【Nature Cancer】

2025年7月-2025年8月刊

论文导读

期刊介绍：

Nature Cancer作为《自然》系列子刊，填补了癌症研究领域缺乏多学科融合期刊的空白，整合生命科学、物理科学、应用科学及社会科学的研究成果，促进跨领域协作‌，2024年影响因子为23.5，稳居医学/肿瘤学领域顶级期刊之列‌。

Volume 6 No 7, July 2025

2025年7月一共发表14篇文章，其中Articles 8篇。

1.Overcoming extracellular vesicle-mediated fratricide improves CAR T cell treatment against solid tumors

克服外泌体介导的同源杀伤可增强CAR-T细胞治疗实体瘤疗效

美国宾夕法尼亚州费城宾夕法尼亚大学

Abstract

The efficacy of chimeric antigen receptor (CAR) T cells against solid tumors is limited. The molecular mechanisms underlying CAR T cell resistance are yet to be elucidated and new strategies need to be developed to improve treatment outcomes. Here we report that solid tumors respond to CAR T cells by upregulating the secretion of small extracellular vesicles carrying tumor antigens, which are horizontally transferred to CAR T cells, leading to antigen recognition and CAR T cell fratricide. Engineered CAR T cells armored with Serpin B9, a major granzyme B inhibitor, show decreased fratricide and increased vitality, tumor infiltration, and antitumor activity in female mice. Moreover, Serpin B9-armored CAR T cells show higher efficacy than parental CAR T cells in treating solid tumors when combined with the anti- programmed death 1 antibody. Our study demonstrates a mechanism that limits CAR T cell function and suggests an improved strategy in tumor treatment.

摘要

CAR-T治疗实体瘤的疗效常受局限，其耐药机制尚未明晰，亟需开发新型策略以提升治疗效果。该研究发现，实体瘤在遭遇CAR-T细胞时，会通过上调分泌携带肿瘤抗原的小型外泌体（sEVs）；这些sEVs可水平转移至CAR-T细胞，引发抗原识别并导致CAR-T细胞发生同源杀伤，从而削弱其效应功能。通过工程化改造使CAR-T细胞装备丝氨酸蛋白酶抑制剂B9（一种重要的颗粒酶B抑制剂），能有效减弱同源杀伤，并在雌性小鼠模型中显著增强CAR-T细胞活力、肿瘤浸润能力及抗肿瘤活性。进一步研究发现，当Serpin B9强化型CAR-T细胞与抗PD-1抗体联用时，其治疗实体瘤的效果优于为改造的亲本CAR-T细胞。该研究不仅揭示了限制CAR-T细胞功能的外泌体介导机制，更为肿瘤治疗提供了优化新策。

2.Glofitamab in refractory or relapsed diffuse large B cell lymphoma after failing CAR-T cell therapy: a phase 2 LYSA study

格洛菲他滨治疗CAR-T治疗后的难治复发性弥漫大B细胞淋巴瘤：LYSA二期研究

法国里昂大学医院血液科

Abstract

Persons with diffuse large B cell lymphoma (DLBCL) refractory or in first progression/relapsed (R/R) after chimeric antigen receptor T (CAR-T) cell therapy exhibit dramatic outcomes. We enrolled such persons in a phase 2 single-arm, nonblinded trial (NCT04703686) to evaluate the efficacy and safety of glofitamab, a CD20-CD3 T cell- engaging bispecific antibody, using a short ramp-up regimen to reach full dose within 1 week. A total of 46 participants received at least one glofitamab infusion following obinutuzumab (anti-CD20 monoclonal antibody) pretreatment. The primary endpoint was overall survival (OS). Secondary endpoints included independent-assessed best overall metabolic response rate (OMRR) and complete metabolic response rate (CMRR), progression-free survival (PFS), duration of response, safety and tolerability and health-related quality of life. After a median follow-up of 15.3 months (95% confidence interval (CI), 10.1-17.7), the primary endpoint was met, achieving a median OS of 14.7 months (90% CI, 8.8-not reached). The best OMRR was 76.1%. The best CMRR was 45.7%. The median PFS was 3.8 months (95% CI, 2.4-19.6). Despite the shortened setup dosing, no excess cytokine release syndrome or neurotoxicity events were observed (grade ≥ 3, 0% for both). In conclusion, glofitamab improved OS in participants with R/R DLBCL after CAR-T cell therapy, with a favorable safety profile.

