原创 邹宇豪 华西医院耳鼻喉科
华西耳鼻喉前沿学术速递——文献导读（第68期）
【Nature Cancer】2025年1月-2025年2月论文导读
《Nature Cancer》是癌症研究领域的重要学术期刊，致力于为全球研究人员提供生命科学、物理科学、应用科学及社会科学领域与癌症相关的最新突破性进展。该期刊聚焦多个核心研究方向：其一是基础性临床前研究，旨在深入探索肿瘤发生与发展的分子机制；其二是转化医学研究，重点关注癌症诊断与治疗新方法的开发及其临床转化应用；其三是临床研究，为癌症的诊断、治疗和预防提供科学依据；其四是癌症对全球社会影响的相关研究，探索癌症防控的社会学意义。作为国际顶尖学术期刊，《Nature Cancer》在学术界和行业领域具有广泛影响力，其最新影响因子高达23.5，充分体现了其在癌症研究领域的重要地位和学术价值。
在2024年1月2日-2月12日，Nature Cancer共发表38篇文章，其中包括18篇Article，1篇Analysis，2篇News & Views，3篇Research Briefing，2篇Review Article，2篇Viewpoint.
1. Targeting ADAR1 with a small molecule for the treatment of prostate cancer
使用小分子药物靶向ADAR1治疗前列腺癌
中国，中国药科大学天然药物国家重点实验室
Despite the initial response to androgen signaling therapy, most cases of prostate cancer (PCa) eventually relapse and remain incurable. The specific function of ADAR1 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 ADAR1 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 ADAR1 represses the translation of MTDH in an editing-dependent manner, which drives cell proliferation and invasion in PCa. Collectively, our findings suggest that ADAR1 is a druggable target in PCa and highlight the widespread applicability of ADAR1 inhibitors for a broad spectrum of malignancies.
尽管前列腺癌（PCa）患者最初对雄激素信号治疗有反应，但大多数病例最终会复发并难以治愈。目前，ADAR1在前列腺癌进展中的具体功能及其特异性抑制剂的研究仍较为有限。本研究发现高表达的ADAR1是前列腺癌中一个关键的致癌靶点，并开发了一种高效的小分子ADAR1抑制剂ZYS-1，该抑制剂表现出显著的抗肿瘤效果和良好的安全性。无论是通过基因手段还是药物手段抑制ADAR1，均能显著抑制前列腺癌的生长和转移，并增强抗肿瘤免疫反应。此外，ZYS-1能够增强免疫治疗的抗肿瘤效果。本研究还揭示了ADAR1通过编辑依赖的方式抑制MTDH的翻译，从而驱动前列腺癌细胞的增殖和侵袭。综上所述，本研究表明ADAR1是前列腺癌中一个可成药的靶点，并强调了ADAR1抑制剂在多种恶性肿瘤中的广泛应用潜力。
2. FLASH radiation reprograms lipid metabolism and macrophage immunity and sensitizes medulloblastoma to CAR-T cell therapy
FLASH放疗重编程脂质代谢和巨噬细胞免疫，使髓母细胞瘤对CAR-T细胞疗法敏感
美国，宾夕法尼亚大学，放射肿瘤学系；杜克大学，医学中心放射肿瘤学系
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-γ (PPARγ) 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 PPARγ activity, while standard radiation induces reactive oxygen species-dependent PPARγ 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.
超高剂量率辐射递送（ FLASH ）放射治疗因其在正常组织中的较低毒性而展现出治疗实体瘤的巨大潜力，但其对肿瘤免疫的影响仍不明确。本研究利用基因工程小鼠髓母细胞瘤模型，发现FLASH放射治疗能促进肿瘤巨噬细胞向促炎表型极化。单细胞转录组分析表明，FLASH质子束辐射使巨噬细胞向促炎表型倾斜，并增加了T细胞浸润。此外，FLASH放射治疗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，并抑制了刺激诱导条件下的免疫抑制性巨噬细胞极化。从机制上看，FLASH放射治疗通过抑制脂质氧化酶表达和氧化低密度脂蛋白生成来降低PPARγ活性，而标准辐射则通过活性氧类依赖的PPARγ激活作用于巨噬细胞。值得注意的是，FLASH放射治疗改善了嵌合抗原受体（CAR）T细胞的浸润和活化，并使髓母细胞瘤对GD2 CAR-T细胞疗法更加敏感。因此，FLASH放射治疗通过重编程巨噬细胞脂质代谢，逆转了肿瘤免疫抑制。FLASH与CAR放射免疫治疗的联合应用可能为实体瘤治疗提供新的机遇。
3. 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和可解释人工智能解析泛癌治疗疗效
德国，埃森大学医院 （AöR）医学人工智能研究所
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 AI-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.
