【Cancer Cell】2025年11-12月刊

论文导读

期刊介绍：

Cancer Cell创刊于2002年，由CELL PRESS出版商出版，收稿方向涵盖医学-肿瘤学全领域，在行业领域中学术影响力很大，属于TOP期刊，国际一流期刊。审议手稿的主要标准是研究是否在回答与自然发生的癌症有关的重要问题方面取得重大进展。影响因子指数48.8。2025年11-12月一共发表29篇，包括Commentary 2篇，Preview 7篇，Review 1篇，Article 17篇，Report 1篇，Correction 1篇。

Nov 10, 2025

Volume 43Issue 11p1973-2174

2025年1月一共发表15篇，包括Commentary 1篇，Preview 3篇，Review 1篇，Article 8篇，Report 1篇，Correction 1篇。

1.Comprehensive tumor-immune profiling reveals mediators of paradoxical immune sensitivity in sarcomatoid renal cell carcinoma

全面的肿瘤-免疫图谱揭示肉瘤样肾癌中矛盾性免疫敏感性的介导因素

Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA

美国纽约州布法罗市 Roswell Park 综合癌症中心 免疫学系

Renal cell carcinoma with sarcomatoid features (sRCC) is a highly aggressive tumor type yet preferentially responds to immune checkpoint blockade (ICB). To better understand microenvironmental mediators of this paradoxical immune sensitivity, we performed single-cell analyses of human sRCC tumors compared against clear cell RCC (ccRCC), with validation spatially and in bulk transcriptomic datasets totaling over 3,000 RCC tumors. We describe a robust immune network in sRCC using these orthogonal approaches: tumor-infiltrating T cells in sRCC are more activated, and subsequently exhausted, while being enriched for CXCL13 expression. Congruently, tertiary lymphoid structures are pervasive in sRCC, paralleling functional enrichment of humoral immune activity. Tumor clone analysis revealed increased iron-associated programs in sRCC, presenting a potential vulnerability. We furthermore leveraged the paradoxical biology of sRCC to derive a genomic dedifferentiation signature (GDS) that, while negatively prognostic, identifies patients most likely to benefit from ICB across cohorts and tumor types.

具有肉瘤样特征的肾癌（sRCC）是一类高度侵袭性的肿瘤，但却对免疫检查点抑制剂（ICB）表现出良好的应答。为了更好理解这种矛盾性免疫敏感性的微环境机制，该研究对人类 sRCC 样本进行了单细胞分析，并与透明细胞肾癌（ccRCC）进行比较，进一步在总计超过 3000 例 RCC 的空间组学和 bulk 转录组数据集中进行了验证。通过这些多角度分析，研究发现sRCC 中具有强有力的免疫网络：其中的肿瘤浸润 T 细胞活化程度更高，随后进入耗竭状态，同时富集表达 CXCL13。与之相一致的结果是，三级淋巴结构在 sRCC 中普遍存在，与体液免疫活性的功能富集相对应。肿瘤克隆分析显示，sRCC中铁相关程序升高，提示其可作为潜在的治疗靶点。进一步地，研究基于 sRCC 这种矛盾的生物学特征提出了一种基因组去分化特征（GDS），该特征虽与预后不良相关，但能够跨队列和肿瘤类型识别最有可能从 ICB 获益的患者。

2.Enhancing anti-tumor immunity of natural killer cells through targeting IL-15R signaling

通过靶向 IL-15R 信号增强自然杀伤细胞的抗肿瘤免疫能力

oNKo-innate Pty Ltd., Moonee Ponds, VIC 3039, Australia

澳大利亚维多利亚州穆尼庞兹 oNKo-innate 私人有限公司

Interleukin-15 receptor (IL-15R) agonists induce anti-tumor immunity in pre-clinical models. However, dose-limiting toxicity has hampered their clinical development. We performed genome-wide CRISPR screens to reveal the complete IL-15R signaling mechanism in natural killer (NK) cells and discovered that ubiquitin-dependent IL-15R degradation is the dominant mechanism restraining IL-15R signaling. Key hits included the NEDD8 E2-conjugating enzyme UBE2F, the ubiquitin E3-ligase ARIH2, and Cullin-5 RING E3 ligase (CRL5) members. We found that UBE2F was required for neddylation and activation of CUL5, whereas ARIH2 contributed to CRL5-mediated IL-15RB degradation. Ablation of ARIH2 or UBE2F increased IL-15RB surface expression and enhanced signaling, resulting in proinflammatory cytokine production and augmented natural and CAR-mediated cytotoxicity. In mice lacking Arih2, Rnf7, or Ube2f, we observed that the IL-15R hyperresponsive NK cells exhibited superior in vivo anti-tumor immunity against primary and disseminated metastatic tumors. Thus, we have identified the enzymes UBE2F and ARIH2 as tractable immunotherapy drug targets.

