerful and indispensable diagnostic technique. Initial implementations used methylation microarrays for data generation, while most current classifiers rely on a fixed methylation feature space. This makes them incompatible with other platforms, especially different flavors of DNA sequencing. Here, we describe crossNN, a neural network-based machine learning framework that can accurately classify tumors using sparse methylomes obtained on different platforms and with different epigenome coverage and sequencing depth. It outperforms other deep and conventional machine learning models regarding accuracy and computational requirements while still being explainable. We use crossNN to train a pan-cancer classifier that can discriminate more than 170 tumor types across all organ sites. Validation in more than 5,000 tumors profiled on different platforms, including nanopore and targeted bisulfite sequencing, demonstrates its robustness and scalability with 99.1% and 97.8% precision for the brain tumor and pan-cancer models, respectively.
基于DNA甲基化的（脑）肿瘤分类技术已成为一种强大且不可或缺的诊断方法。早期研究常使用甲基化微阵列来生成数据，但当前多数分类器依赖于固定的甲基化特征空间，这使得它们难以与其他平台（尤其是不同类型的DNA测序技术）兼容。为此，本研究提出一种基于神经网络的机器学习框架——crossNN，能够利用不同平台获得的稀疏甲基化组数据（具有差异化的表观基因组覆盖度和测序深度）实现精准肿瘤分类。该框架在分类准确性和计算效率上优于其他深度学习与传统机器学习模型，同时保持可解释性。本研究利用crossNN训练了一个泛癌分类器，可区分所有器官部位中超过170种肿瘤类型。在包含纳米孔测序与靶向亚硫酸氢盐测序等不同平台的5,000余例肿瘤样本验证中，其脑肿瘤模型与泛癌模型的分类精度分别达到99.1%和97.8%，证实了该技术的稳健性与可扩展性。
5.RIOK1 phase separation restricts PTEN translation via stress granules activating tumor growth in hepatocellular carcinoma
RIOK1相分离通过应激颗粒抑制PTEN翻译促进肝细胞癌进展的机制研究
中国科学技术大学生命科学与医学部， 中国
Resistance to tyrosine kinase inhibitors (TKIs) dampens their clinical efficacy in hepatocellular carcinoma (HCC). Stress granules formed by phase separation are essential to stress response and can be involved in therapy resistance, but their mechanisms in HCC are unclear. Here our screen shows that the atypical serine/threonine kinase RIOK1 is highly expressed in HCC, linked to poor prognosis, and transcriptionally activated by NRF2 under various stress conditions. RIOK1 undergoes liquid–liquid phase separation by incorporating IGF2BP1 and G3BP1 into stress granules that sequestrate PTEN messenger RNA reducing its translation. This process activates the pentose phosphate pathway, facilitating stress resolution and cytoprotection against TKI. We further show that the small-molecule inhibitor chidamide downregulates RIOK1 and enhances TKI efficacy. RIOK1-positive stress granules are found in donafenib-resistant tumors from patients with HCC. These findings reveal a link between stress granule dynamics, metabolic reprogramming and HCC progression, offering the potential means to improve TKI efficacy.