尽管精准肿瘤学取得了许多进展，但临床决策仍依赖于有限的变量和专业知识。为了解决这一局限性，本研究结合多模态真实世界数据和可解释人工智能（xAI），开发了基于人工智能（AI）的临床决策支持标志物（AID标志物）。研究人员使用 xAI技术，基于350个标志物（包括临床记录、影像衍生的身体成分数据以及肿瘤突变特征），对涵盖38种实体瘤类型的15,726名患者的治疗结局进行了解析。研究表明，xAI能够在患者个体水平上评估每个临床标志物的预后贡献，并从中筛选出114个关键标志物，这些标记物占神经网络决策过程的90%。此外，xAI还发现了可以影响预后的1373个标记物之间的相互作用。本方法在来自美国全国电子健康记录数据库的3288名肺癌患者的独立队列中得到了验证。这些结果表明xAI在革新临床变量评估方式和实现个性化、数据驱动的癌症护理方面的具有很大潜力。
4. Spatially resolved transcriptomics and graph-based deep learning improve accuracy of routine CNS tumor diagnostics
空间转录组学和基于图形的深度学习提高了中枢神经系统肿瘤常规诊断的准确性
德国，海德堡大学，神经病理学系；癌症研究中心（DKFZ）
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-µm tissue sections. NePSTA uses spatial 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.
脑肿瘤的诊断领域正在将全面的分子标志物与传统组织病理学评估相结合。DNA甲基化分析和下一代测序（NGS）已成为中枢神经系统（CNS）肿瘤分类的基石，但其应用受到DNA质量和数量的限制，影响了其可行性。本研究提出了一种名为NePSTA（神经病理学空间转录组分析）的新方法，能够从单张5微米厚的组织切片中实现全面的形态学和分子神经病理学诊断。NePSTA结合空间转录组学和图形神经网络，实现了自动化的组织学和分子评估。通过在四个医疗中心对130名CNS恶性肿瘤患者和健康捐赠者的样本进行训练和评估，NePSTA能够高精度预测组织学特征和基于甲基化的肿瘤亚型。此外，NePSTA能够在仅需极少组织样本的情况下重建免疫组织化学和基因型分析，而这些数据的样本量通常不足以支持传统的分子诊断。这一方法展示了其在增强肿瘤亚型识别方面的潜力，为快速、精准的诊断流程提供了新的可能性。
5.TRIM28-dependent developmental heterogeneity determines cancer susceptibility through distinct epigenetic states
TRIM28依赖的发育异质性通过不同的表观遗传状态决定癌症易感性
美国 密歇根州 大急流城 Van Andel 研究所
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.
癌症风险基因的突变会增加个体的易感性，但并非所有携带者都会发展为癌症。事实上，尽管DNA突变是癌症发生的必要驱动因素，但只有一小部分突变细胞会最终导致癌症。迄今为止，个体癌症易感性的机制仍不清楚。本文利用一种具有内在发育异质性的独特小鼠模型（Trim28+/D9）来探讨生命早期的表观遗传变异是否会影响个体后期的癌症易感性。研究发现，Trim28的杂合性足以产生两种不同的早期表观遗传状态，这两种状态与不同的癌症易感性相关。这些在发育过程中预先形成的表观遗传状态表现为典型异染色质区域的差异性甲基化模式，且早在出生后10天即可检测到。差异性甲基化位点富集于已知具有致癌潜力的基因区域，这些基因在人类癌症中频繁突变并与不良预后相关。本研究提供了遗传学证据，表明内在发育异质性可以决定个体终生的癌症易感性。
6. Systemic IFN-I combined with topical TLR7/8 agonists promotes distant tumor suppression by c-Jun-dependent IL-12 expression in dendritic cells
系统性I型干扰素（IFN-I）联合局部TLR7/8激动剂通过树突状细胞中c-Jun依赖的IL-12表达，实现对远端肿瘤的抑制作用。
奥地利，维也纳医科大学癌症研究中心
Dendritic cell (DC) activation by pattern recognition receptors like Toll-like-receptors (TLRs) is crucial for cancer immunotherapies. Here, we demonstrate the effectiveness of the TLR7/8 agonist imiquimod (IMQ) in treating both local tumors and distant metastases. Administered orally, IMQ activates plasmacytoid DCs (pDCs) to produce systemic type I interferons (IFN-I) required for TLR7/8 upregulation in DCs and macrophages, sensitizing them to topical IMQ treatment, which is essential for therapeutic efficacy. The mechanism involves c-Jun/AP-1 mediating TLR7/8 signaling in IFN-I-primed DCs, upregulating the pDC-recruiting chemokine CCL2 and the anti-angiogenic cytokine interleukin-12, which suppresses VEGF-A production leading to tumor necrosis and regression. Combining topical and systemic IMQ or IFN-I generates a CD8 T cell-dependent response at metastatic sites, reinforced by PD-1 blockade, leading to long-lasting memory. Analysis of cohorts of patients with melanoma demonstrates DC-specific TLR7/8 upregulation by IFN-I, supporting the translational potential of combining systemic IFN-I and topical IMQ to improve immunotherapy of topically accessible tumors.
