Volume 5 Issue 1, January 2024

2023年10月20日-2024年2月29日一共发表66篇，包括Commentary 5篇， Review Article 1篇， Article 30篇，Spotlight 1篇，News&Views 9篇，Research Briefing5篇，Editorial3篇，Research Highlight12篇。

1.Targeting PRMT9-mediated arginine methylation suppresses cancer stem cell maintenance and elicits cGAS-mediated anticancer immunity

靶向 PRMT9介导的精氨酸甲基化可抑制癌症干细胞维持并引发cGAS介导的抗癌免疫

美国加利福尼亚州杜阿尔特市希望之城医疗中心贝克曼研究所

Abstract:

Current anticancer therapies cannot eliminate all cancer cells, which hijack normal arginine methylation as a means to promote their maintenance via unknown mechanisms. Here we show that targeting protein arginine N-methyltransferase 9 (PRMT9), whose activities are elevated in blasts and leukemia stem cells (LSCs) from patients with acute myeloid leukemia (AML), eliminates disease via cancer-intrinsic mechanisms and cancer-extrinsic type I interferon (IFN)-associated immunity. PRMT9 ablation in AML cells decreased the arginine methylation of regulators of RNA translation and the DNA damage response, suppressing cell survival. Notably, PRMT9 inhibition promoted DNA damage and activated cyclic GMP-AMP synthase, which underlies the type I IFN response. Genetically activating cyclic GMP-AMP synthase in AML cells blocked leukemogenesis. We also report synergy of a PRMT9 inhibitor with anti-programmed cell death protein 1 in eradicating AML. Overall, we conclude that PRMT9 functions in survival and immune evasion of both LSCs and non-LSCs; targeting PRMT9 may represent a potential anticancer strategy.

目前的抗癌疗法无法消灭所有的癌细胞，这些癌细胞通过未知机制利用正常的精氨酸甲基化来促进它们的维持。在这里，该研究发现蛋白精氨酸N-甲基转移酶9（PRMT9）的活性在急性髓系白血病（AML）患者的原始细胞和白血病干细胞（LSCs）中升高，靶向PRMT9可以通过癌症内在机制和癌症外在的Ⅰ型干扰素（IFN）相关免疫作用来治疗癌症。该研究发现，AML细胞中的PRMT9消融降低了RNA翻译调控因子的精氨酸甲基化和对DNA损伤应答反应，抑制了AML细胞的存活。值得注意的是，PRMT9的抑制促进了DNA损伤，并激活了环状GMP-AMP合酶，后者是Ⅰ型干扰素反应的基础。同时，在AML细胞中，从基因层面激活环状GMP-AMP合酶能阻止白血病的发生。研究还报道，PRMT9抑制剂与抗程序性细胞死亡蛋白1（PD-1）在AML的根除上有协同作用。总的来说，该研究发现PRMT9在LSCs和非LSCs的存活和免疫逃逸中起作用，靶向PRMT9的治疗可能是一种潜在的抗癌策略。

2.Entinostat, nivolumab and ipilimumab for women with advanced HER2-negative breast cancer: a phase Ib trial

恩替司他、纳武单抗和伊匹单抗治疗晚期HER2阴性乳腺癌女性患者：Ib期试验

美国约翰霍普金斯医学院，南加州大学，爱尔兰科克大学

Abstract:

We report the results of 24 women, 50% (N = 12) with hormone receptor-positive breast cancer and 50% (N = 12) with advanced triple-negative breast cancer, treated with entinostat + nivolumab + ipilimumab from the dose escalation (N = 6) and expansion cohort (N = 18) of ETCTN-9844 (NCT02453620). The primary endpoint was safety. Secondary endpoints were overall response rate, clinical benefit rate, progression-free survival and change in tumor CD8:FoxP3 ratio. There were no dose-limiting toxicities. Among evaluable participants (N = 20), the overall response rate was 25% (N = 5), with 40% (N = 4) in triple-negative breast cancer and 10% (N = 1) in hormone receptor-positive breast cancer. The clinical benefit rate was 40% (N = 8), and progression-free survival at 6 months was 50%. Exploratory analyses revealed that changes in myeloid cells may contribute to responses; however, no correlation was noted between changes in CD8:FoxP3 ratio, PD-L1 status and tumor mutational burden and response. These findings support further investigation of this treatment in a phase II trial.

