【Nature Cancer】2025年2月-2025年5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 Issue 2, February 2025

2025年2-3月一共发表18篇文章，其中Articles 9篇。

Decoding pan-cancer treatment outcomes using multimodal real-world data and explainable artificial intelligence

基于多模态真实世界数据与可解释人工智能的泛癌种治疗结局

埃森大学医院人工智能医学研究所等机构联合发表

Abstract

Despite advances in precision oncology, clinical decision-making still relies on limited variables and expert knowledge. To address this limitation, we combined multimodal real- world data and explainable artificial intelligence (xAI) to introduce Al-derived (AID) markers for clinical decision support. We used xAI to decode the outcome of 15,726 patients across 38 solid cancer entities based on 350 markers, including clinical records, image-derived body compositions, and mutational tumor profiles. xAI determined the prognostic contribution of each clinical marker at the patient level and identified 114 key markers that accounted for 90% of the neural network's decision process. Moreover, xAI enabled us to uncover 1,373 prognostic interactions between markers. Our approach was validated in an independent cohort of 3,288 patients with lung cancer from a US nationwide electronic health record- derived database. These results show the potential of xAI to transform the assessment of clinical variables and enable personalized, data-driven cancer care.

摘要

尽管精准肿瘤学已经取得了重要进展，但临床决策仍主要依赖有限的变量和专家经验。为突破这一局限，研究者通过整合多模态真实世界数据和可解释人工智能（xAI）技术，开发了一种用于临床决策支持的AI衍生（AID）标记物系统。研究者基于15,726例涵盖38种实体肿瘤类型的患者数据，利用xAI技术进行深度解析，分析维度包括临床记录、影像组学特征（如身体成分指标）和肿瘤突变图谱等350项标记物。xAI不仅能在患者个体层面量化每个临床标记物的预后贡献度，还筛选出对神经网络决策影响占比达90%的114个关键标记物。此外，xAI技术还揭示了1,373组临床标记物之间的预后交互作用，为理解复杂的多因子作用协同机制提供了新视角。该研究成果在美国全国性电子健康记录数据库独立的3,288例肺癌患者队列中得到验证。这些成果彰显了xAI在革新临床变量评估体系、推动数据驱动的个性化癌症诊疗方面的巨大潜力。

2.First-in-class ultralong-target-residence-time p38x inhibitors as a mitosis-targeted therapy for colorectal cancer

全球首创超长靶标滞留时间p38α抑制剂——靶向有丝分裂的结直肠癌疗法

德国图宾根大学医院等机构联合发表

Abstract

Colorectal cancer (CRC) constitutes the second leading cause of cancer-related death worldwide and advanced CRCs are resistant to targeted therapies, chemotherapies and immunotherapies. p38x (Mapk14) has been suggested as a therapeutic target in CRC; however, available p38x inhibitors only allow for insufficient target inhibition. Here we describe a unique class of p38x inhibitors with ultralong target residence times (designated ULTR-p38i) that robustly inhibit p38x downstream signaling and induce distinct biological phenotypes. ULTR-p38i monotherapy triggers an uncontrolled mitotic entry by activating Cdc25 and simultaneously blocking Weel. Consequently, CRC cells undergo mitotic catastrophe, resulting in apoptosis or senescence. ULTR-p38i exhibit high selectivity, good pharmaco-kinetic properties and no measurable toxicity with strong therapeutic effects in patient-derived CRC organoids and syngeneic CRC mouse models. Conceptually, our study suggests ultralong-target-residence-time kinase inhibitors as an alternative to covalent inhibitors, which, because of the lack of cysteine residues, cannot be generated for many kinase cancer targets.

摘要

结直肠癌（CRC）是全球癌症相关死亡的第二大病因，尤其是晚期CRC对靶向治疗、化疗及免疫治疗常常产生耐药性。此前已有研究将p38α激酶（Mapk14）视为CRC的潜在治疗靶点，但现有p38α抑制剂因靶点抑制不足而疗效有限。该研究开发了一类具有超长靶标滞留时间的新型p38α抑制剂（命名为ULTR-p38i），其通过延长靶点结合时间实现持续高效的p38α下游信号抑制，并诱导CRC细胞产生独特的生物学表型。ULTR-p38i作为单药治疗时，通过激活Cdc25同时阻断Wee1，触发癌细胞进入不受控的有丝分裂期，最终导致CRC细胞经历有丝分裂灾难，引发细胞凋亡或衰老。该抑制剂具有高选择性、良好药代动力学特性及可忽略的毒性，在患者来源CRC类器官和同源CRC小鼠模型中均展现出显著抗肿瘤疗效。从概念上而言，该研究提出超长靶标滞留时间激酶抑制剂可作为共价抑制剂的替代方案，尤其适用于那些因缺乏半胱氨酸残基而无法开发共价抑制剂的癌症相关激酶靶点。

3.Targeting BRCA1-deficient PARP inhibitor-resistant cells with nickases reveals nick resection as a cancer vulnerability

靶向BRCA1缺陷型PARP抑制剂耐药细胞：核酸酶揭示缺口切除作为癌症治疗新靶点

美国马萨诸塞州伍斯特市马萨诸塞大学等机构联合发表

Abstract

Tumors lacking the BRCA1 and BRCA2 (BRCA) hereditary breast cancer genes display heightened sensitivity to anti-cancer treatments, such as inhibitors of poly (ADP-ribose) polymerase 1 (PARP1). However, when resistance develops, treatments are lacking. Using CRISPR technology, we discovered that enhancing homologous recombination through increased DNA end resection in BRCA1-deficient cells by loss of the 53BP1-Shieldin complex- which is associated with resistance to PARP inhibitors-also heightens sensitivity to DNA nicks. The sensitivity is caused by hyper-resection of nicks into extensive single-stranded regions that trigger cell death. Based on these findings and that nicks limit tumor formation in mice, we propose nickases as a tool for personalized medicine. Moreover, our findings indicate that restricting nick expansion is a critical function of the 53BP1-Shieldin complex.

摘要

BRCA1/2（BRCA）基因缺陷的肿瘤对聚腺苷二磷酸核糖聚合酶1（PARP1）抑制剂等抗癌治疗表现出高度的敏感性。然而，这些肿瘤一旦产生耐药性，目前尚缺乏有效后续治疗手段。本研究通过CRISPR技术筛选发现，在BRCA1缺陷的细胞中敲除与PARP抑制剂耐药相关的53BP1-Shieldin复合物，虽可以增强DNA末端切除所介导的同源重组修复，却意外提高细胞对DNA单链断裂(SSBs）的敏感性。这种敏感性源于缺口被过度切除形成大量单链DNA(ssDNA)区域，从而引发细胞死亡。基于这些发现，以及缺口能抑制小鼠肿瘤形成的事实，研究者提出将核酸酶作为个性化医疗工具。此外，研究者的研究结果表明，限制缺口扩展是53BP1-Shieldin复合物的关键功能。

4.Spatially resolved transcriptomics and graph-based deep learning improve accuracy of routine CNS tumor diagnostics

基于空间转录组学与图深度学习的CNS肿瘤常规诊断精准化研究

德国海德堡海德堡大学医院

Abstract

The diagnostic landscape of brain tumors integrates comprehensive molecular markers alongside traditional histopathological evaluation. DNA methylation and next-generation sequencing (NGS) have become a cornerstone in central nervous system (CNS) tumor classification. A limiting requirement for NGS and methylation profiling is sufficient DNA quality and quantity, which restrict its feasibility. Here we demonstrate NePSTA(neuropathology spatial transcriptomic analysis) for comprehensive morphological and molecular neuropathological diagnostics from single 5-um tissue sections. NePSTA usesspatial transcriptomics with graph neural networks for automated histological and molecular evaluations. Trained and evaluated across 130 participants with CNS malignancies and healthy donors across four medical centers, NePSTA predicts tissue histology and methylation-based subclasses with high accuracy. We demonstrate the ability to reconstruct immunohistochemistry and genotype profiling on tissue with minimal requirements, inadequate for conventional molecular diagnostics, demonstrating the potential to enhance tumor subtype identification with implications for fast and precise diagnostic workup.