树突状细胞（DC）通过模式识别受体（如Toll样受体，TLRs）的激活在癌症免疫治疗中起着关键作用。本研究证明了 TLR7/8 激动剂咪喹莫特（IMQ）在治疗局部肿瘤和远处转移瘤方面的有效性。口服IMQ可激活浆细胞样树突状细胞（pDCs），产生系统性的I型干扰素（IFN-I），从而上调DC和巨噬细胞中的TLR7/8表达，使其对局部IMQ治疗敏感，这是治疗效果的关键。机制上，c-Jun/AP-1介导了IFN-I预处理的DC中的TLR7/8信号传导，上调了pDC招募趋化因子CCL2和抗血管生成细胞因子白介素-12的表达，抑制VEGF-A的产生，最终导致肿瘤坏死和消退。局部和系统性IMQ或IFN-I的联合应用可在转移部位产生CD8 T细胞依赖的反应，并通过PD-1阻断得到加强，从而产生持久的记忆。对黑色素瘤患者队列的分析表明，IFN-I上调了DCs特异性TLR7/8，支持了将全身IFN-I和局部IMQ结合起来改善局部肿瘤免疫疗法的转化潜力。
7.Targeting BRCA1-deficient PARP inhibitor-resistant cells with nickases reveals nick resection as a cancer vulnerability
利用切口酶靶向BRCA1缺陷型PARP抑制剂耐药细胞揭示DNA切口切除是癌症的潜在治疗靶点
美国 马萨诸塞大学
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.
缺乏遗传性乳腺癌基因BRCA1和BRCA2（BRCA）的肿瘤对某些抗癌治疗（如聚ADP核糖聚合酶1（PARP1）抑制剂）表现出高度敏感性。然而，一旦产生耐药性，治疗选择便十分有限。本研究利用 CRISPR 技术发现在BRCA1基因缺陷细胞中，通过删除53BP1-Shieldin 复合物增加DNA末端切除进而增强同源重组--这与PARP抑制剂的抗药性有关--会使细胞对DNA切口更加敏感。这种敏感性是由于切口被过度切除为广泛的单链区域，从而引发细胞死亡。基于这些发现以及切口能够限制小鼠肿瘤形成的事实，本研究提出将切口酶作为个性化医疗的工具。此外，本研究的结果表明，限制切口扩展是53BP1-Shieldin复合物的关键功能。
8. 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的选择性缺失可增强肿瘤免疫原性
美国，哈佛大学医学院；丹娜法伯癌症研究所
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 Nlrc5 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.