白介素-15受体（IL-15R）激动剂在临床前模型中可诱导抗肿瘤免疫，但剂量相关的毒性限制了其临床应用。该研究进行了全基因组CRISPR筛选，以解析自然杀伤（NK）细胞中完整的IL-15R信号机制，并发现依赖泛素的IL-15R降解是限制IL-15R信号的主要机制。其中的关键基因包括NEDD8E2结合酶UBE2F、泛素E3连接酶ARIH2和Cullin-5RINGE3连接酶（CRL5）的成员。该研究发现UBE2F对CUL5的NEDD8化及其激活是必需的，而ARIH2则参与CRL5介导的IL-15RB降解。删除ARIH2或UBE2F会增加IL-15RB的细胞表面表达并增强信号传导，从而导致促炎细胞因子的产生，以及增强自然的和CAR介导的细胞毒性。研究进一步在在缺乏Arih2、Rnf7或Ube2f的小鼠中验证，发现IL-15R高反应性的NK细胞在原发和转移性肿瘤模型中均表现出更强的体内抗肿瘤效应。总的来说，该研究发现酶UBE2F和ARIH2可以作为可开发的免疫治疗药物靶点。

3.Safety and efficacy of a STAT3-targeted cyclic oligonucleotide: From murine models to a phase 1 clinical trial in pet cats with oral cancer

靶向STAT3的环状寡核苷酸的安全性与有效性：从小鼠模型到宠物猫口腔癌I期临床试验

Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, CA, USA

美国加州大学旧金山分校医学院头颈外科系

STAT3 is an oncogenic transcription factor that activates cancer cell signaling and induces an immunosuppressive immune environment, making it an attractive therapeutic target. Transcription factors are exceptionally challenging targets and there are no Food and Drug Administration-approved STAT3 inhibitors. We previously reported positive pharmacodynamics of a linear STAT3 decoy oligonucleotide administered intratumorally in a phase 0 trial in patients with head and neck cancer squamous cell carcinoma (HNSCC). Here, we describe the anti-tumor and immune effects of a systemically administered cyclic STAT3 decoy (CS3D) in immunocompetent HNSCC murine models and the safety and efficacy of CS3D in a clinical trial in pet cats with HNSCC. Responders in the clinical trial (35% disease control rate) showed significant differences in selected peripheral blood immune parameters as well as elevated PD-1 expression in the tumors compared with non-responders. These findings support a clinical trial of CS3D in HNSCC patients.

STAT3是一种致癌性转录因子，可激活癌细胞信号并诱导免疫抑制性微环境，使其成为具有吸引力的治疗靶点。然而，转录因子极难作为药物靶向对象，目前尚无FDA批准的STAT3抑制剂。研究团队此前曾在一项头颈部鳞状细胞癌（HNSCC）患者的0期试验中，发现肿瘤内注射STAT3诱饵寡核苷酸具有良好的药效学表现。本研究进一步描述了系统给药的环状STAT3诱饵（CS3D）在免疫完备的HNSCC小鼠模型中的抗肿瘤及免疫作用，并报告了CS3D在宠物猫HNSCC I期临床试验中的安全性和有效性。结果发现，临床试验中有反应者（疾病控制率35%）在外周血免疫指标上表现出显著差异，且与无反应者相比，其肿瘤组织中PD-1表达更高。这些发现支持在HNSCC患者中进一步开展CS3D的临床研究。

4.Genome-wide CRISPR screens identify critical targets to enhance CAR-NK cell antitumor potency

全基因组CRISPR筛选鉴定增强CAR-NK细胞抗肿瘤效力的关键靶点

Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

美国德克萨斯大学 MD Anderson 癌症中心，干细胞移植与细胞治疗科

Adoptive cell therapy using engineered natural killer (NK) cells is a promising approach for cancer treatment, with targeted gene editing offering the potential to further enhance their therapeutic efficacy. However, the spectrum of actionable genetic targets to overcome tumor and microenvironment-mediated immunosuppression remains largely unexplored. We performed multiple genome-wide CRISPR screens in primary human NK cells and identified critical checkpoints regulating resistance to immunosuppressive pressures. Ablation of MED12, ARIH2, and CCNC significantly improved NK cell antitumor activity against multiple treatment-refractory human cancers in vitro and in vivo. CRISPR editing augmented both innate and CAR-mediated NK cell function, associated with enhanced metabolic fitness, increased secretion of proinflammatory cytokines, and expansion of cytotoxic NK cell subsets. Through high-content genome-wide CRISPR screening in NK cells, this study reveals critical regulators of NK cell function and provides a valuable resource for engineering next-generation NK cell therapies with improved efficacy against cancer.

采用工程化自然杀伤（NK）细胞的过继细胞疗法是癌症治疗中极具潜力的策略，且靶向基因编辑有望进一步增强其治疗效能。然而，能够克服肿瘤及其微环境介导的免疫抑制的可操作基因靶点仍不清楚。本研究在初级人NK细胞中进行了多项全基因组CRISPR筛选，并鉴定了若干关键检查点，这些基因在对抗免疫抑制压力中具有重要调控作用。进一步实验敲除MED12、ARIH2和CCNC可显著增强NK细胞对多种难治性人类癌症的体外和体内抗肿瘤活性。CRISPR编辑增强了NK细胞的天然及CAR介导功能，其机制与代谢适应性增强、促炎细胞因子分泌增加、以及细胞毒性NK细胞亚群扩增相关。总的来说，通过大规模的全基因组筛选，本研究揭示了NK细胞功能的关键调控因子，并为开发下一代、更高效的NK细胞治疗策略提供了宝贵资源。