摘要

脑肿瘤诊断体系已从传统组织病理学评估发展为整合多维度分子标志物的综合诊断模式。尽管基于DNA甲基化检测与新一代测序（NGS）技术已成为中枢神经系统（CNS）肿瘤分类的基石，但其应用受限于测序对DNA质量与数量的严苛要求。因此，该研究开发了一种全新的诊断技术——神经病理空间转录组分析（NePSTA）技术，仅需单张5微米组织切片即可实现形态学与分子病理学的综合诊断。该技术通过空间转录组学捕获全转录组空间表达谱，并耦合图神经网络（GNN）算法，实现对组织学表型、甲基化亚型及拷贝数变异（CNV）的自动化解析。通过对四家医疗中心130例CNS恶性肿瘤患者及健康供体样本的训练验证，NePSTA能高精度预测组织学类型和甲基化亚型。研究证实，该技术可在常规分子诊断无法开展的微量样本条件下，重建免疫组化结果并完成基因分型，为快速精准的肿瘤亚型鉴定提供了新范式。

5.Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity

线粒体呼吸链复合物I亚基Ndufs4/6选择性缺陷诱导肿瘤免疫原性

美国马萨诸塞州波士顿哈佛医学院细胞生物学系

Abstract

Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the NIrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.

摘要

癌细胞常通过代谢重编程维持细胞增殖并逃避免疫监视，但我们对增强免疫监视的代谢靶点仍知之甚少。该研究发现，选择性抑制线粒体呼吸链复合物I（CI）可显著提升肿瘤免疫原性及对免疫检查点阻断剂（ICB）的敏感性。特异性敲除CI亚基（Ndufs4、Ndufs6），而非其他CI亚基，能在黑色素瘤和乳腺癌模型中诱发免疫依赖性肿瘤生长抑制。研究表明，Ndufs4缺失会激活肿瘤细胞主要组织相容性复合体（MHC）I类协同激活因子Nlrc5及抗原呈递相关分子（尤其是H2-K1）的表达。这种MHC相关基因的上调由丙酮酸脱氢酶依赖的线粒体乙酰辅酶A累积驱动，进而导致Nlrc5和H2-K1启动子区组蛋白H3K27乙酰化水平升高。该结果提示，选择性CI抑制可限制肿瘤生长，而特异性靶向Ndufs4或Ndufs6能增强T细胞免疫监视并提升ICB治疗效果。

ETV7 limits the antiviral and antitumor efficacy of CD8+ T cells by diverting their fate toward exhaustion

ETV7通过促使CD8+ T细胞向耗竭状态分化而削弱其抗病毒与抗肿瘤效能

清华大学生命科学学院分子肿瘤学国家重点实验室、北京大学生命科学学院统计科学中心等联合发表

Abstract

Terminal exhaustion is a critical barrier to antitumor immunity. By integrating and analyzing single-cell RNA-sequencing and single-cell assay for transposase-accessible chromatin with sequencing data, we found that ETS variant 7 (ETV7) is indispensable for determining CD8+T cell fate in tumors. ETV7 introduction drives T cell differentiation from memory to terminal exhaustion, limiting antiviral and antitumor efficacy in male mice. Mechanistically, ETV7 acts as a central transcriptional node by binding to specific memory genes and exhaustion genes and functionally skewing these transcriptional programs toward exhaustion. Clinically, ETV7 expression is negatively correlated with progression and responsiveness to immune checkpoint blockade in various human cancers. ETV7 depletion strongly enhances the antitumor efficacy of CD8+ T cells and engineered chimeric antigen receptor T cells in solid tumors. Thus, these findings demonstrate a decisive role for ETV7 in driving CD8+ T cell terminal exhaustion and reveal that ETV7 may be a promising target and biomarker for improving the efficacy of cancer immunotherapy.

摘要

T细胞终末耗竭是抗肿瘤免疫的关键障碍。本研究通过整合分析单细胞RNA测序（scRNA-seq）与转座酶可及染色质单细胞测序（scATAC-seq）数据，首次揭示ETS变异转录因子7（ETV7）是决定肿瘤内CD8+ T细胞命运的核心调控因子。机制上，ETV7通过特异性结合记忆相关基因和耗竭相关基因，同时激活耗竭基因的转录程序，驱动T细胞过表达驱动从记忆状态向终末耗竭状态分化，从而削弱雄性小鼠体内的抗病毒和抗肿瘤免疫效能。临床分析显示，ETV7的表达水平与多种人类癌症的疾病进展及免疫检查点阻断治疗响应呈负相关。敲除ETV7可显著增强CD8+ T细胞及工程化嵌合抗原受体T细胞在实体瘤中的抗肿瘤效果。这些发现不仅证实ETV7在驱动CD8+ T细胞终末耗竭中的决定性作用，更揭示其可能成为提升癌症免疫治疗效能的潜在靶点与生物标志物。

7.ERa dysfunction caused by ESR1 mutations and therapeutic pressure promotes lineage plasticity in ER+ breast cancer

ESR1突变及治疗压力导致的ERα功能失调促进ER阳性乳腺癌谱系可塑性

美国加利福尼亚州南旧金山基因泰克公司

Abstract

Multiple next-generation molecules targeting estrogen receptor a (ERa) are being investigated in breast cancer clinical trials, encompassing thousands of women globally. Development of these molecules was partly motivated by the discovery of resistance- associated mutations in ESR1 (encodes ERa). Here, we studied the impact of Era antagonist/degraders against Esr1 mutations expressed in mouse mammary glands. Inhibition of mutant ERa induced mixed-lineage cells, characterized by aberrant co- engagement of normally disparate master transcription factors. Lineage infidelity was also observed in Esr1-wild-type mice upon long-term estrogen deprivation. In ER+ breast cancer biopsy specimens, heavily pretreated tumors with no ESRI mutation detected (NMD) frequently exhibited mixed-lineage features. ESR1-mutant tumors generally retained luminal features and higher ERa activity and exhibited an anti-proliferative response to the ERa antagonist giredestrant. ESR1-mutant tumors acquired mixed-lineage features following treatment. Lineage heterogeneity in advanced ER+ breast cancer may underpin the differential benefit of investigational ERa therapeutics observed in ESR1-mutant versus NMD contexts.

摘要

目前，全球已有数千名乳腺癌患者正在参与多项靶向雌激素受体α（ERα）的新一代分子药物的临床试验。这些药物的开发在一定程度上受到ESR1（编码ERα）耐药突变研究的推动。为探究ERα拮抗剂/降解剂在ESR1突变背景下的作用机制，该研究通过构建Esr1突变型小鼠乳腺模型，评估了其对ERα拮抗剂/降解剂的反应。结果显示，抑制突变型ERα会诱导谱系混杂细胞的产生，其特征是多个通常互斥的主转录因子异常共表达。在长期雌激素剥夺的Esr1野生型小鼠中也观察到类似的谱系不忠现象。对ER阳性乳腺癌活检标本的分析进一步发现，在未检出ESR1突变（NMD）但经过多线治疗的肿瘤常呈现谱系混杂的特征。而ESR1突变肿瘤通常保留管腔特征和较高ERα活性，并对ERα拮抗剂giredestrant表现出抗增殖反应。但这类突变肿瘤在治疗后也会获得谱系混杂特征。综上，晚期ER阳性乳腺癌的这种谱系异质性，可能是导致两者对实验性ERα靶向药物反应差异的内在原因，也为克服耐药提供了新的干预方向。

8.Immunogenomic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma

肾细胞癌免疫检查点抑制剂超常应答的免疫基因组学决定因素

美国宾夕法尼亚州费城儿童医院

Abstract

Immune checkpoint inhibitors can lead to 'exceptional', durable responses in a subset of persons. However, the molecular basis of exceptional response (ER) to immunotherapy in metastatic clear cell renal cell carcinoma (mccRCC) has not been well characterized. Here we analyzed pretherapy genomic and transcriptomic data in treatment-naive persons with mccRCC treated with standard-of-care immunotherapies: (1) combination of programmed cell death protein and ligand 1 (PD1/PDL1) and cytotoxic T lymphocyte-associated protein 4 inhibitors (IO/IO) or (2) combination of PD1/PDL1 and vascular endothelial growth factor (VEGF) receptor inhibitors (IO/VEGF). In the IO/IO cohort, clonal neoantigen load was significantly higher in persons with ER. In the IO/VEGF cohort, ER participants displayed strong enrichment of B cell receptor signaling-related pathways, tertiary lymphoid structure (TLS) signatures and evidence of increased metabolic activity. Our results suggest that ER may be related to clonal neoantigen-driven cytotoxic T cell responses and TLS formation in tumor microenvironments. Therapeutic combinations that elicit both T cell-directed and B cell-directed antitumor immunity may be important to achieve exceptional benefit to IO- based treatment in ccRCC.