癌细胞经常通过代谢重编程以支持增殖并逃避免疫监视，但人们对可提高免疫监视的代谢靶点知之甚少。本研究揭示了一种特异性抑制线粒体呼吸链复合物I（CI）的方法，可提高肿瘤免疫原性并增强对免疫检查点阻断（ICB）的敏感性。在黑色素瘤和乳腺癌模型中，靶向删除Ndufs4或Ndufs6（而非其他CI亚基）会诱导免疫依赖的生长抑制。Ndufs4的缺失会显著上调主要组织相容性复合体（MHC）Ⅰ类共激活因子Nlrc5和抗原递呈机制成分（尤其是H2-K1）的表达。这种MHC相关基因的诱导是由丙酮酸脱氢酶依赖的线粒体乙酰辅酶A积累驱动的，从而导致Nlrc5和H2-K1启动子区域组蛋白H3K27乙酰化水平增加。综上所述，本研究表明选择性抑制CI可抑制肿瘤生长，特异性靶向 Ndufs4或Ndufs6可提高T细胞的监控能力和对ICB的反应性。
9. First-in-class ultralong-target-residence-time p38α inhibitors as a mitosis-targeted therapy for colorectal cancer
首创超长靶点滞留时间p38α抑制剂：一种针对结直肠癌的有丝分裂靶向疗法
德国，图宾根大学医学院
Colorectal cancer (CRC) constitutes the second leading cause of cancer-related death worldwide and advanced CRCs are resistant to targeted therapies, chemotherapies and immunotherapies. p38α (Mapk14) has been suggested as a therapeutic target in CRC; however, available p38α inhibitors only allow for insufficient target inhibition. Here we describe a unique class of p38α inhibitors with ultralong target residence times (designated ULTR-p38i) that robustly inhibit p38α downstream signaling and induce distinct biological phenotypes. ULTR-p38i monotherapy triggers an uncontrolled mitotic entry by activating Cdc25 and simultaneously blocking Wee1. 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.
结肠直肠癌（CRC）是全球癌症相关死亡的第二大原因，晚期CRC对靶向疗法、化疗和免疫疗法均表现出耐药性。p38α（Mapk14）被认为是CRC的潜在治疗靶点；然而，现有的p38α抑制剂无法实现充分的靶点抑制。本文报道了一类独特的具有超长靶点停留时间的p38α抑制剂（命名为ULTR-p38i），它能强效抑制p38α下游信号传导并诱导不同的生物表型。ULTR-p38i单药疗法通过激活Cdc25并同时阻断Wee1，引发不受控制的有丝分裂。因此，CRC细胞会发生有丝分裂灾难，导致凋亡或衰老。ULTR-p38i具有高选择性、良好的药物动力学特性，并且在源自患者CRC类器官和人工构建的CRC小鼠模型中表现出显著的治疗效果且无明显的毒性。本研究提出了超长靶标驻留时间激酶抑制剂作为共价抑制剂的替代品，因为许多激酶癌症靶点缺乏半胱氨酸残基，无法设计共价抑制剂。
10. Neoadjuvant atezolizumab in combination with dual HER2 blockade plus epirubicin in women with early HER2-positive breast cancer: the randomized phase 2 ABCSG-52/ATHENE trial
阿替利珠单抗联合双HER2阻断及表柔比星用于早期HER2阳性女性乳腺癌患者的新辅助治疗：随机2期ABCSG-52/ATHENE试验
奥地利，格拉茨医科大学
The role of anthracyclines in the treatment of early breast cancer (EBC) is increasingly being challenged, especially in de-escalation strategies. However, owing to their immunogenic effects, anthracyclines are promising combination partners with immunotherapies. In the randomized phase 2 trial ABCSG-52 (EudraCT no. 2019-002364-27), we investigated epirubicin plus immunotherapy in women with human epidermal growth factor receptor 2 (HER2)-positive EBC. A total of 58 patients were randomized 1:1 to two cycles of a chemotherapy-free induction phase (part 1) of dual HER2 blockade with trastuzumab and pertuzumab (TP) plus the anti-programmed death ligand 1 antibody atezolizumab (TP-A) or TP alone. Thereafter, all patients received four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint, pathological complete response (pCR), was met in 35 patients (60.3%; 95% confidence interval (CI) 47.5% to 71.9%), 19 patients (65.5%) in the TP-A group and 16 patients (55.2%) in the TP group. The residual cancer burden 0/I rate and objective response rate (secondary endpoints) in all patients with evaluable data were 80.0% (n = 44/55; 95% CI 67.6% to 88.4%) and 89.3% (n = 50/56; 95% CI 78.5% to 95.0%), respectively. Grade ≥3 adverse events were reported in 17 patients (29.3%). Based on our findings, we conclude that a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab and epirubicin is effective and safe in patients with HER2-positive EBC.