5.Long-range cholinergic input promotes glioblastoma progression

远程胆碱能输入促进胶质母细胞瘤进展

Institute of Pathology & Southwest Cancer Center, Glioma Medical Research Center, Southwest Hospital, Third Military Medical University (Army Medical University), and The Key Laboratory of Tumor Immunopathology, The Ministry of Education of China, Chongqing 400038, China中国教育部肿瘤免疫病理学重点实验室；陆军军医大学（第三军医大学）西南医院病理研究所，西南癌症中心，胶质瘤医学研究中心。

Glioblastoma (GBM), the most aggressive primary brain tumor, is shaped by its integration into neural networks. While glutamatergic input is linked to tumor progression, the broader architecture and function of neuron-glioma connectomes remain unclear. Using monosynaptic rabies tracing, we map brain-wide neural input to patient-derived xenografts and reveal a consistent organizational logic: local inputs are primarily glutamatergic, while long-range connections exhibit diverse neurotransmitter profiles, with basal forebrain cholinergic projections emerging as a conserved input across sites. Functionally, presynaptic acetylcholine release promotes GBM progression through muscarinic receptor CHRM3 in a circuit-specific manner. Mechanistically, glutamatergic and cholinergic signals converge to enhance glioma calcium transients but diverge in temporal transcriptional control, with their dual blockade producing additive anti-tumor effects. Therapeutically, the anticholinergic drug scopolamine attenuates glioma growth, whereas the acetylcholinesterase inhibitor donepezil exacerbates disease. These findings reveal the complexity of neuron-glioma connectivity, highlighting long-range neuromodulatory pathways as promising therapeutic targets in GBM.

胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤，其病程受到其与神经网络整合方式的深刻影响。虽然输入谷氨酸能已被证明与肿瘤进展相关，但更广泛的神经元–胶质瘤连接组结构及其功能仍不清楚。本研究使用单突触狂犬病毒示踪技术，对患者来源的异种移植瘤进行全脑输入映射，并揭示了一种一致的组织逻辑：局部输入主要为谷氨酸能，而远程连接则呈现多样的神经递质谱系，其中基底前脑的胆碱能投射在不同部位均为保守存在的输入。功能上，突触前释放乙酰胆碱可通过毒蕈碱受体CHRM3以回路特异性的方式促进GBM进展。机制上，谷氨酸能和胆碱能信号共同增强胶质瘤的钙瞬变，但在转录调控时间尺度上存在差异；同时阻断两者可产生叠加的抗肿瘤效应。治疗方面，抗胆碱药东莨菪碱可抑制胶质瘤生长，而乙酰胆碱酯酶抑制剂多奈哌齐则加剧疾病进展。总的来说，本研究揭示了神经元–胶质瘤连接的复杂性，并强调远程神经调节通路是GBM的潜在治疗靶点。

6.Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAFV600E metastatic colorectal cancer

针对微卫星稳定（MSS）BRAFV600E转移性结直肠癌的恩考芬尼+塞克替尼+纳武利尤单抗联合治疗的 I/II 期临床试验

Departments of Gastrointestinal Medical Oncology, Houston, TX 77030, USA

美国得克萨斯州休斯顿胃肠道肿瘤内科

The BRAF inhibitor encorafenib and anti-epidermal growth factor receptor (EGFR) antibody cetuximab modestly improve survival for patients with microsatellite stable (MSS) BRAFV600E metastatic colorectal cancer (mCRC), characterized by higher immune activation than MSS BRAFwild-type colorectal cancer (CRC). In this phase 1/2 study (NCT04017650) of 26 participants with MSS BRAFV600E mCRC who received encorafenib, cetuximab, and anti-PD-1 antibody nivolumab, we report an overall response rate of 50% (95% confidence interval [CI] 29–71) and median progression-free survival of 7.4 months (95% CI, 5.6–9.6). Transcriptomic profiling of pretreatment biopsies and extracellular vesicle RNA (evRNA) isolated from plasma show enrichment of non-canonical mitogen-activated protein kinase (MAPK) signaling and immune activation signatures for responders. Complement pathway activation enriches in non-responder biopsies. On serial evRNA profiling, decreased MAPK signature and increased interferon gamma response signature associate with sustained treatment benefit. MSS BRAFV600E mCRC with baseline MAPK activation and immune activation signatures may benefit from the triple combination but not with complement pathway activation.

BRAF抑制剂恩考芬尼联合抗EGFR抗体塞克替尼可使微卫星稳定（MSS）的BRAFV600E型转移性结直肠癌（mCRC）患者生存获得改善，而该患者群体较MSS的BRAF野生型CRC表现出更高的免疫激活状态。在本I/II期临床试验（NCT04017650）中，26名MSS的BRAFV600E mCRC患者接受恩考芬尼、塞克替尼和抗PD-1抗体纳武利尤单抗的三联治疗，研究观察到客观缓解率为50%（95%CI 29–71），无进展生存期中位数为7.4个月（95%CI 5.6–9.6）。治疗前的肿瘤活检及血浆来源的细胞外囊泡RNA（evRNA）的转录组分析显示，反应者富集非经典MAPK信号通路和免疫激活特征；而非反应者的肿瘤中补体通路激活更为显著。在连续evRNA分析中，MAPK信号下降及IFN-γ反应增加与持续获益相关。总体而言，基线呈现MAPK激活和免疫激活特征的MSS的BRAFV600E mCRC患者可能从该三联疗法中获益，而补体通路激活者可能无效。

7.Ketogenic diet inhibits glioma progression by promoting gut microbiota-derived butyrate production