摘要

免疫检查点抑制剂（ICIs）能使部分转移性透明细胞肾细胞癌（mccRCC）患者获得“超常”且持久的治疗应答反应，但超常应答（ER）的分子机制尚未明确。本研究整合初治mccRCC患者的治疗前全外显子组与转录组数据，对比两类标准治疗方案：（1）程序性死亡蛋白1及其配体1（PD1/PDL1）与细胞毒性T淋巴细胞相关蛋白4抑制剂联合治疗（IO/IO）；（2）PD1/PDL1与血管内皮生长因子（VEGF）受体抑制剂联合治疗（IO/VEGF）。在IO/IO队列中，具有ER特征的患者其克隆性新抗原负荷显著更高；而在IO/VEGF队列中，ER患者则表现出B细胞受体信号通路、三级淋巴结构（TLS）特征及相关代谢活性的显著增强。研究结果表明，ER可能与克隆性新抗原驱动的细胞毒性T细胞应答及肿瘤微环境中TLS的形成相关。在ccRCC的治疗中，同时激发T细胞和B细胞抗肿瘤免疫的联合治疗方案，可能是获得基于IO治疗超常获益的关键。

9. TRIM28-dependent developmental heterogeneity determines cancer susceptibility through distinct epigenetic states

基于TRIM28的发育异质性通过差异化表观遗传状态决定癌症易感性

美国密歇根州大急流城范安德研究所表观遗传学系

Abstract

Mutations in cancer risk genes increase susceptibility, but not all carriers develop cancer. Indeed, while DNA mutations are necessary drivers of cancer, only a small subset of mutated cells go on to cause the disease. To date, the mechanisms underlying individual cancer susceptibility remain unclear. Here, we took advantage of a unique mouse model of intrinsic developmental heterogeneity (Trim28+/D9) to investigate whether early-life epigenetic variation influences cancer susceptibility later in life. We found that heterozygosity of Trim28 is sufficient to generate two distinct early-life epigenetic states associated with differing cancer susceptibility. These developmentally primed states exhibit differential methylation patterns at typically silenced heterochromatin, detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential, frequently mutated in human cancers and correlated with poor prognosis. This study provides genetic evidence that intrinsic developmental heterogeneity can prime individual, lifelong cancer susceptibility

摘要

虽然癌症风险基因突变会增加个体的患病易感性，但并非所有携带者都会罹患癌症。事实上，尽管DNA突变是癌症发生的必要驱动因素，但仅有少数突变细胞最终会发展成恶性肿瘤。迄今为止，个体癌症易感性的内在机制仍不明确。因此，该研究利用具有发育异质性特征的小鼠模型（Trim28+/D9），探究生命早期表观遗传变异是否影响个体终生的癌症易感性。研究发现，Trim28杂合性足以诱导产生两种不同的早期表观遗传状态，分别对应高、低癌症易感性。这些由发育程序决定的表观状态，在通常沉默的异染色质区域呈现差异化甲基化模式，且早在出生后10天即可检测到。值得注意的是，差异甲基化位点富集于具有已知致癌潜力的基因（如在人类癌症中频繁突变且与不良预后相关的基因）。该研究从遗传学角度证明：内在发育异质性可决定个体终生的癌症易感倾向。

Volume 6 Issue 3, March 2025

2025年3月一共发表14篇文章，其中Articles 8篇。

1.Neutrophils physically interact with tumor cells to form a signaling niche promoting breast cancer aggressiveness

中性粒细胞与肿瘤细胞发生物理相互作用，形成一个信号微环境，促进乳腺癌的侵袭性

以色列特拉维夫大学医学与健康科学学院临床微生物学与免疫学系

Abstract

Tissue remodeling and cell plasticity in the mammary gland are activated by multilineage communications; however, the dynamic signaling promoting breast cancer remains unclear. Here, by RNA sequencing of single cells and physically interacting cells (PICs) along mammary gland development and carcinogenesis, we uncovered that neutrophils appear transiently during early development and re-emerge in physical interaction with tumor cells in advanced carcinoma. Neutrophil heterogeneity analysis characterized transcriptional states linked to age and cancer stage. Integrating ligand-receptor and PIC sequencing analyses with various functional experiments unveiled a physical and secreted protumorigenic signaling niche. This approach revealed that neutrophils are recruited by tumor-activated macrophages and physically interact with tumor cells, increasing tumor cell proliferative and invasive properties, as well as endothelial proliferation and angiogenesis. The molecular program upregulated in neutrophil-PICs correlates with lower survival in advanced breast cancer patients. Our interaction-driven perspective highlights potential molecular targets and biomarkers for breast cancer treatment.

摘要

乳腺组织的重塑与细胞可塑性的激活依赖于多谱系之间的复杂通讯网络；然而，推动乳腺癌发生的动态信号机制仍存在认知空白。本研究创新性地整合单细胞RNA测序与物理接触细胞（PICs）分析技术，系统解析了乳腺发育与癌变过程中的细胞互作特征，首次揭示了中性粒细胞在早期发育阶段的短暂出现及其在晚期癌变过程中与肿瘤细胞重建物理接触的关键现象。对中性粒细胞异质性的分析揭示了其与年龄和癌症分期相关的转录状态。结合配体–受体分析与PIC测序，并辅以多种功能实验，研究者识别出一个由物理接触和分泌信号组成的促肿瘤微环境。研究显示，中性粒细胞在肿瘤激活的巨噬细胞的招募下，与肿瘤细胞形成物理接触，从而增强肿瘤细胞的增殖与侵袭能力，同时促进内皮细胞的增殖和血管生成。在中性粒细胞PICs中上调的分子程序，与晚期乳腺癌患者的较低生存率相关。基于细胞相互作用的研究视角为乳腺癌治疗提供了潜在的分子靶点和生物标志物。

2.Neoadjuvant cabozantinib for locally advanced nonmetastatic clear cell renal cell carcinoma: a phase 2 trial

新辅助卡博替尼治疗局部晚期非转移性透明细胞肾细胞癌：一项第二阶段临床试验

美国佐治亚州亚特兰大埃默里大学温希普癌症研究所

Abstract

Cabozantinib is an oral multikinase inhibitor approved for treatment in metastatic renal cell carcinoma (RCC). We conducted a phase 2, nonrandomized, single-arm clinical trial (NCT04022343) of cabozantinib treatment for 12 weeks in 17 patients with locally advanced, biopsy-proven, nonmetastatic clear cell RCC before surgical resection. The primary end point was the objective response rate (complete and partial responses) at week 12 and secondary end points included safety, tolerability, clinical and surgical outcomes, and quality of life. Six patients (35%) experienced a partial response and 11 patients (65%) had stable disease. The most common adverse events were diarrhea (n = 12, 70.6%), anorexia, fatigue and hypertension (n = 10, 58.8%), nausea and palmar-plantar erythrodysesthesia syndrome (n = 9, 52.9%). No treatment grade 4 or 5 adverse events related to cabozantinib or surgery occurred. The 1-year disease-free survival and overall survival were 82.4% (95% CI 54.7-93.9%) and 94.1% (95% CI 65-99.1%), respectively. Cabozantinib treatment activated CD8+ T cells in the blood, depleted myeloid populations and induced immune niches for TCF1+ stem-like CD8+ T cells. Cabozantinib was clinically active and safe in the neoadjuvant setting in patients with locally advanced nonmetastatic clear cell RCC.