蒽环类药物在早期乳腺癌（EBC）治疗中的作用正日益受到挑战，尤其是在降阶梯治疗策略中。然而，由于其免疫原性效应，蒽环类药物与免疫治疗的联合应用显示出广阔前景。在随机2期试验ABCSG-52（EudraCT编号：2019-002364-27）中，研究者探究了表柔比星联合免疫治疗在人类表皮生长因子受体2（HER2）阳性EBC患者中的疗效。本研究共纳入58例患者，按1:1随机分配至两个周期的无化疗诱导阶段（第一部分），分别接受双HER2阻断（曲妥珠单抗和帕妥珠单抗，TP）联合抗程序性死亡配体1抗体阿替利珠单抗（TP-A）或单独TP治疗。此后，所有患者均接受四个周期的TP-A联合表柔比星治疗（第二部分）。主要终点病理完全缓解（pCR）率为60.3%（35例；95%CI：47.5%-71.9%），其中TP-A组为65.5%（19例），TP组为55.2%（16例）。在所有具有可评估数据的患者中，残留肿瘤负荷0/I率和客观缓解率（次要终点）分别为80.0%（44/55例；95% CI：67.6%-88.4%）和89.3%（50/56例；95%CI：78.5%-95.0%）。17例患者（29.3%）报告了≥3级不良事件。基于该研究结果，可得出结论：曲妥珠单抗、帕妥珠单抗、阿替利珠单抗联合表柔比星的新辅助化疗降阶梯免疫治疗方案对HER2阳性EBC患者有效且安全。
11. Efficacy and tolerability of neoadjuvant therapy with Talimogene laherparepvec in cutaneous basal cell carcinoma: a phase II trial (NeoBCC trial)
使用Talimogene Laherparepvec 新辅助治疗皮肤基底细胞癌的疗效和耐受性：一项 II 期临床试验（NeoBCC 试验）
奥地利，维也纳医科大学
We present a single-arm, phase II, neoadjuvant trial with the oncolytic virus talimogene laherparepvec (T-VEC) in 18 patients with difficult-to-resect cutaneous basal cell carcinomas. The primary end point, defined as the proportion of patients, who after six cycles of T-VEC (13 weeks), become resectable without the need for plastic reconstructive surgery, was already achieved after stage I (9 of 18 patients; 50.0%); thus the study was discontinued for early success. The objective response rate was 55.6% and the complete pathological response rate was 33.3%. Secondary end points included safety, relapse-free survival and overall survival, time to occurrence of new basal cell carcinomas and biological read outs. Only mild adverse events occurred. The 6-month relapse-free survival and overall survival rates were 100%. In two patients a new basal cell carcinoma was diagnosed. T-VEC led to a significant increase in cytotoxic T cells (P = 0.0092), B cells (P = 0.0004) and myeloid cells (P = 0.0042) and a decrease in regulatory T cells (P = 0.0290) within the tumor microenvironment. Together, neoadjuvant T-VEC represents a viable treatment option for patients with difficult-to-resect basal cell carcinomas (EudraCT no. 2018-002165-19).
本研究开展了一项单臂II期新辅助临床试验，评估溶瘤病毒talimogene laherparepvec（T-VEC）在18例难以切除的皮肤基底细胞癌患者中的疗效。主要终点为经过六个周期的 T-VEC（13 周）治疗后，无需整形重建手术即可切除的患者比例，该终点在第一阶段（18 例患者中有 9 例；50.0%）后已经达到，因此研究因早期成功而终止。客观反应率为 55.6%，完全病理反应率为 33.3%。次要终点包括安全性、无复发生存期和总生存期、出现新基底细胞癌的时间和生物学指标的测定。只有轻微的不良反应事件发生。6个月无复发生存率和总生存率均为100%。T-VEC使肿瘤微环境中的细胞毒性T细胞（P = 0.0092）、B细胞（P = 0.0004）和髓样细胞（P = 0.0042）显著增加，调节性T细胞（P = 0.0290）减少。总之，对于难以切除的基底细胞癌患者来说，新辅助T-VEC是一种可行的治疗选择（EudraCT编号：2018-002165-19）。
12. ETV7 limits the antiviral and antitumor efficacy of CD8+ T cells by diverting their fate toward exhaustion
ETV7 通过改变 CD8+ T 细胞的命运使其走向耗竭从而限制其抗病毒和抗肿瘤功效
奥地利，维也纳医科大学
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.