摘要

针对嵌合抗原受体T细胞疗法后的难治或首次进展/复发的弥漫性大B细胞淋巴瘤患者，其治疗的临床预后效果往往极不理想。该研究采用单臂、非盲设计的二期临床试验（NCT04703686），旨在评估CD20-CD3双特异性T细胞衔接抗体格洛菲他滨的疗效与安全性——该药通过短期剂量递增方案，可在一周内达到全治疗剂量。共计46位受试者在接受奥滨尤妥珠单抗（抗 CD20 单抗）预处理后，至少完成了一次格洛菲他滨输注。研究主要终点为总生存期（OS），次要终点包括独立评估的最佳总体代谢缓解率（OMRR）与完全代谢缓解率（CMRR）、无进展生存期（PFS）、缓解持续时间、安全性和耐受性以及健康相关生活质量指标。在中位随访15.3个月（95% CI：10.1–17.7）后，主要终点达成，中位总生存期达14.7个月（90% CI：8.8–未达到）。最佳总体代谢缓解率为76.1%，完全代谢缓解率达45.7%，中位无进展生存期为3.8个月（95% CI：2.4–19.6）。尽管采用加速递增给药方案，未观察到严重细胞因子释放综合征或神经毒性事件（3级以上）发生。该研究证实，格洛菲他滨能显著改善CAR-T治疗后的难治复发弥漫大B细胞淋巴瘤患者的总生存期，并具有良好的安全性。

3.PILRa on tumor cells interacts with the T cell surface protein CD99 to suppress antitumor immunity

肿瘤细胞上的PILRα与T细胞表面蛋白CD99相互作用以抑制抗肿瘤免疫

厦门大学药学院翔安生物医药实验室传染病疫苗国家重点实验室

Abstract

Immune checkpoint blockade using anti-programmed cell death protein 1/programmed cell death 1 ligand 1 antibody effectively targets the tumor-T cell interaction in cancer treatment, yet the overall response rate of less than 30% necessitates the identification of additional immune checkpoints modulating T cell function. Here, we identified the tumor cell- expressed paired immunoglobulin-like type 2 receptor alpha (PILRa) as an immune suppressor targeting T cells using high-throughput screening. PILRa inhibits T cell activation,proliferation and effector function by targeting CD99, a T cell surface antigen, suppressin ZAP70/NFAT/IL-2/JAK/STAT signaling. A cluster of O-glycosylated serine and threonine residues within the stalk region is critical for PILRa-CD99 interactions. Blocking these interactions with a stalk-targeting anti-PILRa antibody enhances T cell antitumor immunity and suppresses tumor growth. When combined with programmed cell death protein 1 antibody, anti-PILRa antibody shows synergistic tumor suppression. Notably, PILRa is highly expressed in several human cancers and predicts poor prognosis. These findings unveil PILRa as an immune checkpoint with therapeutic potential for clinical cancer immunotherapy.

摘要

尽管抗PD-1/PD-L1抗体通过阻断肿瘤与T细胞间相互作用的机制在癌症治疗中取得显著疗效，但其总体应答率不足30%，亟需鉴定更多能够调控T细胞功能的免疫检查点。该研究通过高通量筛选，首次鉴定出肿瘤细胞表达的配对免疫球蛋白样2型受体α（PILRα）作为靶向T细胞的免疫抑制因子。PILRα通过结合T细胞表面抗原CD99，抑制ZAP70/NFAT/IL-2/JAK/STAT信号通路传导，进而削弱T细胞活化、增殖及效应功能。其茎部区域的一簇O-糖基化丝氨酸/苏氨酸残基是PILRα-CD99互作的关键作用位点。采用靶向该茎部的抗PILRα抗体阻断上述相互作用，可显著增强T细胞抗肿瘤免疫力并抑制肿瘤生长。当与PD-1抗体联用时，抗PILRα抗体展现出协同抑瘤效应。值得注意的是，PILRα在多种人类肿瘤组织中呈高表达，且与不良预后密切相关。该研究发现揭示了PILRα作为新型免疫检查点的功能及其作为癌症免疫治疗靶点的潜在临床应用价值。