酪氨酸激酶抑制剂（TKI）耐药性限制了其在肝细胞癌（HCC）治疗中的临床效果。由相分离形成的应激颗粒在应激应答中起关键作用，并可参与治疗的耐药性，但其在HCC中的机制尚不明确。本研究通过筛选发现，非典型丝氨酸/苏氨酸激酶RIOK1在HCC中高表达且与不良预后相关，其在多种应激条件下可被核因子E2相关因子2（NRF2）转录激活。RIOK1通过液-液相分离机制募集IGF2BP1与G3BP1形成应激颗粒，进而隔离PTEN信使RNA并抑制其蛋白翻译。该过程通过激活磷酸戊糖途径促进应激解联并产生针对TKI的细胞保护效应。进一步研究发现，小分子抑制剂西达本胺可下调RIOK1表达并增强TKI疗效。在HCC患者的多纳非尼耐药肿瘤组织中检测到RIOK1阳性应激颗粒的存在。这些发现揭示了应激颗粒动态调控、代谢重编程与HCC进展之间的分子关联，为改善TKI疗效提供了潜在策略。
6.TRMT6-mediated tRNA m1A modification acts as a translational checkpoint of histone synthesis and facilitates colorectal cancer progression
TRMT6介导的tRNA m1A修饰作为组蛋白合成翻译检查点驱动结直肠癌进展的分子机制
上海交通大学消化内科，中国
Transfer RNA modifications have emerged as critical regulators of translational reprogramming, yet their roles in colorectal cancer (CRC) remain largely elusive. Here, we find that tRNA N1-methyladenosine (m1A) methyltransferase TRMT6 is upregulated in human CRC tissues and high TRMT6 expression correlates with poor survival in patients with CRC. Using orthotopic, metastatic and conditional knockout mouse models, we establish the oncogenic role of TRMT6 in CRC. Mechanistically, TRMT6 increases tRNA m1A levels by maintaining the stability of the TRMT6–TRMT61A complex. Targeting TRMT6-mediated tRNA m1A modification in CRC cells destabilizes tRNA-Lys-TTT-1-1 and impairs histone mRNA translation in a codon-biased manner, thereby restricting histone synthesis and hindering cell cycle progression. Our study provides evidence that TRMT6 functions as a translational checkpoint in the accelerated histone synthesis of CRC cells, highlighting TRMT6 as a promising target for potential anti-CRC therapies.
tRNA修饰已成为翻译重编程的关键调控因子，但其在结直肠癌（CRC）中的功能仍不甚明确。本研究发现，tRNA N1-甲基腺苷（m1A）甲基转移酶TRMT6在人类CRC组织中表达显著上调，且高TRMT6表达水平与患者不良预后显著相关。通过构建原位移植瘤、转移性肿瘤及条件性基因敲除小鼠模型，本研究证实了TRMT6在CRC中的促癌功能。机制研究表明，TRMT6通过维持TRMT6-TRMT61A复合体的稳定性增加tRNA m1A修饰水平。靶向抑制CRC细胞内TRMT6介导的tRNA m1A修饰可破坏tRNA-Lys-TTT-1-1的稳定性，并以密码子偏倚方式损害组蛋白mRNA的翻译效率，从而抑制组蛋白合成并阻碍细胞周期进程。因此，本研究揭示了TRMT6作为CRC细胞加速组蛋白合成的翻译检查点核心功能，为开发靶向TRMT6的抗CRC治疗策略提供了科学依据。
7.Glioblastoma shift from bulk to infiltrative growth is guided by plexin-B2-mediated microglia alignment in invasive niches
胶质母细胞瘤从团块生长向侵袭性生长的模式转换受侵袭性微环境中plexin-B2B2介导的胶质细胞在侵袭生态位中的定向排列调控
西奈山伊坎医学院弗里德曼脑研究所，美国
Glioblastoma (GBM) lethality stems from uncontrolled growth and infiltration. Using an immunocompetent murine model, we mapped GBM invasion and tumor-associated microglia and macrophage (TAM) interactions. We show that microglia are mobilized ahead of invasion, transforming morphologically and functionally—first forming glial nets around tumor infiltrates and then organizing into ‘oncostreams’ guiding collective migration. Single-cell RNA sequencing revealed three distinct states for tumor cells and microglia, corresponding to invasive niches versus tumor bulk. The invasive patterns and niche-specific gene signatures of tumor cells and TAMs were validated in human GBMs. We further identified a critical role of plexin-B2 in TAMs for resolving cell collision, aligning GBM cells and restructuring the extracellular matrix. Plexin-B2 ablation in TAMs disrupted invasion tracks, shifting GBM growth from infiltrative to bulk expansion. Understanding niche-specific TAM mobilization and anatomical–functional invasion units opens new strategies to target GBM invasion.