终末耗竭是抗肿瘤免疫的一个关键障碍。通过整合和分析单细胞 RNA 测序和单细胞转座酶染色质检测测序数据，本研究发现ETS变体7（ETV7）是决定肿瘤中CD8+ T细胞命运不可或缺的因素。ETV7 的引入可以促使T细胞从记忆状态分化到终末耗竭状态，从而限制了雄性小鼠的抗病毒和抗肿瘤功效。从机制上讲，ETV7通过结合特定的记忆基因和耗竭基因，并功能性地将这些转录程序偏向耗竭状态，从而作为核心转录节点发挥作用。在临床上，ETV7的表达与各种人类癌症的进展和对免疫检查点阻断的反应呈负相关。在实体瘤中，ETV7的耗竭可显著增强CD8+ T细胞和工程嵌合抗原受体T细胞的抗肿瘤疗效。因此，这些发现证明ETV7在驱动CD8+ T细胞终末耗竭中的决定性作用，并揭示了ETV7可能是提高癌症免疫疗法疗效的一个有前途的靶点和生物标记物。
13. ERα dysfunction caused by ESR1 mutations and therapeutic pressure promotes lineage plasticity in ER+ breast cancer
由 ESR1 突变和治疗压力引起的ERα功能障碍促进了ER阳性乳腺癌的谱系可塑性。
美国，基因泰克生物技术公司
Multiple next-generation molecules targeting estrogen receptor α (ERα) 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 ERα). Here, we studied the impact of ERα antagonist/degraders against Esr1 mutations expressed in mouse mammary glands. Inhibition of mutant ERα 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 ESR1 mutation detected (NMD) frequently exhibited mixed-lineage features. ESR1-mutant tumors generally retained luminal features and higher ERα activity and exhibited an anti-proliferative response to the ERα 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 ERα therapeutics observed in ESR1-mutant versus NMD contexts.
目前，针对雌激素受体α（ERα）的多种新一代分子正在乳腺癌临床试验中进行研究，涉及全球数千名女性。这些分子的开发部分源于对ESR1（编码ERα）耐药性突变的发现。本文研究了ERα拮抗剂/降解剂对携带Esr1突变的小鼠乳腺的影响。抑制突变的ERα会诱导混合谱系细胞的出现，其特征是正常情况下不同的主转录因子异常地共同参与。在Esr1野生型小鼠中，长期雌激素剥夺同样导致了谱系不稳定性。在ER阳性乳腺癌活检标本中，未检测到ESR1突变（NMD）且经过多次化疗或靶向治疗的肿瘤经常表现出混合谱系特征。ESR1突变肿瘤通常保留管腔特征和较高的ERα活性，并对ERα拮抗剂吉瑞司群表现出抗增殖反应。ESR1突变肿瘤在治疗后出现了混合谱系特征。晚期ER阳性乳腺癌中的谱系异质性可能是导致ESR1突变与NMD背景下实验性ERα治疗疗效差异的原因。
14. Immunogenomic determinants of exceptional response to immune checkpoint inhibition in renal cell carcinoma
肾细胞癌对免疫检查点抑制异常反应的免疫基因组学决定因子
美国，费城儿童医院
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.
免疫检查点抑制剂可使一部分人产生 “特殊”且持久的治疗反应。然而，转移性透明细胞肾细胞癌（mccRCC）对免疫疗法产生特殊反应（ER）的分子基础尚未得到充分阐明。本文分析了接受以下标准免疫疗法治疗的mccRCC患者治疗前的基因组和转录组数据：（1）程序性细胞死亡蛋白和配体 1 (PD1/PDL1) 与细胞毒性T淋巴细胞相关蛋白4抑制剂的联合疗法（IO/IO）；或（2）PD1/PDL1 与血管内皮生长因子 (VEGF) 受体抑制剂的联合疗法（IO/VEGF）。在IO/IO队列中，ER患者的克隆新抗原负荷明显较高。在IO/VEGF队列中，ER患者的B细胞受体信号相关通路、三级淋巴结构（TLS）特征显著富集，新陈代谢活动增加。研究结果表明，ER 可能与肿瘤微环境中克隆新抗原驱动的细胞毒性 T 细胞反应和 TLS 的形成有关。能够同时引起T细胞导向和B细胞导向的抗肿瘤免疫的治疗组合可能对ccRCC基于IO的治疗取得特殊疗效非常重要。
15. Prospective validation of ORACLE, a clonal expression biomarker associated with survival of patients with lung adenocarcinoma
ORACLE的前瞻性验证：一种与肺腺癌患者生存相关的克隆表达生物标志物
英国，癌症研究中心；伦敦大学
Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study. We prospectively validate the survival association of a clonal expression biomarker, Outcome Risk Associated Clonal Lung Expression (ORACLE), in combination with clinicopathological risk factors, and in stage I disease. We expand our mechanistic understanding, discovering that clonal transcriptional signals are detectable before tissue invasion, act as a molecular fingerprint for lethal metastatic clones and predict chemotherapy sensitivity. Lastly, we find that ORACLE summarizes the prognostic information encoded by genetic evolutionary measures, including chromosomal instability, as a concise 23-transcript assay.