生酮饮食通过促进肠道菌群来源的丁酸生成抑制胶质瘤进展

陆军军医大学（第三军医大学）西南医院：病理研究所、胶质瘤医学研究中心、西南癌症中心、第一附属医院；基础医学院；教育部肿瘤免疫病理学重点实验室

The ketogenic diet (KD) is a potential therapeutic strategy for glioma; however, the underlying mechanisms remain unclear. Herein, we first identify that glioma patients exhibit a distinct gut microbial profile characterized by reduced butyrate-producing bacteria abundance, particularly R. faecis, along with decreased butyrate levels. Notably, KD reshapes the gut microbiota especially enriching A. muciniphila in a mucin-2-dependent manner, elevates butyrate production, and activates caspase-3 in microglia. These changes promote an anti-tumor microglial phenotype, ultimately suppressing glioma progression in mice. Crucially, KD’s anti-glioma effect is notably abolished by antibiotics treatment; germ-free condition; or specific depletion of mucin-2, microglia, or microglial caspase-3. Furthermore, butyrate, A. muciniphila, R. faecis, or A. muciniphila plus R. faecis restores KD-induced microglial caspase-3 activation and the anti-tumor phenotype of microglia in antibiotics-treated or germ-free mice. These findings highlight that targeting the gut microbiota by KD or supplementing with butyrate could be an effective strategy for glioma therapy.

生酮饮食（KD）被认为是胶质瘤潜在的治疗策略，但其机制尚未明晰。本研究首先发现，胶质瘤患者的肠道微生物组成具有特征性改变：产丁酸菌（特别是R.faecis）减少，丁酸水平下降。KD可重塑肠道菌群，特别是以黏蛋白2（mucin-2）依赖方式富集A. 胶原菌属，提高丁酸产量，并激活小胶质细胞中的caspase-3。这些变化促成抗肿瘤的小胶质细胞表型，从而显著抑制小鼠胶质瘤进展。重要的是，抗生素处理、无菌环境、或特异性耗竭mucin-2、小胶质细胞、或小胶质caspase-3均可显著削弱KD的抗胶质瘤效果。此外，丁酸、A. 胶原菌属、R. 肠杆菌或两者联合可在接受抗生素或无菌处理的小鼠中恢复KD诱导的小胶质caspase-3活化及其抗肿瘤表型。本研究表明，通过KD调节肠道菌群或直接补充丁酸可能成为治疗胶质瘤的有效策略。

8.Protein-based classification reveals an immune-hot subtype in IDH mutant astrocytoma with worse prognosis

基于蛋白的分型揭示一种免疫热型的预后更差的IDH突变星形细胞瘤亚型

Division of Life Science, Department of Chemical and Biological Engineering, State Key Laboratory of Nervous System Disorders, The Hong Kong University of Science and Technology, Hong Kong SAR, China

中国香港特别行政区，香港科技大学生命科学部；化学与生物工程学系；神经系统疾病国家重点实验室

Intertumoral heterogeneity complicates treatment of IDH-mutant astrocytoma. We analyze spatiotemporal multi-omics data and discover four clusters: adipogenesis/fatty-acid-metabolism (AFM), proliferative/progenitor (PPR), immune/mesenchymal-enriched (IME), and neuronal (NEU). PPR and IME are associated with poorer prognosis, a result validated in The Cancer Genome Atlas (TCGA) and a Chinese cohort of 273 IDH-mutant astrocytomas. Longitudinal analysis of 189 initial-recurrent pairs shows an evolutionary shift toward PPR/IME subtypes. Mechanistically, PPR is enriched for CDKN2A/B deletions, whereas IME features increased gemistocytic differentiation (GD) and infiltration by exhausted T cells and plasma cells. Spatial multi-omics link GD morphology to mesenchymal-like (MES-like) tumor cell aggregates and lymphocyte-rich niches. MES-like tumor cells in IME overexpress interferon-stimulated genes such as GBP1, which we show promotes proliferation and migration. Finally, we develop an AI-powered classifier for patient stratification. Our work delineates protein-based clustering of IDH-mutant astrocytoma and reveals an immune-hot subgroup that may inform therapeutic development.

肿瘤间异质性增加了IDH突变星形细胞瘤的治疗复杂性。本研究利用时空多组学数据解析出四种肿瘤亚型：脂肪生成/脂肪酸代谢（AFM）、增殖/祖细胞样（PPR）、免疫/间质富集（IME）以及神经元样（NEU）。其中PPR和IME与更差的预后相关，这一结果在TCGA队列及一个包含273例中国患者的队列中得到验证。对189对初诊–复发样本进行纵向分析表明，肿瘤演化趋向PPR/IME亚型。在机制层面，PPR亚型富集CDKN2A/B缺失，而IME具有更高的巨噬样分化以及耗竭T细胞和浆细胞的浸润。空间多组学进一步将巨噬样分化形态与近端间质样（MES-like）肿瘤细胞团簇及富含淋巴细胞的微环境联系起来。IME中的MES-like细胞高表达干扰素刺激基因，如GBP1，并被证明可促进肿瘤增殖和迁移。最后，研究开发了一种AI驱动的分类器用于患者分层。总的来说，本研究揭示了一种基于蛋白的IDH突变星形细胞瘤分型，并发现一种免疫热但预后较差的亚型，有望为治疗策略提供参考。