4.p95HER2, a truncated form of the HER2 oncoprotein, drives an immunosuppressive program in HER2+ breast cancer that limits trastuzumab deruxtecan efficacy

p95HER2通过驱动免疫抑制程序限制德曲妥珠单抗在HER2阳性乳腺癌中的疗效

美国明尼苏达州罗切斯特梅奥诊所检验医学和病理学系

Abstract

Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies and immuno-oncology agents poses a major challenge in treating HER2-positive breast cancer. Here we demonstrate that p95HER2, a truncated form of HER2, drives immune evasion in HER2-positive female breast cancer, enhancing tumor growth and conferring therapy resistance. This stems from the unique ability of p95HER2 to promote cancer cell-intrinsic programmed death ligand 1 expression and secretion of immunosuppressive mediators including interleukin 6. In preclinical models, this impairs the efficacy of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate (ADC) that relies on immunogenic responses to cell death for full efficacy. Importantly, we find that neratinib potently directs proteasomal degradation of p95HER2, relieving its immunosuppressive effects, and provide proof of concept that neratinib and/or agents targeting p95HER2 downstream mediators can restore antitumor immunity and trastuzumab deruxtecan efficacy. This study reveals a p95HER2-specific therapy resistance mechanism in HER2-positive female breast cancer and highlights the potential value of targeting p95HER2 to improve outcomes with ADCs or immuno-oncology agents.

摘要

针对HER2的靶向治疗及肿瘤免疫疗法所产生的耐药性，是HER2阳性乳腺癌临床治疗中的重大挑战。该研究揭示，HER2的截短形式p95HER2在HER2阳性女性乳腺癌中驱动免疫逃逸，进而促进肿瘤生长并赋予治疗耐药性。这一机制源于p95HER2独特的生物学功能：它可促进癌细胞内在PD-L1的表达，并诱导包括白介素6等多种免疫抑制因子的分泌。在临床前模型中，这种免疫抑制程序削弱了德曲妥珠单抗（一种依赖细胞死亡免疫原性反应实现完全疗效的HER2靶向抗体偶联药物）的治疗效果。值得关注的是，研究者发现来那替尼可有效引导p95HER2的蛋白酶体降解，从而解除其免疫抑制效应，并通过概念验证实验表明：来那替尼和/或靶向p95HER2下游免疫抑制介质的药物，能够重建抗肿瘤免疫力并恢复德曲妥珠单抗疗效。综上，本研究揭示了HER2阳性女性乳腺癌中由p95HER2驱动的特异性耐药机制，并凸显了靶向p95HER2在提升抗体偶联药物及肿瘤免疫疗法疗效方面的潜在价值。

5.RIOKI phase separation restricts PTEN translation via stress granules activating tumor growth in hepatocellular carcinoma

RIOK1通过相分离在应激颗粒中限制PTEN翻译，进而激活肝细胞癌肿瘤生长

中国科学技术大学第一附属医院肝胆外科

Abstract

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 RIOKI 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 RIOKI 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.

摘要

酪氨酸激酶抑制剂(TKIs)耐药性显著削弱了其在肝细胞癌(HCC)治疗中的临床疗效。由相分离形成的应激颗粒是细胞应激应答的重要组成部分，亦已被证实参与治疗耐药过程，然而其在肝癌中的具体机制尚未明确。该研究通过筛选发现，非典型丝氨酸/苏氨酸激酶RIOK1在肝癌组织中高表达且与不良预后相关，其转录活性受NRF2调控并在多种应激条件下在转录水平被激活。RIOK1通过液-液相分离过程，将IGF2BP1与G3BP1招募至应激颗粒，进而禁锢PTEN信使RNA并抑制其翻译。该过程激活磷酸戊糖途径，促进应激化解并增强肿瘤细胞对TKI药物的耐受性。研究者进一步证实小分子抑制剂西达本胺可下调RIOK1表达并增强TKI疗效。此外，在肝癌患者对多纳非尼耐药的肿瘤样本中，研究者观察到RIOK1阳性应激颗粒的存在。该研究揭示了应激颗粒动态组装、代谢重编程与肝癌进展间的关键联系，为提升TKI疗效提供了潜在策略。