人类肿瘤在自然病程和治疗反应上表现出多样性，这种多样性部分源于遗传和转录组的异质性。在临床实践中，单部位针刺活检通常用于评估肿瘤的异质性，但由于肿瘤内部的空间基因组异质性，癌症生物标志物的检测可能受到干扰。本研究通过分析TRACERx研究中184例肺腺癌患者的450个肿瘤区域的多区域全外显子和RNA测序数据，探讨了克隆表达基因作为解决采样偏差问题的潜在方案。本研究前瞻性地验证了一种克隆表达生物标志物——与预后风险相关的克隆肺表达（ORACLE）——结合临床病理风险因素在I期疾病中的生存相关性。此外，本研究进一步揭示了其机制，发现克隆转录信号在组织侵袭前即可被检测到，可作为致死性转移克隆的分子印记，并预测化疗敏感性。最后，我们发现ORACLE能够将遗传进化指标（包括染色体不稳定性）编码的预后信息浓缩为一种简洁的23个转录本检测方法。
16. Ongoing replication stress tolerance and clonal T cell responses distinguish liver and lung recurrence and outcomes in pancreatic cancer
持续复制应激耐受和克隆 T 细胞反应可区分胰腺癌的肝脏和肺部复发及预后
美国，俄勒冈健康与科学大学
Patients with metastatic pancreatic ductal adenocarcinoma survive longer if disease spreads to the lung but not the liver. Here we generated overlapping, multi-omic datasets to identify molecular and cellular features that distinguish patients whose disease develops liver metastasis (liver cohort) from those whose disease develops lung metastasis without liver metastases (lung cohort). Lung cohort patients survived longer than liver cohort patients, despite sharing the same tumor subtype. We developed a primary organotropism (pORG) gene set enriched in liver cohort versus lung cohort primary tumors. We identified ongoing replication stress response pathways in high pORG/liver cohort tumors, whereas low pORG/lung cohort tumors had greater densities of lymphocytes and shared T cell clonal responses. Our study demonstrates that liver-avid pancreatic ductal adenocarcinoma is associated with tolerance to ongoing replication stress, limited tumor immunity and less-favorable outcomes, whereas low replication stress, lung-avid/liver-averse tumors are associated with active tumor immunity that may account for favorable outcomes.
患有转移性胰腺导管腺癌的患者如果肿瘤扩散到肺部而非肝脏，则其生存时间更长。本文通过整合多组学数据集，鉴定了区分发生肝转移（肝组）和仅发生肺转移但无肝转移（肺组）患者的分子和细胞特征。尽管具有相同的肿瘤亚型，但肺队列患者的存活时间长于肝队列患者。本研究建立了一个原发器官趋向性（pORG）基因组，发现其富集于肝脏队列和肺脏队列的原发性肿瘤中。在高pORG/肝队列肿瘤中发现了持续的复制应激反应通路，而低pORG/肺队列肿瘤则有更高密度的淋巴细胞和共同的T细胞克隆反应。研究表明，偏向肝脏转移的PDAC 具有对复制压力的耐受性、较低的抗肿瘤免疫活性和较差的预后，而低复制压力、肺嗜性/肝排斥肿瘤与活跃的肿瘤免疫力有关，这可能是预后良好的原因。
17. Circulating tumor cell plasticity determines breast cancer therapy resistance via neuregulin 1–HER3 signaling
循环肿瘤细胞的可塑性通过神经调节蛋白1-HER3信号通路决定乳腺癌治疗的耐药性
德国，海森堡癌症研究中心；干细胞技术和实验医学研究所
Circulating tumor cells (CTCs) drive metastasis, the leading cause of death in individuals with breast cancer. Due to their low abundance in the circulation, robust CTC expansion protocols are urgently needed to effectively study disease progression and therapy responses. Here we present the establishment of long-term CTC-derived organoids from female individuals with metastatic breast cancer. Multiomics analysis of CTC-derived organoids along with preclinical modeling with xenografts identified neuregulin 1 (NRG1)–ERBB2 receptor tyrosine kinase 3 (ERBB3/HER3) signaling as a key pathway required for CTC survival, growth and dissemination. Genome-wide CRISPR activation screens revealed that fibroblast growth factor receptor 1 (FGFR1) signaling serves a compensatory function to the NRG1–HER3 axis and rescues NRG1 deficiency in CTCs. Conversely, NRG1–HER3 activation induced resistance to FGFR1 inhibition, whereas combinatorial blockade impaired CTC growth. The dynamic interplay between NRG1–HER3 and FGFR1 signaling reveals the molecular basis of cancer cell plasticity and clinically relevant strategies to target it. Our CTC organoid platform enables the identification and validation of patient-specific vulnerabilities and represents an innovative tool for precision medicine.