Dec 08, 2025

Volume 43Issue 12p2175-2326

2025年12月一共发表14篇，包括Commentary 1篇，Preview 4篇，Article 9篇。

9.Extrachromosomal DNA associates with nuclear condensates and reorganizes chromatin structures to enhance oncogenic transcription

染色体外DNA与细胞核凝聚体相互作用并重塑染色质结构以增强致癌转录

Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA

美国华盛顿大学基因组科学系

Extrachromosomal, circular DNA (ecDNA) is a prevalent oncogenic alteration in cancer genomes, often associated with aggressive tumor behavior and poor patient outcome. While previous studies proposed a chromatin-based mobile enhancer model for ecDNA-driven oncogenesis, its precise mechanism and impact remains unclear across diverse cancer types. Our study, utilizing advanced multi-omics profiling, epigenetic editing, and imaging approaches in three cancer models, reveals that ecDNA hubs are an integrated part of nuclear condensates and exhibit cancer-type specific chromatin connectivity. Epigenetic silencing of the ecDNA-specific regulatory modules or chemically disrupting nuclear condensates breaks down ecDNA hubs, displaces MED1 co-activator binding, inhibits oncogenic transcription, and promotes cell death. These findings substantiate the trans-activator function of ecDNA and underscore a structural mechanism driving oncogenesis. This refined understanding expands our views of oncogene regulation and opens potential avenues for alternative therapeutic strategies in cancer treatment.

染色体外环状DNA（ecDNA）是癌症基因组中常见的致癌突变，通常与肿瘤侵袭性增强及患者预后不良相关。尽管既往研究提出了ecDNA通过“可移动增强子”介导致癌的模型，但其精确机制及在不同癌种中的影响仍不完全清楚。本研究利用多组学分析、表观遗传编辑及成像技术，在三个癌症模型中揭示：ecDNA形成的“hub”是细胞核凝聚体的重要组成部分，并呈现癌种特异性的染色质互作结构。通过表观遗传沉默ecDNA特异性的调控模块，或化学方式破坏核凝聚体，可导致ecDNA hub解体、MED1共同激活因子结合减少、致癌转录受抑以及肿瘤细胞死亡。本研究证实了ecDNA的跨染色体激活（trans-activation）功能，并强调其在驱动致癌过程中的结构性机制。这一更细致的认识拓展了研究者对癌基因表达调控方式的理解，并为癌症治疗提供潜在的新策略。

10.Restraint of cancer cell plasticity by spatial homotypic clustering

空间同质聚集能抑制癌细胞可塑性

Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL 33136, USA

美国迈阿密大学米勒医学院 Sylvester综合癌症中心

Tumor heterogeneity fueled by plasticity of cancer cells is a key to therapy failure. Here, we define the role of proximal communications of malignant cells in glioblastoma plasticity. We find that tumor cell state coherence is maximal in cells organized in homotypic clusters with defined relationships with non-malignant cells, whereas randomly dispersed cells downregulate the original state, acquire alternative phenotypes and exhibit changes in the microenvironment. We demonstrate the intrinsic propensity of glioblastoma cells to develop into clustered and dispersed spatial patterns in orthotopic mouse models and experimentally validate the cell state-specific mechanisms of cell-cell adhesion that prevent phenotype deviation with pharmacologic perturbations in patients-derived glioblastoma models. We establish the generality of “homotypic clustered cell identity” in circulating clustered and single breast cancer cells and show that the glioblastoma glycolytic-plurimetabolic dispersed cellular state uniquely confers shorter survival, thus assigning clinical significance to the spatial patterning of cancer cells in human tumors.

由癌细胞高度可塑性推动的肿瘤异质性是治疗失败的重要原因。本研究阐明了恶性细胞在胶质母细胞瘤中的近距离空间通讯对细胞可塑性的作用。结果发现，当肿瘤细胞以同质聚集的空间结构组织时，其细胞状态的一致性达到最高，并与周围非肿瘤细胞形成特定关系；相反，随机分散的肿瘤细胞则会下调原有细胞状态、获得替代表型，并改变其局部微环境。在小鼠原位模型中，研究验证了胶质母细胞瘤细胞内在地倾向产生“聚集”与“分散”两种空间模式。进一步实验证实，细胞状态特异性的细胞黏附机制能够在患者来源模型中通过药物干预维持其表型稳定性。研究还揭示了“同质聚集细胞身份”在乳腺癌循环肿瘤细胞中的普遍性，并发现糖酵解–多代谢型的分散模式细胞与显著更短的生存期相关，从而强调癌细胞空间结构在临床上的重要意义。

11.Single-cell resolution spatial analysis of antigen-presenting cancer-associated fibroblast niches

单细胞分辨率的抗原呈递型肿瘤相关成纤维细胞生态位空间图谱分析

Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

美国德州大学西南医学中心外科系

Recent studies identify a unique subtype of cancer-associated fibroblasts (CAFs) termed antigen-presenting CAFs (apCAFs), which remain poorly understood. To gain a comprehensive understanding of the origin and function of apCAFs, we construct a fibroblast molecular atlas across 15 types of tissues and solid tumors. Our integration study unexpectedly reveals two distinct apCAF populations present in most cancer types: one associated with mesothelial-like cells and the other with fibrocytes. Using a high-resolution single-cell spatial imaging platform, we characterize the spatial niches of these apCAF populations. We find that mesothelial-like apCAFs are located near cancer cells, while fibrocyte-like apCAFs are associated with lymphocyte-enriched niches. Additionally, we discovered that both apCAF populations can up-regulate secreted phosphoprotein 1 (SPP1), which facilitates primary tumor formation, peritoneal metastasis, and therapy resistance. Taken together, this study offers an unprecedented resolution in analyzing apCAFs and their spatial niches.