胶质母细胞瘤（GBM）的致命性源于其不可控的增殖与侵袭特性。本研究利用免疫健全的小鼠模型，系统描绘了GBM侵袭过程与肿瘤相关的小胶质细胞/巨噬细胞（TAM）的相互作用网络。研究发现，小胶质细胞在肿瘤侵袭前沿被优先激活，经历形态与功能的双重转变：首先在肿瘤侵袭区形成包裹性胶质网，继而组织成引导肿瘤细胞集体迁移的“肿瘤流”结构。单细胞RNA测序分析揭示了肿瘤细胞与小胶质细胞的三种特定功能状态，分别对应于侵袭生态位与肿瘤团块微环境。肿瘤细胞与TAMs的侵袭模式及生态位特异性基因特征在人类GBM样本中得到验证。进一步研究发现了plexin-B2在TAMs中的关键作用——通过协调细胞碰撞响应、定向排列GBM细胞并重构细胞外基质来维持侵袭路径。特异性敲除TAMs中的plexin-B2可破坏侵袭路径，迫使GBM生长模式从侵袭性转变为团块性扩张。阐明生态位特异性的TAM动员机制及其解剖-功能侵袭单元的形成规律，为开发靶向GBM侵袭的新型治疗策略提供了理论依据。
8.Cardiomyocyte-localized CCDC25 senses NET DNA to promote doxorubicin cardiotoxicity by activating autophagic flux
心肌细胞定位的CCDC25通过识别NET DNA激活自噬流促进阿霉素心脏毒性
中山大学肿瘤医院， 广东省肿瘤临床医学研究中心，中国
Cardiotoxicity restricts the clinical use of anthracyclines. Although recent evidence indicates that aberrant activation of the cytosolic DNA-sensing pathway mediates cardiotoxicity, the function of extracellular DNA remains unclear. Here we observe a substantial increase in circulating neutrophil extracellular trap (NET) DNA in individuals with lymphoma experiencing cardiotoxicity after anthracycline-containing treatment. Using mouse models and human organotypic myocardial slices, we demonstrate that doxorubicin induces HMGB1-dependent cardiac NET formation, thereby promoting cardiac remodeling and dysfunction. Mechanistically, extracellular NET DNA is recognized by the transmembrane protein CCDC25 on cardiomyocytes, and their cross-talk generates reactive oxygen species and activates autophagic flux, subsequently impairing cardiac function. Targeting CCDC25 significantly alleviates anthracycline cardiotoxicity and synergizes with the antitumor efficacy of doxorubicin in lymphoma and breast cancer models. Overall, our findings demonstrate a previously unrecognized role of NETs and CCDC25 in anthracycline cardiotoxicity and suggest that targeting CCDC25 could provide a dual therapeutic and cardioprotective advantage.
蒽环类药物心脏毒性限制了其临床应用。尽管近期研究表明细胞质DNA感知通路的异常激活参与了心脏毒性的发生，但细胞外DNA的作用仍不明确。本研究发现，接受含蒽环类药物治疗后出现心脏毒性的淋巴瘤患者循环中的中性粒细胞胞外诱捕（NET）DNA水平显著升高。通过小鼠模型与人源器官型心肌切片实验，证实阿霉素诱导高迁移率族蛋白B1（HMGB1）依赖心脏NET形成，进而促进心脏重构与功能障碍。机制研究表明，胞外NET DNA被心肌细胞膜表面蛋白CCDC25识别，其相互作用通过产生活性氧（ROS）并激活自噬流，最终导致心脏功能损伤。靶向抑制CCDC25可显著减轻蒽环类心脏毒性，并协同增强阿霉素在淋巴瘤及乳腺癌模型中的抗肿瘤效果。该研究首次揭示了NET-DNA/CCDC25轴在蒽环类心脏毒性中的调控作用，表明靶向CCDC25可产生心脏保护与肿瘤治疗的双重获益。
9.Skeletal muscle endothelial dysfunction through the activin A–PGC1α axis drives progression of cancer cachexia
骨骼肌内皮功能障碍通过激活素A–PGC1α轴驱动癌症恶病质进展的机制研究
伊利诺伊大学医学院生物化学和分子遗传学系，美国
Cachexia is the wasting of skeletal muscle in cancer and is a major complication that impacts a person’s quality of life. We hypothesized that cachexia is mediated by dysfunction of the vascular system, which is essential for maintaining perfusion and tempering inappropriate immune responses. Using transparent tissue topography, we discovered that loss of muscle vascular density precedes muscle wasting in multiple complementary tumor models, including pancreatic adenocarcinoma, colon carcinoma, lung adenocarcinoma and melanoma models. We also observed that persons suffering from cancer cachexia exhibit substantial loss of muscle vascular density. As tumors progress, increased circulating activin A remotely suppresses the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) in the muscle endothelium, thus inducing vascular leakage. Restoring endothelial PGC1α activity preserved vascular density and muscle mass in tumor-bearing mice. Our study suggests that restoring muscle endothelial function could be a valuable therapeutic approach for cancer cachexia.