6.Multipotent lineage potential in B cell acute lymphoblastic leukemia is associated with distinct cellular origins and clinical features

B细胞急性淋巴细胞白血病的多系分化潜能揭示其独特的细胞起源与临床特征

美国田纳西州孟菲斯市圣裘德儿童研究医院病理学系

Abstract

Developmental origins and their associations with lineage plasticity and treatment response in B-cell progenitor acute lymphoblastic leukemia (B-ALL) are mostly unexplored. Here, we integrated single-cell transcriptome sequencing (scRNA-seq) of 89 B-ALL samples with a single-cell atlas of normal human B cell development incorporating functional and molecular assays. We observed subtype- and sample-dependent correlation with normal developmental stage, with intra-subtype and intra-patient heterogeneity. We show that subtypes prone to shift from the B-lineage (for example BCR:ABL1, KMT2A-R and DUX4-R B-ALL) are enriched for multipotent progenitors and show this developmental stage exhibits CEBPA activation and retains myeloid potential, providing a mechanistic explanation for this clinical observation. We developed a 'multipotency score' most enriched in subtypes exhibiting lineage plasticity that was independently associated with inferior survival. Thus, multipotent B-ALL states reflect the early progenitor origins of a subset of patients with B-ALL and may be relevant for understanding lineage shifting following conventional chemotherapy or immunotherapies.

摘要

B细胞前体急性淋巴细胞白血病（B-ALL）的发育起源及其与谱系可塑性、治疗反应的关联，至今仍未被充分探索。该研究整合了89例B-ALL样本的单细胞转录组测序（scRNA-seq）数据与涵盖正常人B细胞发育过程的单细胞图谱，并结合多项功能及分子实验验证。研究者发现，白血病细胞与正常发育阶段之间的相关性呈现明显的亚型及样本特异性，且存在亚型内与患者内的异质性。研究证实，易发生B系谱转换的亚型（如BCR::ABL1、KMT2A重排及DUX4重排B-ALL）富含多能祖细胞，并揭示该发育阶段呈现CEBPA激活状态且保留髓系分化潜能，为这一临床现象提供了机制性解释。研究者开发的"多能性评分"在展现谱系可塑性的亚型中富集程度最高，且该评分与患者较差的生存率独立相关。因此，多能性B-ALL状态反映了部分患者的白血病起源于早期祖细胞，这一发现对理解传统化疗或免疫疗法后出现的谱系转换现象具有重要启示。

7.Self-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer

自扩增的NRF2–EZH2表观遗传回路将KRAS始动的祖细胞驱动为侵袭性胰腺癌。

美国圣地亚哥医学院

Abstract

Pancreatic ductal adenocarcinoma (PDAC) emerges from mutant KRAS-harboring but dormant low-grade pancreatic intraepithelial neoplasia (PanIN). To examine the role of oxidative stress, a putative PDAC risk factor, we established an organoid-based transformation system. Although the prototypic oxidant H2O2 induced organoid transformation, its effect was nonmutational and was mediated by the oxidant-responsive transcription factor NRF2, which induced the histone methyltransferase EZH2. Congruently, nonoxidizing NRF2 activators triggered organoid malignant conversion through NRF2 and EZH2, establishing a hitherto unknown epigenetic mechanism underlying PanIN-to-PDAC progression. While NRF2 induced EZH2 gene transcription in mouse and human PDAC, EZH2, a general repressor, coactivated transcription of NRF2-encoding NFE2L2 and interacted with other transcription factors to induce genes that sustain PDAC metabolic demands. The self- amplifying NRF2-EZH2 epigenetic loop also accounted for inflammation-driven PanIN-to- PDAC progression in vivo and was upregulated in established human PDAC, whose malignancy was maintained by NRF2 binding to the EZH2 promoter.