近年研究鉴定出一种特殊的肿瘤相关成纤维细胞（CAF）亚型，即抗原呈递CAF（apCAF），但对其来源与功能仍知之甚少。为全面解析apCAF，本研究构建了覆盖15种组织与实体瘤的成纤维细胞分子图谱。整合分析意外发现，在多数癌种中均存在两类不同起源的apCAF亚群：一类与间皮样细胞相关，另一类与成纤维细胞/单核细胞谱系（fibrocytes）相关。借助高分辨率单细胞空间成像技术，研究鉴定了这两类apCAF的空间生态位：间皮样apCAF位于肿瘤细胞附近，而fibrocyte-like apCAF则富集于淋巴细胞丰富的微环境。此外，两类apCAF均可上调分泌蛋白SPP1，促进原发肿瘤形成、腹膜转移及治疗耐受性。本研究以空间的分辨率描绘了apCAF及其生态位，显著深化对其生物学功能的理解。

12.Sensory neurons drive pancreatic cancer progression through glutamatergic neuron-cancer pseudo-synapses

感觉神经元通过谷氨酸能神经–癌细胞伪突触促进胰腺癌进展

Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany

德国慕尼黑工业大学医学院

Cancers thrive on neuronal input. Here, we demonstrate the presence of pseudo-synaptic connections between sensory nerve endings and cancer cells in an extracerebral cancer, i.e., pancreatic ductal adenocarcinoma (PDAC). These synaptic sites exhibit a selective enrichment of the glutamatergic N-methyl-D-aspartate receptor (NMDA) receptor subunit NMDAR2D (GRIN2D) on the cancer cells, which turns PDAC cells responsive to neuron-derived glutamate and promotes tumor growth and spread. Intriguingly, neurons transform a subset of co-cultured PDAC cells into calcium-responsive cells via GRIN2D-type glutamate receptors at the neuron-cancer pseudo-synapses. We found that the expression of this subunit is due to the increased glutamate availability provided by sensory innervation in a neurotrophic feedforward loop. Moreover, interference with the glutamate-GRIN2D signaling at these neuron-cancer pseudo-synapses markedly improved survival in vivo. This discovery of peripheral cancer-neuron pseudo-synapses may provide an opportunity for cancer-neuroscience-instructed oncological therapies.

肿瘤生长高度依赖神经输入。本研究首次在中枢神经系统以外的肿瘤——胰腺导管腺癌（PDAC）中鉴定出感觉神经末梢与癌细胞之间的伪突触结构。这些伪突触部位在癌细胞上表现出NMDA受体亚基NMDAR2D（GRIN2D）的选择性富集，使其能够响应神经元来源的谷氨酸并促进肿瘤生长与扩散。值得注意的是，神经元可通过GRIN2D依赖的机制，将部分PDAC细胞转化为能够对谷氨酸诱导产生钙信号的“响应型细胞”。研究发现，GRIN2D的表达增加源于感觉神经提供的谷氨酸供应，形成神经营养性正反馈环。进一步阻断伪突触处的谷氨酸–GRIN2D信号可显著延长小鼠生存期。总的来说，该研究揭示了外周肿瘤中的神经–癌细胞伪突触，为“神经–肿瘤互作”指导的癌症治疗策略提供新的可能性。

13.Neoadjuvant nab-paclitaxel plus gemcitabine followed by modified FOLFIRINOX for resectable pancreatic cancer: A randomized phase 3 trial

可切除胰腺癌中新辅助白蛋白紫杉醇联合吉西他滨序贯改良FOLFIRINOX的III期随机试验

Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

浙江大学医学院附属第一医院 肝胆胰外科

This single-center, randomized phase 3 trial (NCT03750669) evaluated sequential neoadjuvant nab-paclitaxel plus gemcitabine followed by modified FOLFIRINOX versus upfront surgery in 324 patients with resectable pancreatic cancer. Patients in the neoadjuvant group received nab-paclitaxel plus gemcitabine followed by modified FOLFIRINOX before surgery and then four cycles of adjuvant therapy (preferably gemcitabine plus capecitabine), while those in the upfront surgery group underwent immediate resection followed by six cycles of adjuvant therapy. The primary endpoint was event-free survival. Notably, 50% of patients had tumors in the pancreatic body or tail. Median event-free survival was 15.3 months (95% confidence interval [CI], 12.6–19.3) versus 10.9 months (95% CI, 9.1–13.5; hazard ratio [HR], 0.71; 95% CI, 0.54–0.93; p = 0.0136). Median overall survival was 35.4 months versus 27.2 months (HR, 0.73; 95% CI, 0.53–1.00; nominal p = 0.0477). Grade ≥3 adverse events occurred in 47.6% versus 30.7% of patients. This neoadjuvant regimen improves event-free survival with manageable safety.