恶病质是癌症中骨骼肌萎缩的重要病理过程，严重影响患者生活质量。本研究提出假说：作为维持组织灌注与免疫稳态的关键系统，血管系统功能障碍可能介导恶病质发生。通过透明组织拓扑成像技术，本研究在胰腺导管腺癌、结肠癌、肺腺癌及黑色素瘤等多种互补肿瘤模型中发现骨骼肌血管密度下降早于肌肉萎缩。临床数据分析同样显示，癌症恶病质患者骨骼肌血管密度显著降低。随着肿瘤进展，循环激活素A水平升高可远程抑制骨骼肌内皮细胞中过氧化物酶体增殖物激活受体γ共激活因子1α（PGC1α）的表达，进而诱导血管渗漏。在荷瘤小鼠模型中恢复内皮PGC1α的活性可维持血管密度与肌肉质量。综上所述，本研究表明，修复骨骼肌内皮功能可能成为癌症恶病质的有效治疗策略。
10.Cellular hierarchies of embryonal tumors with multilayered rosettes are shaped by oncogenic microRNAs and receptor–ligand interactions
伴有多层菊形团的胚胎性肿瘤细胞层级结构由致癌性微RNA及受体-配体相互作用调控的分子机制
波士顿儿童癌症和血液疾病中心，美国
Embryonal tumor with multilayered rosettes (ETMR) is a pediatric brain tumor with dismal prognosis. Characteristic alterations of the chromosome 19 microRNA cluster (C19MC) are observed in most ETMR; however, the ramifications of C19MC activation and the complex cellular architecture of ETMR remain understudied. Here we analyze 11 ETMR samples from patients using single-cell transcriptomics and multiplexed spatial imaging. We reveal a spatially distinct cellular hierarchy that spans highly proliferative neural stem-like cells and more differentiated neuron-like cells. C19MC is predominantly expressed in stem-like cells and controls a transcriptional network governing stemness and lineage commitment, as resolved by genome-wide analysis of microRNA-mRNA binding. Systematic analysis of receptor–ligand interactions between malignant cell types reveals fibroblast growth factor receptor and Notch signaling as oncogenic pathways that can be successfully targeted in preclinical models and in one patient with ETMR. Our study provides fundamental insights into ETMR pathobiology and a powerful rationale for more effective targeted therapies.
伴有多层菊形团的胚胎性肿瘤（ETMR）是一种预后极差的儿童脑肿瘤。ETMR的特征性19号染色体微RNA簇（C19MC）改变可见于多数病例，但C19MC激活的生物学效应及ETMR复杂的细胞结构尚未明确。本研究通过单细胞转录组学与多重空间成像技术分析了11例ETMR患者样本，揭示了由高增殖性神经干细胞样细胞与分化程度更高的神经元样细胞构成的空间特异性细胞层级结构。研究表明，C19MC主要在干细胞样细胞中表达，并通过全基因组微RNA-mRNA结合分析证实其通过调控转录网络来维持干细胞特性并控制谱系分化进程。对恶性肿瘤细胞间受体-配体相互作用的系统性分析发现，成纤维细胞生长因子受体（FGFR）和Notch信号通路可作为致癌靶点，并已在临床前模型及一名ETMR患者中成功验证。因此，本研究为理解ETMR的病理生物学提供了重要理论依据，并为开发更有效的靶向治疗奠定了科学基础。
11.Tumor antigens preferentially derive from unmutated genomic sequences in melanoma and non-small cell lung cancer
黑色素瘤与非小细胞肺癌中肿瘤抗原主要源自未突变基因组序列
蒙特利尔大学，加拿大
Melanoma and non-small cell lung cancer (NSCLC) display exceptionally high mutational burdens. Hence, immune targeting in these cancers has primarily focused on tumor antigens (TAs) predicted to derive from nonsynonymous mutations. Using comprehensive proteogenomic analyses, we identified 589 TAs in cutaneous melanoma (n = 505) and NSCLC (n = 90). Of these, only 1% were derived from mutated sequences, which was explained by a low RNA expression of most nonsynonymous mutations and their localization outside genomic regions proficient for major histocompatibility complex (MHC) class I-associated peptide generation. By contrast, 99% of TAs originated from unmutated genomic sequences specific to cancer (aberrantly expressed tumor-specific antigens (aeTSAs), n = 220), overexpressed in cancer (tumor-associated antigens (TAAs), n = 165) or specific to the cell lineage of origin (lineage-specific antigens (LSAs), n = 198). Expression of aeTSAs was epigenetically regulated, and most were encoded by noncanonical genomic sequences. aeTSAs were shared among tumor samples, were immunogenic and could contribute to the response to immune checkpoint blockade observed in previous studies, supporting their immune targeting across cancers.