摘要

胰腺导管腺癌（PDAC）通常起源于携带KRAS突变但处于休眠状态的低级别胰腺上皮内瘤变（PanIN）。为探究氧化应激（一个公认的PDAC风险因子）在其中发回的作用，研究者建立了基于类器官的转化研究体系。尽管典型氧化剂过氧化氢能诱导类器官恶性转化，但其作用并非通过依赖基因突变，而是经由氧化应激应答转录因子NRF2介导，该因子可诱导组蛋白甲基转移酶EZH2的表达。相应地，非氧化性NRF2激活剂同样通过NRF2与EZH2诱导类器官发生恶性转化，这揭示了一种此前未知的、驱动PanIN向PDAC进展的表观遗传机制。在鼠源及人源PDAC中，NRF2可诱导EZH2基因转录；而作为普遍转录抑制因子的EZH2，却反常地共激活编码NRF2的NFE2L2基因转录，并协同其他转录因子诱导维持PDAC代谢需求的基因表达。这种自扩增的NRF2-EZH2表观遗传回路不仅解释了体内炎症驱动PanIN向PDAC转化的过程，并在已形成的人源PDAC中持续上调——其恶性状态的维持正依赖于NRF2与EZH2启动子的结合。

8.ccrossNN is an explainable framework for cross- platform DNA methylation-based classification of tumors

crossNN：用于跨平台DNA甲基化数据的可解释肿瘤分类框架

柏林夏里特大学实验神经学系

Abstract

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.

摘要

基于DNA甲基化谱的（脑）肿瘤分类技术，已成为一项强大且不可或缺的诊断手段。早期方案采用甲基化微阵列生成数据，而目前多数分类器仍依赖固定的甲基化特征空间，导致其难以兼容其他技术平台——尤其是不同类型DNA测序技术。该研究介绍的crossNN是一种基于神经网络的机器学习框架，可利用在不同平台获取、且表观基因组覆盖度与测序深度各异的稀疏甲基化组数据，实现精准的肿瘤分类。该框架在准确性与计算效率上均优于传统机器学习及其他深度学习模型，同时仍保持模型的可解释性。研究者运用crossNN训练的全癌种分类器，可鉴别跨越所有器官部位的170余种肿瘤类型。通过来自多种平台包括纳米孔测序、靶向亚硫酸氢盐测序等获取的5,000余例肿瘤样本进行验证，证明该模型具备出色的稳健性与扩展性——其脑肿瘤模型与全癌种模型的分类精准度分别达到99.1%与97.8%。

Volume 6 N0 8, August 2025

2025年8月一共发表12篇文章，其中Articles 8篇

1.Development and validation of an autonomous artificial intelligence agent for clinical decision-making in oncology

肿瘤临床决策自主人工智能系统的研发与验证

德国海德堡大学医院国家肿瘤疾病中心

Abstract

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 Al 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 Al 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 Al-driven personalized oncology support systems.

摘要

肿瘤临床决策过程错综复杂，亟需整合多模态数据与多领域专业知识。该研究开发并评估了一款自主临床人工智能（AI）体，其融合GPT-4语言模型与多模态精准肿瘤工具，旨在为个性化临床决策提供支持。该系统集成视觉Transformer模型（用于从病理切片检测微卫星不稳定性及KRAS/BRAF突变）、MedSAM医学图像分割模型，以及OncoKB、PubMed与谷歌等网络检索工具。在20例模拟真实场景的多模态患者案例测试中，该智能体以87.5%的准确率自主调用工具，在91.0%的案例得出正确临床结论，75.5%的指南引用精准无误。与单独使用GPT-4相比，集成式智能体将临床决策准确率从30.3%显著提升至87.2%。该研究证实：通过将语言模型与精准肿瘤工具及检索系统深度融合，可大幅提升临床决策精准度，为部署基于人工智能的个性化肿瘤辅助系统奠定了坚实基础。

2.Skeletal muscle endothelial dysfunction through the activin A-PGCla axis drives progression of cancer cachexia

骨骼肌内皮细胞通过激活素A–PGC1α轴发生功能障碍，驱动癌症恶病质的进展

美国伊利诺伊大学医学院生物化学与分子遗传学系

Abstract

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-ycoactivator la (PGC1a) in the muscle endothelium, thus inducing vascular leakage. Restoring endothelial PGCla 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..