摘要

卡博替尼作为一种口服多靶点酪氨酸激酶抑制剂，目前已被批准用于转移性肾细胞癌（RCC）的治疗。研究者开展了一项第二阶段、非随机、单臂的临床试验（NCT04022343），在接受手术切除前，对17例局部晚期、经活检确诊的非转移性透明细胞肾细胞癌患者进行为期12周的卡博替尼治疗。主要终点是第12周的客观缓解率（完全缓解和部分缓解），次要终点包括安全性、耐受性、临床和手术结局，以及生活质量。结果显示，6名患者（35%）达到部分缓解，11名患者（65%）病情稳定。最常见的不良事件包括腹泻（12例，70.6%）、食欲减退、疲劳和高血压（各10例，58.8%）、恶心以及手足红斑感觉异常综合征（各9例，52.9%）。未出现与卡博替尼或手术相关的4级或5级治疗不良事件。1年无病生存率和总生存率分别为82.4%（95% CI：54.7–93.9%）和94.1%（95% CI：65–99.1%）。卡博替尼治疗激活了外周血中的CD8+ T细胞，减少了髓系细胞群，并诱导了TCF1+干样CD8+ T细胞的免疫“生态位”。研究表明，在局部晚期非转移性透明细胞肾细胞癌的新辅助治疗中，卡博替尼不仅具有良好的临床活性，而且展现出可接受的安全性。

Atezolizumab following definitive chemoradiotherapy in patients with unresectable locally advanced esophageal squamous cell carcinoma - a multicenter phase 2 trial (EPOC1802)

不可切除的局部晚期食管鳞状细胞癌患者在根治性放化疗后接受阿替利珠单抗治疗——一项多中心第二阶段临床试验（EPOC1802）

日本柏市国立癌症中心东院肠胃肿瘤科

Abstract

Platinum-based definitive chemoradiotherapy (dCRT) is the standard treatment for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC) that invades the aorta, vertebral body or trachea; however, complete response rates remain low (11-25%), leading to poor survival. To evaluate the additive efficacy of the anti-PD-L1 antibody drug atezolizumab, we conducted a phase 2, multicenter, single-arm trial of 1 year of atezolizumab treatment following dCRT in 40 patients with unresectable locally advanced ESCC recruited from seven Japanese centers (UMIN000034373). The confirmed complete response (cCR) rate (primary end point) of the first consecutive 38 patients was 42.1% (90% CI 28.5-56.7%). Regarding the secondary end points, the median progression-free survival and 12-month progression-free survival rates of all 40 patients were 3.2 months and 29.6%, respectively, and the preliminary median overall survival with short-term follow-up and 12-month overall survival rate were 31.0 months and 65.8%, respectively. Other secondary end points evaluated included the cCR rate determined by an investigator's assessment in the locoregionally recurrent ESCC cohort, cCR rate determined by central assessment, overall response rate and incidence of adverse events. No treatment-related death occurred during the study. Atezolizumab monotherapy after dCRT resulted in a promising cCR rate, although long-term survival data are required.

摘要

基于铂类的根治性放化疗（dCRT）是治疗侵犯主动脉、椎体或气管等关键结构的不可切除局部晚期食管鳞状细胞癌（ESCC）患者的标准方案但该方案的完全缓解率仍不理想（11-25%），导致患者长期生存率不佳。为了评估抗PD-L1抗体药物阿替利珠单抗的潜在疗效，研究者开展了一项多中心、单臂Ⅱ期临床试验，在接受dCRT治疗后的40名不可切除局部晚期ESCC患者中，进行为期1年的阿替利珠单抗治疗，这些患者来自日本7个中心（UMIN000034373）。在首批连续38名患者中，确认的完全缓解率（cCR，主要终点）为42.1%（90% CI：28.5–56.7%）。在次要终点方面，40名患者的中位无进展生存期为3.2个月，12个月无进展生存率为29.6%；初步随访数据显示中位总生存期为31.0个月，12个月总生存率为65.8%。其他次要终点包括局部区域复发ESCC队列中研究者评估的cCR率、中央评估的cCR率、总缓解率以及不良事件发生率。研究期间未发生治疗相关死亡。阿替利珠单抗单药在dCRT后的应用显示出令人鼓舞的cCR率，但仍需长期生存数据以进一步验证。

4.FLASH radiation reprograms lipid metabolism and macrophage immunity and sensitizes medulloblastoma to CAR-T cell therapy

FLASH放射治疗重新编程脂质代谢和巨噬细胞免疫，并使髓母细胞瘤对CAR-T细胞疗法更加敏感

美国宾夕法尼亚州费城宾夕法尼亚大学放射肿瘤学系

Abstract

FLASH radiotherapy holds promise for treating solid tumors given the potential lower toxicity in normal tissues but its therapeutic effects on tumor immunity remain largely unknown. Using a genetically engineered mouse model of medulloblastoma, we show that FLASH radiation stimulates proinflammatory polarization in tumor macrophages. Single-cell transcriptome analysis shows that FLASH proton beam radiation skews macrophages toward proinflammatory phenotypes and increases T cell infiltration. Furthermore, FLASH radiation reduces peroxisome proliferator-activated receptor-y (PPARy) and arginase 1 expression and inhibits immunosuppressive macrophage polarization under stimulus-inducible conditions. Mechanistically, FLASH radiation abrogates lipid oxidase expression and oxidized low- density lipid generation to reduce PPARy activity, while standard radiation induces reactive oxygen species-dependent PPARy activation in macrophages. Notably, FLASH radiotherapy improves infiltration and activation of chimeric antigen receptor (CAR) T cells and sensitizes medulloblastoma to GD2 CAR-T cell therapy. Thus, FLASH radiotherapy reprograms macrophage lipid metabolism to reverse tumor immunosuppression. Combination FLASH- CAR radioimmunotherapy may offer exciting opportunities for solid tumor treatment.

摘要

FLASH放射治疗作为一种新兴的放射治疗技术，因其对正常组织具有显著保护作用而在实体瘤治疗领域展现出广阔前景，然而其对肿瘤免疫的调控机制尚未阐明。本研究利用一种基因工程小鼠髓母细胞瘤模型，首次系统揭示FLASH放射能够促进肿瘤巨噬细胞向促炎性方向极化。单细胞转录组分析显示，FLASH质子束放射促使巨噬细胞偏向促炎性表型，并增强T细胞的浸润。此外，FLASH放射降低了过氧化物酶体增殖物激活受体γ（PPARγ）和精氨酸酶1的表达，并在诱导性刺激条件下抑制免疫抑制型巨噬细胞的极化。在机制上，FLASH放射通过抑制脂质氧化酶表达和氧化低密度脂蛋白的生成，从而降低PPARγ活性，而标准放射则会诱导依赖活性氧的PPARγ在巨噬细胞中被激活。值得注意的是，FLASH放射治疗增强了嵌合抗原受体（CAR）T细胞的浸润与激活，使髓母细胞瘤对GD2 CAR-T细胞治疗展现显著的治疗响应。因此，FLASH放射通过重编程巨噬细胞的脂质代谢有效逆转肿瘤免疫抑制。FLASH与CAR的联合放射免疫治疗可能为实体瘤治疗开辟极具转化潜力的新方向。

5.Targeting ADARI with a small molecule for the treatment of prostate cancer

用小分子靶向ADAR1治疗前列腺

中国药科大学天然药物国家重点实验室

Abstract

Despite the initial response to androgen signaling therapy, most cases of prostate cancer (PCa) eventually relapse and remain incurable. The specific function of ADARI that governs PCa progression and specific inhibitors of ADAR are underexplored. In this study, we demonstrate that highly expressed ADAR1 is a crucial oncogenic target in PCa and develop an effective small-molecule ADAR1 inhibitor, ZYS-1, with marked antitumor efficacy and a favorable safety profile. Either genetic or pharmacological inhibition of ADARI dramatically suppressed PCa growth and metastasis and potentiated the antitumor immune response. Moreover, ZYS-1 can enhance the antitumor effect of immunotherapy. We also reveal that ADARI represses the translation of MTDH in an editing-dependent manner, which drives cell proliferation and invasion in PCa. Collectively, our findings suggest that ADARI is a druggable target in PCa and highlight the widespread applicability of ADARI inhibitors for a broad spectrum of malignancies.