黑色素瘤和非小细胞肺癌（NSCLC）具有极高的肿瘤突变负荷，因此这些癌症的免疫靶向研究集中于预测源自非同义突变的肿瘤抗原（TAs）。通过综合蛋白质基因组学分析，本研究在皮肤黑色素瘤（n=505）和NSCLC（n=90）中鉴定出589个TAs。其中仅有1%的TAs来源于突变序列，其原因是大多数非同义突变的RNA表达水平较低，且其基因组定位位于主要组织相容性复合体（MHC）I类相关肽生成的有效区域之外。相比之下，99%的TAs源自未突变的基因组序列：包括癌症特异性异常表达的肿瘤抗原（aeTSAs，n=220）、癌组织过表达的肿瘤相关抗原（TAAs，n=165）以及原始细胞谱系特异性抗原（LSAs，n=198）。aeTSAs的表达受表观遗传调控，且大部分由非经典基因组序列编码。aeTSAs在肿瘤样本间具有共享性，且具有免疫原性，可能参与了既往研究中观察到的免疫检查点阻断治疗应答，这一发现支持了aeTSAs在泛癌免疫靶向治疗中的潜在应用价值。
12. Age-associated nicotinamide adenine dinucleotide decline drives CAR-T cell failure
衰老相关烟酰胺腺嘌呤二核苷酸水平下降导致CAR-T细胞治疗失效的分子机制
洛桑大学肿瘤学系，瑞士
Chimeric antigen receptor (CAR) T cell therapy is one of the most promising cancer treatments. However, different hurdles are limiting its application and efficacy. In this context, how aging influences CAR-T cell outcomes is largely unknown. Here we show that CAR-T cells generated from aged female mice present a mitochondrial dysfunction derived from nicotinamide adenine dinucleotide (NAD) depletion that leads to poor stem-like properties and limited functionality in vivo. Moreover, human data analysis revealed that both age and NAD metabolism determine the responsiveness to CAR-T cell therapy. Targeting NAD pathways, we were able to recover the mitochondrial fitness and functionality of CAR-T cells derived from older adults. Altogether, our study demonstrates that aging is a limiting factor to successful CAR-T cell responses. Repairing metabolic and functional obstacles derived from age, such as NAD decline, is a promising strategy to improve current and future CAR-T cell therapies.