该研究报告了24名女性的试验结果，其中50%（N=12）患有激素受体阳性的乳腺癌，另外50%（N=12）患有晚期三阴性乳腺癌，在这个临床试验中，她们接受了恩替司他+纳武单抗+伊匹单抗治疗，包括剂量递增组（N=6)和扩展队列(N =18)。试验的主要结局指标是安全性。次要结局指标包括总缓解率、临床获益率、无进展生存期和肿瘤CD8：FoxP3比值的变化。试验结果表明，该治疗方案没有剂量限制性毒性，并且在可评估的参与者（N=20）中，总缓解率为25%（N=5），其中三阴性乳腺癌为40%（N=4），激素受体阳性的乳腺癌为10%（N=1）。临床获益率为40%（N=8），6个月无进展生存率为50%。该研究通过探索性分析发现，髓样细胞的变化可能有助于治疗反应，但是没有发现CD8：FoxP3比率、PD-L1状态与肿瘤突变负荷的变化和治疗反应的变化之间的相关性。这些发现支持研究者进一步在II期试验中研究这种治疗方法。

3.Efferocytosis reprograms the tumor microenvironment to promote pancreatic cancer liver metastasis

胞吞作用重新编程肿瘤微环境促进胰腺癌肝转移

英国利物浦大学

Abstract：

Pancreatic ductal adenocarcinoma is a highly metastatic disease and macrophages support liver metastases. Efferocytosis, or engulfment of apoptotic cells by macrophages, is an essential process in tissue homeostasis and wound healing, but its role in metastasis is less well understood. Here, we found that the colonization of the hepatic metastatic site is accompanied by low-grade tissue injury and that efferocytosis-mediated clearance of parenchymal dead cells promotes macrophage reprogramming and liver metastasis. Mechanistically, progranulin expression in macrophages is necessary for efficient efferocytosis by controlling lysosomal acidification via cystic fibrosis transmembrane conductance regulator and the degradation of lysosomal cargo, resulting in LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1. Pharmacological blockade of efferocytosis or macrophage-specific genetic depletion of progranulin impairs macrophage conversion, improves CD8+ T cell functions, and reduces liver metastasis. Our findings reveal how hard-wired functions of macrophages in tissue repair contribute to liver metastasis and identify potential targets for prevention of pancreatic ductal adenocarcinoma liver metastasis.

胰腺导管腺癌是一种高度转移性的癌症，肝转移是其常见的远处转移方式之一，而巨噬细胞在该过程中发挥了重要作用。巨噬细胞通过吞噬凋亡细胞的过程，即胞葬作用，在组织稳态维持和伤口愈合中发挥着关键作用，但其在癌症转移过程中的确切作用尚不完全清楚。该研究发现，癌灶肝转移的定植常伴随着轻度组织损伤，而通过吞噬介导的凋亡细胞清除促进了巨噬细胞的重编程和肝转移的发生。在机制上，巨噬细胞中的前粒蛋白通过囊性纤维化跨膜传导调节剂控制溶酶体酸化和降解溶酶体货物，从而影响胞葬作用的效率，并引起LXRα/RXRα介导的巨噬细胞的转变和精氨酸酶1的上调。同时，通过药物阻断胞葬作用或特异性地基因敲除巨噬细胞中的前粒蛋白，可以阻止巨噬细胞的转变，改善CD8+T细胞的功能，并减少胰腺导管腺癌肝转移的发生。总的来说，该研究揭示了巨噬细胞在组织修复过程中的固有功能促进胰腺导管腺癌肝转移的发生的机制，并发现了预防胰腺导管腺癌肝转移的潜在靶点。