摘要

尽管雄激素信号治疗在早期前列腺癌（PCa）治疗中有效，但大多数病例最终会复发且仍无法治愈。ADAR1在调控PCa进展中的具体功能以及靶向ADAR1的特异性抑制剂尚未被深入研究。在该研究中，研究者证明高度表达的ADAR1是PCa中的一个关键致癌靶点，并开发出一种有效的小分子ADAR1抑制剂ZYS-1，该抑制剂具有显著的抗肿瘤效果和良好的安全性。研究发现，无论是通过基因还是药物抑制ADAR1，都能显著抑制PCa的生长和转移，并增强抗肿瘤免疫反应。此外，ZYS-1还能增强免疫治疗的抗肿瘤效果。研究者还发现，ADAR1以编辑依赖的方式抑制MTDH的翻译，而MTDH驱动了PCa细胞的增殖和侵袭。总体而言，研究者的研究结果表明，ADAR1是PCa中一个治疗的新靶点，并强调了ADAR1抑制剂在恶性肿瘤中的广泛应用潜力。

6.Microbiome dysbiosis, neutrophil recruitment and mesenchymal transition of mesothelial cells promotes peritoneal metastasis of colorectal cancer

微生物组失调、中性粒细胞募集和间皮细胞的间充质转化共同促进结直肠癌的腹膜转移

复旦大学上海肿瘤防治中心结直肠外科

Abstract

Peritoneal metastasis (PM) is common in colorectal cancer (CRC), yet its underlying mechanisms are poorly understood. Here, we explored the transcriptional profile of CRC, PM and adjacent tissues revealing key players that facilitate PM. Single-cell analysis of 48 matched samples from 12 patients revealed that remodeling of malignant cells and the tumor microenvironment promotes CRC progression and metastasis. Multiplexed imaging confirmed depletion in PM by enrichment in CRC tissues of neutrophils associated with mucosal immunity disruption, intestinal microbiota dysbiosis and mesenchymal transition of both cancerous and mesothelial cells. Functional analyses in cell lines, organoids and in vivo models demonstrated that dysbiosis promoted inflammation and protumor neutrophil recruitment, while coupled mesenchymal transition of malignant and mesothelial cells disrupted the stromal structure and increased cancer cell invasiveness. Our findings suggest that targeting mesothelial cells and tumor microenvironment remodeling may offer therapeutic strategies for CRC-PM.

摘要

腹膜转移（PM）在结直肠癌（CRC）中很常见，但其潜在机制有待阐明。研究整合分析了12例CRC患者的48个匹配样本，探索了CRC原发灶、PM灶及其邻近组织的转录组特征，揭示了促进PM发生的关键因素。恶性细胞和肿瘤微环境的重塑推动了CRC的进展和转移。多重成像证实，与CRC组织中富集的中性粒细胞（相关于黏膜免疫受损）、肠道微生物组失调及癌细胞和间皮细胞的间充质转化相比，PM组织中这些成分明显耗竭。细胞系、类器官和体内模型中的功能分析表明，微生物组失调通过募集促炎性中性粒细胞促进肿瘤微环境的炎症反应，而恶性细胞与间皮细胞的耦联间充质转化破坏了基质结构并增强了癌细胞的侵袭性。研究者的研究结果表明，靶向间皮细胞和肿瘤微环境重塑可能为CRC腹膜转移提供新的治疗策略。

7.An antibody-toxin conjugate targeting CD47 linked to the bacterial toxin listeriolysin O for cancer immunotherapy

一种靶向CD47并连接细菌毒素单核李斯特溶素O的抗体-毒素缀合物，用于癌症免疫治疗

美国德克萨斯州休斯顿德克萨斯大学 MD 安德森癌症中心放射肿瘤学系

Abstract

Antigen-presenting cells phagocytose tumor cells and subsequently cross-present tumor- derived antigens. However, these processes are impeded by phagocytosis checkpoints and inefficient cytosolic transport of antigenic peptides from phagolysosomes. Here, using a microbial-inspired strategy, we engineered an antibody-toxin conjugate (ATC) that targets the 'don't eat me' signal CD47 linked to the bacterial toxin listeriolysin O from the intracellular bacterium Listeria monocytogenes via a cleavable linker (CD47-LLO). CD47-LLO promotes cancer cell phagocytosis by macrophages followed by LLO release and activation to form pores on phagolysosomal membranes that enhance antigen cross-presentation of tumor- derived peptides and activate cytosolic immune sensors. CD47-LLO treatment in vivo significantly inhibited the growth of both localized and metastatic breast and melanoma tumors and improved animal survival as a monotherapy or in combination with checkpoint blockade. Together, these results demonstrate that designing ATCs to promote immune recognition of tumor cells represents a promising therapeutic strategy for treating multiple cancers.

摘要

抗原呈递细胞可通过吞噬肿瘤细胞并交叉呈递肿瘤来源的抗原来激活免疫反应。然而，该过程会受到吞噬检查点的抑制，以及抗原肽从吞噬溶酶体向胞质转运效率低下的限制。本研究借鉴微生物机制，设计了一种抗体–毒素偶联物（ATC），其靶向“不要吃我”信号CD47，并通过可裂解连接子连接细菌毒素李斯特菌溶素O（Listeriolysin O，LLO），构建为CD47–LLO。CD47–LLO可促进巨噬细胞对癌细胞的吞噬，随后释放并激活LLO，在吞噬溶酶体膜上形成孔洞，从而增强肿瘤源性肽的抗原交叉呈递效率，并激活胞质免疫传感器。小鼠模型实验显示，CD47–LLO治疗可有效抑制局部及转移性乳腺癌和黑色素瘤的生长，显著延长动物生存时间。该治疗在单药使用或联合免疫检查点抑制剂时均展现出良好疗效。总体而言，本研究结果表明，设计CD47–LLO治疗显著抑制了局部及转移性乳腺癌和黑色素瘤的生长，并在单药治疗或与检查点抑制联用时提高了动物ATC以增强免疫系统对肿瘤细胞的识别，是治疗多种癌症的一种有前景的治疗策略。

8.Odronextamab monotherapy in patients with relapsed/refractory diffuse large B cell lymphoma: primary efficacy and safety analysis in phase 2 ELM-2 trial

Odronextamab单药治疗复发/难治性弥漫大B细胞淋巴瘤患者：ELM-2 II期临床试验的主要疗效与安全性分析

韩国成均馆大学医学院，三星医疗中心血液肿瘤科

Abstract

The phase 2, multicohort, ongoing ELM-2 study evaluates odronextamab, a CD20xCD3 bispecific antibody, in patients with relapsed/refractory (R/R) B cell non-Hodgkin lymphoma after ≥2 lines of therapy. Here primary analysis of the diffuse large B cell lymphoma (DLBCL) cohort is reported. Patients received intravenous odronextamab in 21-day cycles until progression or unacceptable toxicity, with cycle 1 step-up dosing to mitigate cytokine release syndrome (CRS) risk. The primary endpoint was objective response rate (ORR). Secondary endpoints included complete response (CR) rate, duration of response, progression-free survival (PFS) and overall survival. A total of 127 patients were enrolled. At the 29.9-month efficacy follow-up, the ORR was 52.0% and CR rate was 31.5%. Median durations of response and CR were 10.2 and 17.9 months, respectively. Undetectable minimal residual disease at cycle 4 day 15 was associated with PFS benefit. With a step-up of 0.7 to 4 to 20 mg (n = 60), CRS was the most common treatment-emergent adverse event (53.3% (grade ≥3, 1.7%)). No immune effector cell-associated neurotoxicity syndrome was reported. Infections were reported in 82/127 (64.6%) patients (grade ≥3, 38.6%; coronavirus disease 2019, 18.1% (grade ≥3, 12.6%)). In conclusion, odronextamab showed encouraging efficacy in heavily pretreated R/R DLBCL and generally manageable safety with supportive care. Clinical trial registration: NCT03888105.