嵌合抗原受体（CAR）T细胞疗法是目前最具前景的肿瘤治疗手段之一，但其临床应用与疗效仍受多重因素限制。其中，衰老作为一个重要限制因素，其对CAR-T细胞治疗效果的影响机制尚不明确。本研究发现，老年雌性小鼠来源的CAR-T细胞因烟酰胺腺嘌呤二核苷酸（NAD）耗竭引发线粒体功能障碍，导致其干性特征缺失且体内抗肿瘤活性显著降低。临床数据分析进一步证实，患者年龄与NAD代谢水平共同决定CAR-T细胞治疗的应答效率。通过靶向干预NAD代谢通路，可有效恢复老年个体来源CAR-T细胞的线粒体功能稳态与抗肿瘤活性。该研究系统揭示了衰老是制约CAR-T细胞疗效的关键因素，而针对NAD水平下降等年龄相关代谢/功能缺陷的纠正策略，将为现有及未来CAR-T疗法的优化提供理论依据。
13.MCSP+ metastasis founder cells activate immunosuppression early in human melanoma metastatic colonization
MCSP+转移起始细胞在人类黑色素瘤转移定植早期激活免疫抑制
雷根斯堡大学，德国
To investigate the early, poorly understood events driving metastatic progression, we searched for the earliest detectable disseminated cancer cells (DCCs), also often referred to as disseminated tumor cells (DTCs), in sentinel lymph node (SLN) biopsies of 492 patients with stage I–III melanoma. Using micromanipulator-assisted isolation of rare DCCs, single-cell mRNA and DNA sequencing, codetection by indexing immunofluorescence imaging and survival analysis, we identified melanoma-associated chondroitin sulfate proteoglycan (MCSP)+ melanoma cells as metastasis founder cells (MFCs). We found that DCCs entering SLNs predominantly exhibited a transitory phenotype that, upon interferon-γ exposure triggered by CD8 T cells, dedifferentiated into a neural-crest-like phenotype. This was accompanied by increased production of small extracellular vesicles (sEVs) carrying the immunomodulatory proteins CD155 and CD276 but rarely programmed cell death protein 1 ligand 1. The sEVs suppressed CD8 T cell proliferation and function, facilitating colony formation. Targeting MCSP+ MFCs or their immune escape mechanisms could be key to curing melanoma early by preventing manifestation of metastasis.
为解析驱动转移进展的早期关键事件，本研究基于492例I–III期黑色素瘤患者前哨淋巴结（SLN）活检标本，系统追踪了转移进程中最早可检测的播散性癌细胞（DCCs，又称播散性肿瘤细胞DTCs）。通过显微操作辅助的稀有DCC分离技术、单细胞mRNA与DNA测序、索引免疫荧光成像联用检测及生存分析，本研究鉴定出黑色素瘤相关硫酸软骨素蛋白聚糖(MCSP)+黑色素瘤细胞作为转移起始细胞（MFCs）。研究发现，进入SLN的DCCs主要呈现过渡型表型，在CD8 T细胞触发的干扰素-γ刺激下去分化为神经嵴样表型。此过程伴随携带免疫调节蛋白CD155和CD276（而非程序性死亡配体1）的小细胞外囊泡（sEVs）的大量分泌。这类sEVs通过抑制CD8 T细胞增殖与功能，促进转移灶的形成。靶向清除MCSP+ MFCs或阻断其免疫逃逸机制，可能成为通过早期预防转移实现黑色素瘤根治的关键策略。
14.Sensitizing solid tumors to CAR-mediated cytotoxicity by lipid nanoparticle delivery of synthetic antigens
通过脂质纳米颗粒递送合成抗原增强CAR介导的实体瘤细胞毒性作用
佐治亚理工学院和埃默里大学医学院，美国
Chimeric antigen receptor (CAR) T cell immunotherapy relies on CAR targeting of tumor-associated antigens; however, heterogenous antigen expression, interpatient variation and off-tumor expression by healthy cells remain barriers. Here we develop synthetic antigens to sensitize solid tumors for recognition and elimination by CAR T cells. Unlike tumor-associated antigens, we design synthetic antigens that are orthogonal to endogenous proteins to eliminate off-tumor targeting and that have a small genetic footprint to facilitate efficient tumor delivery to tumors by lipid nanoparticles. Using a camelid single-domain antibody (VHH) as a synthetic antigen, we show that adoptive transfer of anti-VHH CAR T cells to female mice bearing VHH-expressing tumors reduced tumor burden in multiple syngeneic and xenograft models of cancer, improved survival, induced epitope spread, protected against tumor rechallenge and mitigated antigen escape in heterogenous tumors. Our work supports the in situ delivery of synthetic antigens to treat antigen-low or antigen-negative tumors with CAR T cells.