摘要

恶病质是癌症中以骨骼肌消耗为特征的病理状态，亦是影响患者生存质量的主要并发症。研究者提出假说：血管系统功能障碍是介导恶病质的关键机制——这一系统对维持组织灌注及抑制不当免疫反应至关重要。通过透明组织拓扑成像技术，研究者在胰腺癌、结肠癌、肺腺癌及黑色素瘤等多种肿瘤模型中发现，骨骼肌血管密度的下降早于肌肉萎缩的发生。在癌症恶病质患者样本中，研究者同样观察到显著的骨骼肌血管密度丢失。随着肿瘤进展，循环系统中激活素A水平升高，远程调控抑制肌肉内皮细胞过氧化物酶体增殖物激活受体γ共激活因子1α的表达，从而诱发血管渗漏。在荷瘤小鼠模型中，恢复内皮PGC1α活性可有效维持血管密度与肌肉质量。该研究提示：改善骨骼肌内皮功能或将成为治疗癌症恶病质的有效策略。

3.Efficacy of pembrolizumab and vorinostat combination in patients with recurrent and/or metastatic squamous cell carcinomas: a phase 2 basket trial

帕博利珠单抗与伏立诺他联合疗法在复发/转移性鳞状细胞癌患者中的疗效评估：一项2期篮式研究

美国伊利诺伊大学医学院生物化学与分子遗传学系

Abstract

Immune checkpoint inhibitors improve the treatment of many solid tumors and have shown encouraging results in advanced squamous cell carcinoma (SCC), yet only a minority of patients respond to immune checkpoint inhibitor monotherapy. We conducted the PEVOsq trial, an open-label, nonrandomized, multicenter, basket phase 2 trial to evaluate the combination of pembrolizumab and vorinostat in recurrent/metastatic SCC of various origins. The primary endpoint was the objective response rate (ORR) in each tumor cohort during treatment as per the investigators' assessment. Secondary endpoints included safety and antitumor activity evaluation in terms of centrally confirmed ORR, progression-free survival, overall survival and duration of response. In the efficacy population (n = 107), the ORR was met in cervical (39%), anal (31%) and vulvar/vaginal (19%) cancer cohorts, but not in head and neck SCC (19%) or penile (18%) cancer cohorts (overall ORR = 26%). Median progression-free survival was 4.0 months (95% confidence interval: 2.6-4.3), and median overall survival was 11.1 months (95% confidence interval: 9.2-17.4). In the safety population, 101 (91%) of 111 patients developed at least one treatment-related adverse event, with 39% and 5.4% of patients experiencing at least one grade 3 and grade 4 treatment-related adverse event, respectively. Vorinostat-related toxicity prompted a dose reduction/interruption in 66% of patients. Whole-exome sequencing analyses revealed several potential predictive biomarkers of response to treatment. Further studies in a larger number of patients are required to validate these findings. ClinicalTrials.gov identifier: NCT04357873.

摘要

免疫检查点抑制剂革新了众多实体瘤的治疗模式，在晚期鳞状细胞癌（SCC）领域亦展现出鼓舞人心的疗效，然其单药治疗仅能使少数患者获益。遂开展PEVOsq临床试验——一项开放标签、非随机、多中心的二期篮式研究，旨在评估帕博利珠单抗与伏立诺他联用治疗不同来源复发/转移性鳞癌的疗效。研究主要终点为经研究者评估的各肿瘤队列客观缓解率（ORR）；次要终点包括安全性及经中心实验室确认的客观缓解率、无进展生存期（PFS）、总生存期（OS）与缓解持续时间等抗肿瘤活性指标。在疗效分析集（n=107）中，宫颈癌（39%）、肛管癌（31%）及外阴/阴道癌（19%）队列达到主要终点，而头颈部鳞癌（19%）与阴茎癌（18%）队列未达终点（总体客观缓解率为26%）。中位无进展生存期为4.0个月（95% CI: 2.6–4.3），中位总生存期达11.1个月（95% CI: 9.2–17.4）。在安全性分析集中，111例患者有101例发生至少一次治疗相关不良事件，其中39%与5.4%的患者分别出现≥3级和4级事件。因伏立诺他相关毒性导致剂量调整/中断者占66%。全外显子组测序分析揭示多个潜在疗效预测生物标志物。当前发现仍需更大规模研究予以验证。

4.Long-acting IL-2 release from pressure-fused biomineral tablets promotes antitumor immune response

压力融合生物矿物片剂通过白介素-2的长效释放促进抗肿瘤免疫应答

先进给药与释放系统国家重点实验室、浙江大学药学院

Abstract

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 calciumcarbonate 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.