摘要

ELM-2研究是一项多队列的II期临床试验，旨在评估一种新型靶向CD20×CD3的双特异性抗体odronextamab在接受过≥2线治疗的复发/难治性（R/R）B细胞非霍奇金淋巴瘤患者中的疗效和安全性。本次分析聚焦的是的是弥漫大B细胞淋巴瘤（DLBCL）队列的127例患者数据。患者接受静脉注射odronextamab治疗，每21天为一个周期，持续给药直至疾病进展或出现不可接受的毒性反应。为降低细胞因子释放综合征（CRS）的风险，第1周期采用阶梯式加量给药方案。主要终点为客观缓解率（ORR），次要终点包括完全缓解率（CRR）、缓解持续时间、无进展生存期（PFS）和总生存期（OS）。在中位29.9个月的疗效随访中，ORR为52.0%，CRR为31.5%。中位缓解持续时间为10.2个月，中位完全缓解持续时间为17.9个月。在第4周期第15天检测到微小残留病灶（MRD）阴性与PFS延长相关。在0.7-4-20 mg阶梯加量组（n=60）中，CRS是最常见的治疗相关不良事件（发生率为53.3%，其中≥3级为1.7%）。未观察到免疫效应细胞相关神经毒性综合征（ICANS）。共有82/127（64.6%）名患者出现感染事件（≥3级为38.6%，其中新冠肺炎占18.1%，≥3级为12.6%）。总之，odronextamab在既往接受多线治疗失败的R/R DLBCL患者中表现出令人鼓舞的疗效，且在支持治疗下安全性总体可控。临床试验注册号：NCT03888105。

Volume 6 Issue 4, April 2025

2025年3月一共发表17篇文章，其中Articles 9篇

1.Regorafenib plus avelumab in advanced gastroenteropancreatic neuroendocrine neoplasms: a phase 2 trial and correlative analysis

瑞戈非尼联合阿维鲁单抗治疗晚期胃肠胰神经内分泌肿瘤：一项II期临床试验及相关性分析

法国波尔多贝尔戈尼埃研究所医学部

Abstract

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous tumors with limited treatment options. This phase 2 Bayesian study evaluated the combination of regorafenib, a multikinase inhibitor, and avelumab, a programmed death 1 (PD1) ligand 1 inhibitor, in advanced grade 2-grade 3 well-differentiated GEP neuroendocrine tumors or grade 3 GEP neuroendocrine carcinomas after progression on prior therapies. A total of 47 participants were enrolled and 42 were evaluable for efficacy. Participants received regorafenib (160 mg per day) and avelumab (10 mg kg-1 biweekly) in 28-day cycles. The primary endpoint, 6-month objective response rate per the response evaluation criteria in solid tumors version 1.1, was 18% (95% confidence interval (CI): 8-31%), with a median progression-free survival of 5.5 months (95% CI: 3.6-8). Durable responses were noted (16.6 months; 95% CI: 3.7-no response). Treatment-related adverse events were manageable, with fatigue, diarrhea and palmar-plantar erythrodysesthesia being most common. Exploratory biomarker analysis identified PD1 and indoleamine 2,3-dioxygenase 1 expression and activity as potential resistance markers. These findings highlight the clinical potential of regorafenib and avelumab in GEP-NENs, emphasizing the need for predictive biomarkers and validation in future randomized trials. Clinical Trial registration: NCT03475953.

摘要

胃肠胰神经内分泌肿瘤（GEP-NENs）是一类异质性强、治疗选择有限的肿瘤。该项II期贝叶斯研究评估了多靶点激酶抑制剂瑞戈非尼联合程序性死亡配体1（PD-L1）抑制剂阿维鲁单抗，用于治疗既往接受治疗后病情进展的晚期2-3级分化良好的GEP神经内分泌肿瘤或3级GEP神经内分泌癌的疗效与安全性。

本研究共纳入47名受试者，其中42例可用于疗效评估。受试者按28天为一周期，接受瑞戈非尼（160 mg/日）与阿维鲁单抗（每两周一次，10 mg/kg）联合治疗。主要终点为基于实体瘤疗效评估标准RECIST v1.1的6个月客观缓解率，结果为18%（95%置信区间：8%–31%），中位无进展生存期（PFS）为5.5个月（95% CI：3.6–8）。部分患者获得持久缓解（中位缓解持续时间为16.6个月；95% CI：3.7个月–尚未达到）。

治疗相关不良事件整体可控，最常见的包括乏力、腹泻和手足红肿感觉异常综合征。探索性生物标志物分析发现，PD1及吲哚胺2,3-双加氧酶1（IDO1）的表达和活性可能是潜在的耐药相关标志物。

这些结果显示，瑞戈非尼与阿维鲁单抗联合治疗在GEP-NENs中具有一定临床潜力，同时强调了预测性生物标志物的重要性，以及未来在随机对照试验中验证这些结果的必要性。临床试验注册号：NCT03475953。

2.CAR T or NK cells targeting mismatched HLA-DR molecules in acute myeloid leukemia after allogeneic hematopoietic stem cell transplant

异基因造血干细胞移植后，CAR T细胞或NK细胞靶向错配的HLA-DR分子用于急性髓系白血病的治疗

日本大阪大学国际免疫学前沿研究中心

Abstract

Acute myeloid leukemia (AML)-specific target antigens are difficult to identify. Here we demonstrate that HLA-DRBI can serve as a leukemia-specific target of chimeric antigen receptor (CAR) T cells in patients with AML after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified KG2032 as a monoclonal antibody specifically bound to AML cells in about half of patients, but not to normal leukocytes other than B lymphocytes. KG2032 reacted with a subset of HLA-DRB1 molecules, specifically those in which the 86th amino acid was not aspartic acid. KG2032 reacted minimally with nonhematopoietic tissues. These results indicate that KG2032 reactivity is highly specific for AML cells in patients who carry KG2032-reactive HLA-DRB1 alleles and who received allo-HCT from a donor carrying KG2032-nonreactive HLA-DRBI alleles. KG2032-derived CAR T or natural killer cells showed significant anti-leukemic activity in preclinical models in female mice, suggesting that they may cure patients with AML who are incurable with allo-HCT.

摘要

急性髓系白血病（AML）特异性靶抗原的识别一直是该领域的关键科学难题。研究发现，在接受异基因造血干细胞移植（allo-HCT）的AML患者中，HLA-DRB1可以作为嵌合抗原受体（CAR）T细胞的白血病特异性靶点。研究者鉴定出单克隆抗体KG2032，其能特异性识别、结合约一半AML患者的白血病细胞，但对除B淋巴细胞以外的正常白细胞无显著反应。KG2032可识别一部分HLA-DRB1分子，具体是那些第86位氨基酸不是天冬氨酸的亚型。另外，KG2032与非造血组织的反应极低。这些结果表明，在携带KG2032可识别的HLA-DRB1等位基因，并接受来自KG2032不可识别型等位基因供者的allo-HCT的患者中，KG2032的反应性对白血病细胞高度特异。基于KG2032构建的CAR T细胞或自然杀伤（NK）细胞在雌性小鼠的临床前模型中展现出显著抗白血病活性。这项研究为无法通过常规allo-HCT获得治愈的AML患者提供极具前景的治愈策略。

3.Engineered bacteria for near-infrared light-inducible expression of cancer therapeutics

用于近红外光诱导表达抗癌治疗物的工程化细菌

上海基因组编辑与细胞治疗前沿科学中心、生物医药合成生物学研究中心、上海市调控生物学重点实验室、华东师范大学上海自然科学研究院（SANS）生物医学研究所和生命科学学院（SANS）

Abstract

Bacteria-based therapies hold great promise for cancer treatment due to their selective tumor colonization and proliferation. However, clinical application is hindered by the need for safe, precise control systems to regulate local therapeutic payload expression and release. Here we developed a near-infrared (NIR) light-mediated PadC-based photoswitch (NETMAP) system based on a chimeric phytochrome-activated diguanylyl cyclase (PadC) and a cyclic diguanylate monophosphate-dependent transcriptional activator (MrkH). The NETMAP-engineered bacteria exhibited antitumor performance in mouse tumor models with different levels of immunogenicity. Specifically, in immunogenic lymphoma tumors, NIR-induced PD- L1 and CTLA-4 nanobodies enhanced the activation of adaptive immunity. In low-immunogenic tumors-including mouse-derived colon cancer models, an orthotopic human breast cancer cell line-derived xenograft model and a colorectal cancer patient-derived xenograft model-NIR-induced azurin and cytolysin A predominantly led to tumor inhibition. Our study identifies an NIR light-mediated therapeutic platform for engineered bacteria- based therapies with customizable outputs and precise dosage control.