这是一项单中心、随机、III期临床试验（NCT03750669），它比较了新辅助白蛋白紫杉醇联合吉西他滨序贯改良FOLFIRINOX与直接手术治疗在324例可切除胰腺癌患者中的疗效。新辅助组在手术前接受白蛋白紫杉醇+吉西他滨，再序贯改良FOLFIRINOX，术后给予4个周期辅助治疗（优选吉西他滨+卡培他滨）；而直接手术组术后接受6个周期辅助治疗。主要终点为无事件生存期（EFS）。值得注意的是，50%的患者肿瘤位于胰体尾部。结果显示，新辅助组的中位EFS为15.3个月，对比直接手术组的10.9个月（HR=0.71；95%CI，0.54–0.93；p=0.0136）。中位总生存期分别为35.4个月与27.2个月（HR=0.73；95%CI，0.53–1.00；名义p=0.0477）。3级及以上不良事件发生率分别为47.6% vs. 30.7%。总体而言，该新辅助方案在可控安全性下显著改善无事件生存。

14.TROP-2-targeted antibody-drug conjugate SHR-A1921 for advanced or metastatic solid tumors: A first-in-human phase 1 study

TROP-2靶向ADC药物（抗体-药物偶联物）SHR-A1921用于晚期或转移性实体瘤：首次人体I期研究

State Key Laboratory of Molecular Oncology, CAMS Key Laboratory of Translational Research on Lung Cancer, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China

中国医学科学院肿瘤医院/国家癌症中心

This study is a first-in-human, three-stage, phase 1 trial (NCT05154604) designed to evaluate the trophoblast cell-surface antigen 2 (TROP-2)-targeted antibody-drug conjugate SHR-A1921 (1.5–6.0 mg/kg every 3 weeks) in 391 patients with pretreated advanced/metastatic solid tumors. Grade ≥3 treatment-related adverse events occurred in 132 patients (33.8%), with the most common being stomatitis, affecting 57 patients (14.6%). SHR-A1921 showed a low incidence of hematologic toxicities, with only 3.1% of patients experiencing grade ≥3 decreases in neutrophil count. The overall objective response rate was 24.8% (95% confidence interval [CI], 20.6–29.4), ranging from 18.2% to 43.1% across cohorts with platinum-resistant ovarian cancer, triple-negative breast cancer, small-cell lung cancer, non-small cell lung cancer, hormone receptor-positive breast cancer, cervical cancer, and biliary tract cancer. No significant correlation was found between TROP-2 expression and treatment efficacy. In summary, SHR-A1921 exhibited promising antitumor activity and a manageable safety profile, with 3.0 mg/kg every 3 weeks selected for further clinical development.

本研究是一项人体、三阶段的I期临床研究（NCT05154604），首次用于评估靶向滋养层细胞表面抗原2（TROP-2）的抗体偶联药SHR-A1921（1.5–6.0mg/kg，每3周一次）在391名既往系统治疗的晚期实体瘤患者中的安全性与抗肿瘤活性。结果显示，安全性方面，共有132例（33.8%）出现≥3级治疗相关不良事件，其中最常见的是口腔炎（14.6%）。血液学毒性发生率低，仅3.1%出现≥3级中性粒细胞减少。疗效上，总体客观缓解率为24.8%（95%CI，20.6–29.4），不同队列（包括铂耐药卵巢癌、三阴乳腺癌、小细胞肺癌、非小细胞肺癌、HR+乳腺癌、宫颈癌、胆道癌）范围为18.2%–43.1%。并且，TROP-2表达水平与疗效间无显著相关性。综上，SHR-A1921展现出良好的抗肿瘤活性和可管理的安全性，3.0mg/kg每3周方案被选用于后续临床开发。

15.Remodeling of T and endothelial cells during total neoadjuvant therapy in rectal cancer

直肠癌全程新辅助治疗期间T细胞与内皮细胞的重塑

Institute for Data-Driven Tumor Immunology, Chongqing Medical University, Chongqing 400016, China

中国重庆医科大学数据驱动肿瘤免疫学研究所

Total neoadjuvant therapy (TNT) is a standard care for locally advanced rectal cancer (LARC), yet the immune remodeling mechanisms underlying its efficacy remain unclear. Using single-cell RNA, T cell receptor, and spatial transcriptome sequencing of matched pre- and post-treatment samples, we depicted the tumor microenvironment (TME) dynamics induced by different neoadjuvant therapies. TNT is associated with reduced regulatory T cells and increased IFNG+CD8+ effector memory T cells with high IFNG expression, potentially contributing to improved complete response rates. The abundance of tumor-infiltrating CD8+ T cells is correlated with the enrichment of the ACKR1+ endothelial subset after TNT. We further validated that endothelial cells (ECs), when stimulated by IFNγ, potentially released by CD8+ T cells, acquire an enhanced ability for presenting antigens and activating CD8+ T cells. Together, our study systematically characterizes the TME dynamics and uncovers the unique interaction between activated CD8+ T cells and ECs after TNT.