摘要

长效、可控的药物递送系统因其能增强疗效、降低给药频率而备受青睐。该研究通过融合并消除碳酸钙与磷酸钙非晶相的界面，成功构建了动力学可控的长期白细胞介素-2释放平台。与简单的混合物不同，研究者在高压环境下制备出一组化学通式为Ca(CO3)x(PO4)2(1−x)/3的杂化生物矿物材料（CaCPs，0<x<1），该材料通过结晶驱动释放机制精准优化IL-2的体内命运。其中Ca(CO3)1/2(PO4)1/3组分能动态重塑免疫抑制性肿瘤微环境，通过改善IL-2重分布特性优先激活细胞毒性T细胞与记忆T细胞，并在肿瘤部位实现长达数周的IL-2滞留，且具备良好耐受性与生物安全性。在雌性小鼠黑色素瘤模型中，该材料展现出卓越的抗肿瘤效果：不仅能抑制局部肿瘤复发、阻滞远端未经处理肿瘤的生长，更能维持长效T细胞应答来攻击转移瘤。

5.Cardiomyocyte-localized CCDC25 senses NET DNA to promote doxorubicin cardiotoxicity by activating autophagic flux

心肌细胞定位蛋白CCDC25感应中性粒细胞胞外诱捕网DNA并激活自噬流，驱动阿霉素心脏毒性

中山大学肿瘤防治中心肿瘤内科

Abstract

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.

摘要

心脏毒性是限制蒽环类药物临床应用的主要瓶颈。尽管近期研究提示胞质DNA感应通路的异常激活介导了蒽环类药物相关的心脏毒性，但细胞外DNA的具体功能仍未明晰。该研究发现，在接受含蒽环方案治疗后出现心脏毒性的淋巴瘤患者循环系统中，循环gNET（中性粒细胞胞外诱捕网）DNA水平显著升高。通过小鼠模型及人源心肌组织切片实验，研究者证实阿霉素可诱导HMGB1依赖性心脏NET生成，进而促进心脏重构与功能异常。机制层面，细胞外NET DNA被心肌细胞跨膜蛋白CCDC25识别，二者相互作用产生活性氧并激活自噬流，最终导致心功能障碍。靶向CCDC25不仅能显著缓解蒽环类药物心脏毒性，还在淋巴瘤与乳腺癌模型中与阿霉素抗肿瘤疗效产生协同效应。该研究首次揭示了NETs与CCDC25在蒽环类药物心脏毒性中的关键作用，并提示靶向CCDC25有望实现肿瘤治疗与心脏保护的双重效益。

6.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的肿瘤抗原，主要源自未突变基因组序列

加拿大蒙特利尔大学免疫学与癌症研究所

Abstract

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..

摘要

黑色素瘤与非小细胞肺癌（NSCLC）具有极高的突变负荷，因而其免疫靶向研究长期以来主要聚焦于预测源自非同义突变的肿瘤抗原（TAs）。通过系统的蛋白质基因组学分析，研究者在皮肤黑色素瘤（n = 505）与非小细胞肺癌（n = 90）样本中鉴定出589种肿瘤抗原，其中仅1%源于基因突变——这归因于大多数非同义突变RNA表达量低，且其位于主要组织相容性复合体I类相关肽段生成的有效基因组区域之外。与之形成鲜明对比的是，99%的肿瘤抗原源自未突变基因组序列，包括：癌症特异性异常表达的肿瘤抗原（aeTSAs，n = 220）、癌症中过表达的肿瘤相关抗原（TAAs，n = 165），以及源于原始细胞谱系的谱系特异性抗原（LSAs，n = 198）。表观遗传调控着异常表达肿瘤抗原的呈现，且其中多数由非经典基因组序列编码。这类抗原在肿瘤样本间具有共享性、免疫原性，并能增强免疫检查点阻断治疗的应答反应，表明其具备跨癌种免疫靶向的应用潜力。