摘要

基于细菌的肿瘤治疗策略因其对肿瘤的选择性定植和增殖能力，在癌症治疗中展现出重要应用前景。然而，但现有技术仍面临治疗因子表达时空控制不精确、安全性不足等关键挑战。本研究开发了一种由近红外（NIR）光调控的PadC光控系统（NETMAP），该系统基于嵌合型植物光敏酶活化的二鸟苷酸环化酶（PadC）和一种环二鸟苷酸单磷酸依赖的转录激活因子（MrkH）。在不同免疫原性水平的小鼠肿瘤模型中，经过NETMAP工程改造的细菌均展现出显著抗肿瘤效果。具体而言，在免疫原性较高的淋巴瘤模型中，NIR诱导表达的PD-L1和CTLA-4纳米抗体有效增强了适应性免疫反应的激活；而在免疫原性较低的肿瘤中——包括小鼠结肠癌模型、人源乳腺癌细胞正位异种移植模型以及结直肠癌患者来源的异种移植模型——NIR诱导表达的蓝素蛋白和溶血素A主要实现了肿瘤抑制。本研究提出了一种近红外光调控的治疗平台，适用于工程化细菌疗法，具备输出可定制、剂量精准控制等优势，为癌症治疗提供了新的思路与策略。

4.Targeting the histone reader ZMYND8 inhibits antiandrogen-induced neuroendocrine tumor transdifferentiation of prostate cancer

靶向组蛋白识别蛋白ZMYND8可抑制抗雄激素诱导的前列腺癌神经内分泌肿瘤转分化

中国科学院上海营养与健康研究所组织微环境与肿瘤重点实验室

Abstract

The transdifferentiation from adenocarcinoma to neuroendocrine prostate cancer (NEPC) in men confers antiandrogen therapy resistance. Here our analysis combining CRISPR-Cas9 screening with single-cell RNA sequencing tracking of tumor transition demonstrated that antiandrogen-induced zinc finger MYND-type containing 8 (ZMYND8)-dependent epigenetic programming orchestrates NEPC transdifferentiation. Ablation of Zmynd8 prevents NEPC development, while ZMYND8 upregulation mediated by achaete-scute homolog 1 promotes NEPC differentiation. We show that forkhead box protein MI (FOXMI) stabilizes ZMYND8 binding to chromatin regions characterized by H3K4mel-H3K14ac modification and FOXM1 targeting. Antiandrogen therapy releases the SWI/SNF chromatin remodeling complex from the androgen receptor, facilitating its interaction with ZMYND8-FOXMI to upregulate critical neuroendocrine lineage regulators. We develop iZMYND8-34, a small molecule designed to inhibit ZMYND8's histone recognition, which effectively blocks NEPC development. These findings reveal the critical role of ZMYND8-dependent epigenetic programming induced by androgen deprivation therapy in orchestrating lineage fate. Targeting ZMYND8 emerges as a promising strategy for impeding NEPC development.

摘要

前列腺腺癌向神经内分泌前列腺癌（NEPC）的转分化是男性患者对抗雄激素治疗产生耐药性的关键机制。本研究结合CRISPR-Cas9筛选与单细胞RNA测序追踪肿瘤演变，揭示了抗雄激素诱导的锌指MYND型蛋白8（ZMYND8）依赖性表观遗传调控网络在NEPC转分化过程中的核心调控作用。敲除Zmynd8可抑制NEPC的发生，而由achaete-scute同源基因1介导的ZMYND8上调则促进NEPC分化。进一步研究发现，叉头盒蛋白M1（FOXM1）可稳定ZMYND8在染色质上的结合，该结合位点具有H3K4me1–H3K14ac表观遗传修饰特征，并为FOXM1的靶向区域。抗雄激素治疗会使SWI/SNF染色质重塑复合物从雄激素受体上释放，进而促进其与ZMYND8–FOXM1复合物的相互作用，从而上调关键神经内分泌谱系调控因子。基于此，研究者开发了一种小分子iZMYND8-34，旨在特异性抑制ZMYND8对组蛋白的识别，能有效阻断NEPC的发生。总的来说，该研究揭示了雄激素剥夺治疗诱导的ZMYND8依赖性表观遗传程序在谱系命运调控中的关键作用，并显示出靶向ZMYND8是一种具有潜力的NEPC干预策略。

Design of sensitive monospecific and bispecific synthetic chimeric T cell receptors for cancer therapy

用于癌症治疗的高敏感性单特异性和双特异性合成嵌合T细胞受体的设计

美国华盛顿州西雅图弗雷德-哈钦森癌症中心转化科学与治疗部

Abstract

The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) is effective in B cell malignancies. However, the persistence of cancer cells with low levels or complete absence of the target antigen, thereby evading detection by CAR T cells, leads to relapse. These evasion mechanisms highlight the need for receptors with enhanced sensitivity and multispecificity. We introduce a synthetic chimeric T cell receptor (ChTCR) that confers superior antigen sensitivity compared with CARS and previous hybrid TCR designs and is readily adapted for bispecific targeting. ChTCRs replicate the structure of natural TCRs, form classical immune synapses and demonstrate TCR-like signaling. T cells expressing bispecific ChTCRs (Bi-ChTCRs) are more effective than bispecific CAR T cells in eradicating tumors with heterogeneous antigen expression in vivo in female mice. The Bi-ChTCR architecture is resilient and can be designed to target pairs of B cell and multiple myeloma antigens. These findings provide a widely applicable strategy to combat tumor heterogeneity and prevent relapse.

摘要

表达嵌合抗原受体（CAR）的T细胞过继转移治疗在B细胞恶性肿瘤中已展现出显著疗效。然而，部分癌细胞通过下调目标抗原的表达水平，从而逃避免疫系统中CAR T细胞的识别，导致疾病复发。这类免疫逃逸机制凸显了开发具备更高抗原敏感性和多特异性的受体系统的必要性。本研究在此提出一种新型合成的嵌合T细胞受体（ChTCR），其抗原敏感性优于传统CAR和以往的杂合TCR设计，并可轻松适配双特异性靶向结构。ChTCR仿照天然TCR的结构，能形成经典免疫突触，并展现出类似TCR的信号传导特性。研究表明，表达双特异性ChTCR（Bi-ChTCR）的T细胞在体内（雌性小鼠模型中）清除具有异质性抗原表达的肿瘤时，比双特异性CAR T细胞更为有效。Bi-ChTCR的结构稳定，可广泛设计用于靶向B细胞和多发性骨髓瘤等多种抗原组合。上述研究成果为应对肿瘤抗原异质性、预防治疗后复发提供了一种广泛适用的治疗策略。

6.A Gremlin 1-expressing splenic niche cell population restrains chronic myeloid leukemia by antagonizing the BMP pathway

一种表达Gremlin 1的脾脏微环境细胞群通过拮抗BMP通路抑制慢性髓性白血病的发展

上海交通大学医学院、生物医学工程学院、仁济医院泌尿外科、仁济-Med-X 干细胞研究中心、肿瘤系统医学国家重点实验室

Abstract

The spleen plays a critical role in the pathogenesis of leukemia. However, our understanding of the splenic niche is very limited. Herein, we report that induced expression of the secreted protein Gremlin 1 in a mouse model restrains chronic myeloid leukemia (CML) progression and synergizes with tyrosine kinase inhibitor treatment, whereas blockade of Gremlin 1 promotes CML development. Intriguingly, the effect of Gremlin 1 is most evident in the spleen but not in the bone marrow. Gremlin 1 induces apoptosis of leukemic stem cells via antagonizing the BMP pathway. Single-cell RNA sequencing and experimental validation together show that Gremlin 1 marks a unique stromal cell population in the spleens of both mice and humans. Genetic ablation of Gremlin 1+ cells leads to accelerated CML progression. Collectively, Gremlin 1 and Gremlin 1+ cells are key defensive niche components in the spleen that limit CML progression, revealing an unprecedented mechanism for the body to fight off leukemia.