嵌合抗原受体（CAR）T细胞免疫疗法的核心机制依赖于靶向肿瘤相关抗原，然而其临床应用仍受限于实体瘤抗原表达的异质性、患者个体间的差异性以及健康组织的潜在脱靶风险。本研究开发了一种新型的合成抗原系统，通过特异性修饰实体瘤的免疫识别特征，使其能够被CAR-T细胞高效识别并清除。与传统天然抗原不同，这类合成抗原经精心设计具有双重特性：其一，其抗原表位与内源性蛋白互不干扰，彻底规避脱靶毒性；其二，其遗传编码模块较小，可被脂质纳米颗粒（LNPs）高效递送至肿瘤组织内。实验选用驼源单域抗体（VHH）作为合成抗原模板，在多种同源移植和异种移植实体瘤模型中，向荷瘤雌性小鼠过继转输靶向VHH的CAR-T细胞后，观察到肿瘤负荷显著降低、生存期明显延长，并同时诱导表位扩散效应、形成抗肿瘤免疫记忆，且能有效抑制异质性肿瘤的抗原逃逸。该研究突破性地证明了通过脂质纳米颗粒原位递送合成抗原可重新编程实体瘤的免疫识别信号，为攻克低抗原或抗原阴性实体瘤提供了全新的治疗范式。
15. Evolutionary and immune microenvironment dynamics during neoadjuvant treatment of esophageal adenocarcinoma
食管腺癌新辅助治疗期间的进化与免疫微环境动态演变研究
玛丽皇后大学巴茨癌症研究所，英国
Locally advanced esophageal adenocarcinoma remains difficult to treat and the ecological and evolutionary dynamics responsible for resistance and recurrence are incompletely understood. Here, we performed longitudinal multiomic analysis of patients with esophageal adenocarcinoma in the MEMORI trial. Multi-region multi-timepoint whole-exome and paired transcriptome sequencing was performed on 27 patients before, during and after neoadjuvant treatment. We found major transcriptomic changes during treatment with upregulation of immune, stromal and oncogenic pathways. Genetic data revealed that clonal sweeps through treatment were rare. Imaging mass cytometry and T cell receptor sequencing revealed remodeling of the tumor microenvironment during treatment. The presence of genetic immune escape, a less-cytotoxic T cell phenotype and a lack of clonal T cell expansions were linked to poor treatment response. In summary, there were widespread transcriptional and environmental changes through treatment, with limited clonal replacement, suggestive of phenotypic plasticity.
局部晚期食管腺癌的治疗仍具挑战性，其耐药与复发的生态及进化驱动机制尚未完全阐明。本研究通过MEMORI临床试验对食管腺癌患者进行纵向多组学分析。在27例患者的新辅助治疗前、治疗中和治疗后，执行了多区域多时间点的全外显子组测序与配对转录组测序。研究发现治疗期间发生显著转录组学改变，包括免疫相关通路、基质信号及致癌通路的激活上调。基因组数据显示，治疗期间克隆扫荡现象（即优势克隆替代）十分罕见。通过成像质谱流式技术与T细胞受体测序分析，揭示了治疗过程中肿瘤微环境（TME）的动态重塑。遗传性免疫逃逸特征、低细胞毒性T细胞表型以及缺乏克隆性T细胞扩增与治疗应答不良显著相关。综上所述，治疗过程中普遍存在广泛的转录与环境变化，但克隆替换有限，提示表型可塑性可能是其主要耐药机制。
16.CHD1 loss reprograms SREBP2-driven cholesterol synthesis to fuel androgen-responsive growth and castration resistance in SPOP-mutated prostate tumors
CHD1缺失通过重编程SREBP2驱动的胆固醇合成促进SPOP突变前列腺肿瘤的雄激素响应性生长及去势抵抗性形成
休斯顿德克萨斯大学，美国
Despite undergoing castration, most individuals with prostate cancer (PCa) experience progression to castration-resistant PCa (CRPC), in which the androgen receptor (AR) remains an important driver. Concurrent genetic alterations in SPOP and CHD1 define a unique subtype of PCa, but their interactions in tumor progression and therapy response remain unclear. Here, we provide genetic evidence supporting that CHD1 loss accelerates disease progression and confers resistance to castration in males with SPOP-mutated PCa. By leveraging genetic engineering and multiomics, we uncovered a noncanonical function of CHD1 in lipid metabolism reprogramming via repressing the SREBP2 transcriptome. Loss of CHD1 induces cholesterol production, supplies intratumoral androgen biosynthesis and enhances AR activity, leading to castration resistance of SPOP-mutated PCa. Combining anti-androgen therapy with cholesterol-lowering drugs showed synergistic and durable activity against CRPC harboring CHD1 loss and SPOP mutations. These findings advance our understanding of an emerging PCa subtype and offer biomarker-driven combinatorial treatment strategies for men with CRPC.