全程新辅助治疗（TNT）是局部晚期直肠癌（LARC）的标准治疗，但其免疫重塑机制仍未明晰。本研究基于匹配的治疗前后样本，利用单细胞RNA、TCR和空间转录组测序，描绘了不同新辅助策略诱导的肿瘤微环境动态变化。结果显示，TNT使调节性T细胞减少，而高表达IFNG的IFNG+CD8+效应记忆T细胞显著增加，这可能与更高的病理完全缓解率相关。此外，肿瘤浸润CD8+T细胞丰度与TNT后富集的ACKR1+内皮亚群密切相关。进一步验证显示，被CD8+T细胞释放的IFNγ激活的内皮细胞可增强抗原呈递并促进CD8+T细胞活化。本研究系统刻画了TNT诱导的TME重塑过程，并揭示了TNT后活化CD8+T细胞与内皮细胞间的关键互作。

16.Developing SEMA4A-directed CAR T cells to overcome low BCMA antigen density in multiple myeloma

研发靶向SEMA4A的CAR T细胞以克服多发性骨髓瘤中BCMA低抗原密度带来的耐药性

Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

美国莫菲特癌症中心造血干细胞移植与细胞免疫治疗科

Chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) is effective, but relapses associated with low-to-negative BCMA expression are common, indicating the need for additional targets. We quantitatively profile antigen density in a cohort of patients relapsed after BCMA CAR T therapy, showing high number of SEMA4A molecules/cell where BCMA density is low. SEMA4A deletion limits MM cell growth, migration, tissue infiltration, and osteoclast formation, while extending mouse survival. We generate monoclonal antibodies targeting SEMA4A-extracellular domain for CAR construction, screen engineered T cells for expansion, cytokine release, and cytotoxicity against MM cells. Lead constructs lack reactivity against normal non-hematopoietic tissues. SEMA4A CAR T cells show superior efficacy than BCMA CAR T cells eliminating patient-derived BCMAlow tumors and MM cells progressing under suboptimal doses of BCMA CAR T cells. This study prepares for a phase 1 clinical trial with SEMA4A-directed CAR T cells for MM.

尽管靶向BCMA的CAR T细胞已成为多发性骨髓瘤（MM）治疗的重要突破，但低或缺失BCMA表达导致的肿瘤复发仍十分常见，提示需要开发其他靶点。本研究在BCMA CAR T治疗后复发患者中量化不同抗原密度，发现当BCMA密度低时，SEMA4A分子密度显著升高。敲除SEMA4A可抑制MM细胞生长、迁移、组织浸润及破骨细胞形成，同时延长小鼠生存期。研究进一步开发了识别SEMA4A细胞外结构域的单克隆抗体构建CAR，并筛选具有良好扩增、细胞因子释放及杀伤能力的CAR T细胞。并且领先构型对正常非造血组织无反应。总的来说，SEMA4A CAR T能有效清除患者来源的BCMA低表达肿瘤，并在BCMA CAR T剂量不足时仍可控制疾病。研究结果为开展靶向SEMA4A的CAR T I期临床试验奠定基础。

17.Distinct T cell functions enable efficient immunoediting and prevent tumor emergence of developing sarcomas

T细胞的不同功能实现高效免疫编辑并阻止肉瘤早期发生

Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA

美国耶鲁大学医学院免疫生物学系

T cells edit tumors by eliminating neoantigen-expressing tumor cells. Yet, how and when this is achieved remains uncertain. Using a murine sarcoma model with fluorescent neoantigens, we found that tumors developed later and in fewer T cell-sufficient mice (∼53% penetrance) than T cell-deficient mice (∼100%). With T cells, all emergent tumor cells had silenced neoantigens, but neoantigen-negative tumor cells were also present in every T cell-deficient mouse. This suggested silencing was necessary but not sufficient for outgrowth. Genetic removal of neoantigens restored tumor penetrance if implemented on day 5 post-tumor initiation, but not day 10, because CD8+ and CD4+ T cells infiltrated the tissue and eliminated most neoantigen-positive and -negative tumor cells within 8 days. Single-cell analyses on day-7 tumors showed oncogenic changes including increased proliferation and T cell-dependent upregulation of the IFNγ-response gene Cd274 (PD-L1). T cell-depletion rescued both neoantigen-positive and -negative cells, while IFNγ blockade rescued only negative cells. This shows that T cells efficiently edit sarcomas of neoantigens and prevent early tumors via IFNγ-independent and IFNγ-dependent (bystander) mechanisms.

T细胞通过清除表达新抗原的肿瘤细胞实现免疫编辑，但其作用的时间窗与机制仍不明确。本研究利用带荧光新抗原的鼠肉瘤模型，发现在具有T细胞的鼠群中肿瘤发生更晚且发生率更低（约53%），而T细胞缺陷小鼠中发生率接近100%。在T细胞正常的鼠中，所有出现的肿瘤细胞均沉默了新抗原表达；但在T细胞缺陷鼠中，新抗原阴性细胞也普遍存在。这表明抗原沉默是必要但不足以驱动肿瘤生长的条件。若在肿瘤起始后第5天敲除新抗原可恢复肿瘤发生率，但第10天后实施则不能，因为CD4+与CD8+T细胞已在8天内浸润并清除大多数新抗原阳性及阴性细胞。单细胞分析显示，T细胞存在时，肿瘤中可见增殖增强及IFNγ依赖的PD-L1(Cd274)上调。剔除T细胞可拯救两类细胞，而阻断IFNγ仅拯救新抗原阴性细胞。这些结果表明，T细胞可以高效编辑新抗原肉瘤，并通过IFNγ非依赖和依赖（旁观者效应）两类机制共同抑制早期肿瘤发生。