循环肿瘤细胞（CTC）是乳腺癌转移的驱动因素，也是导致乳腺癌患者死亡的主要原因。由于它们在血液循环中的丰度较低，因此迫切需要强有力的 CTC 扩增方案来有效研究疾病进展和治疗反应。本文介绍了从女性转移性乳腺癌患者身上建立长期 CTC 衍生类器官的方法。对CTC衍生的类器官进行多组学分析，并利用异种移植进行临床前建模，发现神经调节蛋白1（NRG1）-ERBB2受体酪氨酸激酶3（ERBB3/HER3）信号传导是CTC存活、生长和扩散所需的关键通路。全基因组CRISPR激活筛选发现，成纤维细胞生长因子受体1（FGFR1）信号对NRG1-HER3轴具有补偿作用，并能挽救CTC中NRG1的缺乏。相反，NRG1-HER3 激活会诱导对FGFR1抑制的抵抗，而联合阻断则会损害 CTC 的生长。NRG1-HER3和FGFR1信号传导之间的动态相互作用揭示了癌细胞可塑性的分子基础和临床相关的靶向策略。 CTC类器官平台使得患者特异性脆弱点的识别和验证成为可能，代表了一种创新的精准医学工具。
18. Context-dependent effects of CDKN2A and other 9p21 gene losses during the evolution of esophageal cancer
食管癌演变过程中 CDKN2A 和其他 9p21 基因缺失的背景依赖性效应
英国，弗朗西斯克里克研究所
CDKN2A is a tumor suppressor located in chromosome 9p21 and frequently lost in Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). How CDKN2A and other 9p21 gene co-deletions affect EAC evolution remains understudied. We explored the effects of 9p21 loss in EACs and cancer progressor and non-progressor BEs with matched genomic, transcriptomic and clinical data. Despite its cancer driver role, CDKN2A loss in BE prevents EAC initiation by counterselecting subsequent TP53 alterations. 9p21 gene co-deletions predict poor patient survival in EAC but not BE through context-dependent effects on cell cycle, oxidative phosphorylation and interferon response. Immune quantifications using bulk transcriptome, RNAscope and high-dimensional tissue imaging showed that IFNE loss reduces immune infiltration in BE, but not EAC. Mechanistically, CDKN2A loss suppresses the maintenance of squamous epithelium, contributing to a more aggressive phenotype. Our study demonstrates context-dependent roles of cancer genes during disease evolution, with consequences for cancer detection and patient management.
CDKN2A 是位于染色体9p21的肿瘤抑制基因，经常在巴雷特食管（BE）和食管腺癌（EAC）中丢失。CDKN2A 和其他9p21基因共缺失如何影响 EAC 的演变仍未得到充分研究。本研究结合基因组、转录组和临床数据，研究了9p21缺失在EAC以及进展型和非进展型BE中的作用。尽管 CDKN2A 在 BE 中起着癌症驱动因子的作用，但它的缺失可通过对后续 TP53 变异的选择性抑制，阻止了 EAC 的发生。9p21基因共缺失通过对细胞周期、氧化磷酸化和干扰素反应的背景依赖性影响，可预测EAC患者的不良生存率，但不能预测BE患者的不良生存率。利用全转录组、RNAscope和高维组织成像进行的免疫定量分析显示，IFNE缺失会降低BE的免疫细胞浸润，但不会降低EAC的免疫浸润。从机制上讲，CDKN2A的缺失抑制了鳞状上皮的维持，从而导致更具侵袭性的表型。研究表明，癌基因在疾病演变过程中的作用与背景有关，这对癌症检测和患者管理具有重要意义。
汇报人：邹宇豪
导师：刘世喜
审核：李俊虹、冯兰