尽管接受去势治疗，多数前列腺癌（PCa）患者仍会进展为去势抵抗性前列腺癌（CRPC），而雄激素受体（AR）在此过程中仍是关键驱动因子。SPOP与CHD1的并发遗传改变定义了PCa的一种独特亚型，但其在肿瘤进展与治疗应答中的相互作用尚未明确。本研究通过遗传学证据证实，CHD1缺失会加速SPOP突变PCa患者的疾病进展并诱导去势抵抗。结合遗传工程与多组学分析，本研究揭示了CHD1在脂质代谢重编程中的非经典功能——通过抑制SREBP2转录组调控胆固醇合成。CHD1缺失导致胆固醇生成增加，促进瘤内雄激素生物合成并增强AR活性，最终引发SPOP突变PCa的去势抵抗。此外，临床前研究表明，抗雄激素治疗联合降胆固醇药物对携带CHD1缺失与SPOP突变的CRPC具有协同且持久的抑制效应。因此，本研究为CRPC患者提供了基于生物标志物的联合治疗新策略。
17.Impaired T cell and neoantigen retention in time-serial analysis of metastatic non-small cell lung cancer in patients unresponsive to TIL cell therapy
T细胞功能受损及新抗原滞留在非小细胞肺癌转移患者肿瘤浸润淋巴细胞治疗无应答者中的时序分析
西奈山伊坎医学院 ，美国
Features of constrained adaptive immunity and high neoantigen burden have been correlated with response to immune checkpoint inhibitors (ICIs). In an attempt to stimulate antitumor immunity, we evaluated atezolizumab (anti-programmed cell death protein 1 ligand 1) in combination with PGV001, a personalized neoantigen vaccine, in participants with urothelial cancer. The primary endpoints were feasibility (as defined by neoantigen identification, peptide synthesis, vaccine production time and vaccine administration) and safety. Secondary endpoints included objective response rate, duration of response and progression-free survival for participants treated in the metastatic setting, time to progression for participants treated in the adjuvant setting, overall survival and vaccine-induced neoantigen-specific T cell immunity. A vaccine was successfully prepared (median 20.3 weeks) for 10 of 12 enrolled participants. All participants initiating treatment completed the priming cycle. The most common treatment-related adverse events were grade 1 injection site reactions, fatigue and fever. At a median follow-up of 39 months, three of four participants treated in the adjuvant setting were free of recurrence and two of five participants treated in the metastatic setting with measurable disease achieved an objective response. All participants demonstrated on-treatment emergence of neoantigen-specific T cell responses. Neoantigen vaccination plus ICI was feasible and safe, meeting its endpoints, and warrants further investigation. ClinicalTrials.gov registration: NCT03359239.
受限制的适应性免疫特征与高肿瘤新抗原负荷通常与免疫检查点抑制剂（ICIs）的治疗应答相关。为进一步激活抗肿瘤免疫应答，本研究评估了阿替利珠单抗（抗程序性死亡配体1抗体）联合个体化新抗原疫苗PGV001在尿路上皮癌患者中的疗效。其主要终点为治疗方案的可行性（定义为新抗原鉴定效率、多肽合成成功率、疫苗制备时间及给药流程的可操作性）与安全性；次要终点包括转移性患者队列的客观缓解率、缓解持续时间及无进展生存期，辅助治疗队列的至疾病进展时间、总生存期以及疫苗诱导的新抗原特异性T细胞免疫应答。入组的12例患者中有10例成功制备疫苗（中位制备时间20.3周），所有启动治疗的受试者均完成初始免疫周期。最常见的治疗相关不良事件为1级注射部位反应、疲劳及发热。中位随访39个月后，接受辅助治疗的4例患者中3例无复发，而接受转移性治疗的5例可评估患者中2例达到客观缓解。所有患者均观察到治疗期间新抗原特异性T细胞应答的激活。新抗原疫苗联合免疫检查点抑制剂的治疗方案在可行性与安全性方面达到预设终点，值得进一步扩大研究规模。临床试验注册号：NCT03359239。
汇报人：邹宇豪
导师：刘世喜
审核：邱轲、饶郁芳、任建君