7.Concurrent inhibition of tumor growth and metastasis by a lipidated nanophotosensitizer tracing and disabling tumor extracellular vesicles

脂质化纳米光敏剂通过定位并抑制肿瘤外泌体功能，同步阻断肿瘤生长与转移

广东省组织工程构建与检测重点实验室，南方医科大学生物材料研究中心

Abstract

Cancer cells promote tumor growth and metastasis through tumor extracellular vesicle (TEV)-mediated intercellular and intertissue communication. Inhibiting TEVs represents a promising strategy to suppress metastasis; however, effectively and selectively disabling TEVs remains challenging. Herein, we developed palmitic acid surface-displayed nanoparticles using an adjacent hydrophilic molecular engineering strategy. Unexpectedly, these lipidated nanoparticles were not only efficiently taken up and distributed within tumor cells but also coupled with TEV generation, enabling active tracing of TEVs. Exploiting their dual tumor spatial distribution (intracellular and intra-TEV), a lipidated nanophotosensitizer was constructed for metastasis therapy. Under near-infrared light irradiation at the primary tumor site, both intracellular and intra-TEV reactive oxygen species were generated synchronously. This led to photodynamic suppression of the primary tumor and blocked intercellular and intertissue communication by disabling TEVs, effectively inhibiting tumor growth and metastasis in multiple tumor models in female mice. Overall, this work reports a therapeutic paradigm for concurrently inhibiting tumor growth and metastasis.

摘要

肿瘤细胞通过肿瘤外泌体（TEV）介导的细胞间与组织间通讯，来驱动肿瘤生长与转移进程。抑制肿瘤外泌体功能是遏制转移的有效策略，然而对其精准靶向与高效干预仍存挑战。该研究采用邻位亲水分子工程策略，构建了表面展示棕榈酸的纳米颗粒。出乎意料的是，该脂质化纳米颗粒不仅能被肿瘤细胞高效摄取并在胞内分布，更可与TEV的生物发生过程耦合，实现对TEV的主动追踪。基于其在肿瘤细胞内与TEV的双重空间分布特性，研究者进一步开放了用于转移治疗的脂质化纳米光敏剂。在近红外光照射原发瘤部位时，该体系可同步产生活性氧，通过光动力效应抑制原发瘤生长，并通过破坏TEV来阻断细胞间与组织间通讯，最终在多种雌性小鼠肿瘤模型中实现肿瘤生长与转移的双重抑制。该工作为同步遏制肿瘤进展与转移提供了新型治疗模式。

8.TRMT6-mediated tRNA m1A modification acts as a translational checkpoint of histone synthesis and facilitates colorectal cancer progression

TRMT6介导的tRNA m1A修饰充当组蛋白合成的翻译检查点，推动结直肠癌进展

上海交通大学消化内科和肝病科

Abstract

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.

摘要

转运RNA（tRNA）修饰已成为翻译重编程的关键调控因子，然其在结直肠癌（CRC）中的作用机制尚不明确。该研究发现，tRNA N1-甲基腺嘌呤甲基转移酶TRMT6在人类结直肠癌组织中表达上调，且其高表达与患者不良预后密切相关。通过在小鼠模型中对原位移植、转移性及条件性基因敲除展开研究，证实了TRMT6在结直肠癌中的致癌作用。从机制层面看，TRMT6通过维持TRMT6–TRMT61A复合物稳定性以提高tRNA m1A修饰水平。靶向抑制TRMT6介导的tRNA m1A修饰，可破坏 tRNA-Lys-TTT-1-1，并以密码子偏好性方式损害组蛋白mRNA翻译，从而限制组蛋白合成、阻滞细胞周期进程。该研究证实TRMT6在结直肠癌细胞加速组蛋白合成过程中发挥翻译检查点的作用，为抗结直肠癌治疗提供了潜在的新靶点。

汇报人：吴婷婷

导师：任建君

审核：向琳、吴桂儀、任建君