摘要

尽管脾脏在白血病发生发展中起关键作用，但其微环境的调控机制尚不明确。本研究发现，在小鼠模型中诱导分泌蛋白Gremlin 1的表达可抑制慢性髓性白血病（CML）的进展，并与酪氨酸激酶抑制剂（TKI）治疗协同增效；相反，阻断Gremlin 1则会加速CML恶化。有趣的是，Gremlin 1的抑癌作用在脾脏微环境中尤为显著，而在骨髓中则不明显。机制研究显示，Gremlin 1通过拮抗BMP通路诱导白血病干细胞（LSCs）凋亡。单细胞RNA测序结合实验验证表明，Gremlin 1标记了小鼠和人类脾脏中一类独特的基质细胞群。基因敲除Gremlin 1阳性细胞会加速CML的进展。综上所述，Gremlin 1及其阳性细胞构成了脾脏中限制CML进展的重要防御性微环境成分，揭示了机体抵御白血病的一种前所未有的机制。

7.Systemic rewiring of dendritic cells by melanoma- secreted midkine impairs immune surveillance and response to immune checkpoint blockade黑色素瘤分泌的Midkine系统性重塑树突状细胞，削弱了免疫监视功能并降低了对免疫检查点抑制治疗的应答

西班牙国家癌症研究中心（CNIO）分子肿瘤学项目黑色素瘤实验室

Abstract

Cutaneous melanomas express a high number of potential neoepitopes, yet a substantial fraction of melanomas shift into immunologically cold phenotypes. Using cellular systems, mouse models and large datasets, we identify the tumor-secreted growth factor midkine (MDK) as a multilayered inhibitor of antigen-presenting cells. Mechanistically, MDK acts systemically in primary tumors, lymph nodes and the bone marrow, promoting a STAT3- mediated impairment of differentiation, activation and function of dendritic cells (DCs),particularly, conventional type 1 DCs (cDCIs). Furthermore, MDK rewires DCs toward a tolerogenic state, impairing CD8+ T cell activation. Downregulating MDK improves DC- targeted vaccination, CD40 agonist treatment and immune checkpoint blockade in mouse models. Moreover, we present an MDK-associated signature in DCs that defines poor prognosis and immune checkpoint blockade resistance in individuals with cancer. An inverse correlation between MDK- and cDC1-associated signatures was observed in a variety of tumor types, broadening the therapeutic implications of MDK in immune-refractory malignancies.

摘要

尽管皮肤黑色素瘤表达大量潜在的新抗原，但其中相当一部分会转变为免疫“冷”表型（即缺乏免疫细胞浸润的状态）。本研究通过整合细胞系统、小鼠模型和临床大型数据集的分析发现，肿瘤分泌的生长因子Midkine（MDK）是一种多层次抑制抗原呈递细胞的因子。具体而言，MDK在原发肿瘤、淋巴结及骨髓中发挥激活STAT3信号通路，从而损害树突状细胞（DCs）——尤其是传统I型树突状细胞（cDC1）的分化、激活与功能。此外，MDK可重塑DCs向耐受性状态转变，从而削弱CD8+ T细胞的激活能力。在小鼠模型中，抑制MDK表达可增强基于DC的疫苗治疗、CD40激动剂治疗以及免疫检查点抑制治疗的效果。此外，研究者还建立了一个与MDK相关的DC特征表达谱，它可用于预测癌症患者的不良预后及免疫检查点抑制治疗的耐药性。值得注意的是，在多种肿瘤类型中，MDK相关特征与cDC1相关特征之间呈负相关，这进一步拓展了MDK在免疫耐受性肿瘤中的治疗应用前景。

8.Targeting both death and paracaspase domains of MALT1 with antisense oligonucleotides overcomes resistance to immune-checkpoint inhibitors利用反义寡核苷酸同时靶向MALT1的死亡结构域和副半胱天冬酶结构域，可克服对免疫检查点抑制剂的耐药性

中国北京清华大学基础医学院肿瘤生物学研究中心

Abstract

Targeting MALTI's paracaspase activity has been explored for B cell lymphoma and solid tumors. While the role of MALT1 in promoting cancer cell proliferation has been investigated its involvement in immune evasion is unclear. Here we report that MALT1 promotes immune evasion through its paracaspase and death domain. In a paracaspase-dependent manner, MALT1 protects CD274 mRNA from degradation by its cleavage of ROQUIN1 and ROQUIN2. Ir a death-domain-dependent manner, MALT1 promotes the proliferation and polarization of tumor-associated macrophages to generate an immunosuppressive tumor microenvironment. Targeting MALT1 with antisense oligonucleotides inhibits PD-L1 expression in patient-derived tumor cells and suppresses the proliferation and M2-like polarization of tumor-associated macrophages isolated from patients with cancer. In preclinical models of solid tumors in female mice, treatment with MALT1 antisense oligonucleotides overcomes resistance to immune-checkpoint inhibitors. Together, our study demonstrates that targeting MALT1 is a potential strategy to overcome immune- checkpoint inhibitor resistance.

摘要

靶向MALT1的副半胱天冬酶活性已被用于研究B细胞淋巴瘤和实体瘤。尽管MALT1在促进癌细胞增殖方面的作用已有报道，但其在免疫逃逸中的作用尚不明确。本研究发现，MALT1通过其副半胱天冬酶结构域和死亡结构域共同促进免疫逃逸。在副半胱天冬酶依赖的机制中，MALT1通过切割ROQUIN1和ROQUIN2，阻止CD274（PD-L1）mRNA的降解，维持PD-L1的表达。而在死亡结构域依赖的机制中，MALT1促进肿瘤相关巨噬细胞（TAMs）的增殖与极化，进而形成免疫抑制性肿瘤微环境。利用反义寡核苷酸靶向MALT1可抑制患者来源肿瘤细胞中的PD-L1表达，并抑制从癌症患者体内分离的肿瘤相关巨噬细胞的增殖和类M2型极化。在雌性小鼠的实体瘤临床前模型中，使用MALT1反义寡核苷酸治疗可克服对免疫检查点抑制剂的耐药性。综上所述，靶向MALT1是一种有前景的策略，可用于克服免疫检查点抑制治疗的耐药问题。

9.Adoptively transferred tumor-specific IL-9-producing cytotoxic CD8+ T cells activate host CD4+ T cells to control tumors with antigen loss

过继转移的肿瘤特异性IL-9产生性细胞毒性CD8+ T细胞可激活宿主CD4+ T细胞，从而控制抗原缺失的肿瘤

美国休斯顿卫理公会尼尔癌症中心

Abstract

Host effector CD4+ T cells emerge as critical mediators for tumor regression but whether they can be activated by adoptively transferred CD8+ T cells remains unknown. We previously reported that adoptive transfer of interleukin 9 (IL-9)-producing cytotoxic CD8+ T (Tc9) cells achieved long-term control of tumor growth. Here, we demonstrate that murine tumor- specific Tc9 cells control the outgrowth of antigen-loss relapsed tumors by recruiting and activating host effector CD4+ T cells. Tc9 cells secreted IL-24 and recruited CCR7-expressing conventional type 2 dendritic cells (cDC2 cells) into tumor-draining lymph nodes to prime host CD4+ T cells against relapsed tumors. Host CD4+ T cell or cDC2 deficiency impaired the ability of Tc9 cells to control relapsed tumor outgrowth. Additionally, intratumoral IL24 expression correlates with cDC2 and CD4+ T cell gene signatures in human cancers and their expression is associated with better patient survival. This study reports a mechanism for activation of tumor-specific CD4+ T cells in vivo.

摘要

宿主效应性CD4+ T细胞已被证实在肿瘤消退中发挥关键作用，但其是否能否被过继转移的CD8+ T细胞激活仍不明确。此前的研究表明，过继转移分泌白细胞介素9（IL-9）的细胞毒性CD8+ T细胞（Tc9细胞）能够实现对肿瘤生长的长期控制。本研究进一步发现，小鼠中肿瘤特异性Tc9细胞可以通过招募并激活宿主效应性CD4+ T细胞，显著抑制抗原缺失变异体（ALV）肿瘤的复发进展。具体而言，Tc9细胞分泌IL-24，招募表达CCR7的传统II型树突状细胞（cDC2）进入肿瘤引流淋巴结，进而激活宿主CD4+ T细胞应对复发肿瘤。在宿主CD4+ T细胞或cDC2缺失的情况下，Tc9细胞对复发肿瘤的控制的能力显著减弱。此外，在人类肿瘤组织中，IL-24表达水平与cDC2和CD4+T细胞的基因特征呈正相关，其高表达水平也与患者更好的生存预后相关。综上，该研究揭示了Tc9细胞通过IL-24介导cDC2招募与CD4⁺T细胞激活，从而控制肿瘤复发的关键机制，为肿瘤免疫治疗提供了新的策略依据。

汇报人：吴婷婷

导师：任建君

审核：代一冯、夏晓旭、任建君