4.The dopamine transporter antagonist vanoxerine inhibits G9a and suppresses cancer stem cell functions in colon tumors

多巴胺转运体拮抗剂万诺西林可抑制G9a并抑制结肠肿瘤中癌症干细胞的功能

加拿大渥太华大学

Abstract：

Cancer stem cells (CSCs), functionally characterized by self-renewal and tumor-initiating activity, contribute to decreased tumor immunogenicity, while fostering tumor growth and metastasis. Targeting G9a histone methyltransferase (HMTase) effectively blocks CSC functions in colorectal tumors by altering pluripotent-like molecular networks; however, existing molecules directly targeting G9a HMTase activity failed to reach clinical stages due to safety concerns. Using a stem cell-based phenotypic drug-screening pipeline, we identified the dopamine transporter (DAT) antagonist vanoxerine, a compound with previously demonstrated clinical safety, as a cancer-specific downregulator of G9a expression. Here we show that gene silencing and chemical antagonism of DAT impede colorectal CSC functions by repressing G9a expression. Antagonizing DAT also enhanced tumor lymphocytic infiltration by activating endogenous transposable elements and type-I interferon response. Our study unveils the direct implication of the DAT–G9a axis in the maintenance of CSC populations and an approach to improve antitumor immune response in colon tumors.

癌症干细胞（CSCs）具有自我更新和肿瘤启动的能力，同时还能降低肿瘤的免疫原性，并促进肿瘤生长和转移。通过改变多能细胞样的分子网络，靶向G9a组蛋白甲基转移酶（HMTase）可以有效地阻断结直肠肿瘤中CSC的功能。然而，由于安全性问题，现存的可以直接靶向G9aHMTase活性的分子还没能进入临床阶段。在这里，该研究通过基于干细胞的表型药物筛选流程，发现了多巴胺转运体（DAT）拮抗剂万诺西林，这是一种已被证明具有临床安全性的化合物，可以作为癌症特异性的G9a表达抑制剂。研究发现通过基因沉默和化学拮抗DAT可以抑制结直肠CSC的功能，从而抑制G9a表达。DAT的拮抗还通过激活内源性转座元件和Ⅰ型干扰素应答增强了肿瘤淋巴细胞的浸润。总的来说，该研究揭示了DAT-G9a轴对CSC维持的直接作用，并提出了一种改善结肠肿瘤抗肿瘤免疫反应的策略。

5.A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma

腹膜后去分化脂肪肉瘤和四肢/躯干未分化多形性肉瘤新辅助免疫检查点阻断的随机、非比较 2 期研究

美国德克萨斯大学

Abstract：

Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial (NCT03307616) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.

基于免疫检查点阻断（ICB）在晚期分化不良脂肪肉瘤（DDLPS）和未分化的多形性肉瘤（UPS）中已被证实的临床活性，该研究进行了一项随机、非对照的2期试验（NCT03307616），探究在可手术切除的腹膜后DDLPS（n=17）和四肢/躯干UPS（同时接受纳武利尤单抗/放疗治疗；n=10）的患者采用新辅助治疗（纳武利尤单抗或纳武利尤单抗/伊匹木单抗）的疗效。该研究主要结局指标是病理学反应（透明化百分比），在DDLPS中为8.8％，在UPS中为89％。次要结局指标是免疫浸润、放射影像学反应、12和24个月的无复发生存率和总体生存率的变化。研究还发现，治疗前调节性T细胞的密度低与主要病理学反应（透明化＞30％）有关。新辅助治疗后，肿瘤的B细胞浸润增加，并且与DDLPS的总体生存率相关。另外，治疗前的肿瘤B细胞浸润与调节性T细胞的密度高相关，而在ICB治疗后，这种关联消失了。总的来说，该研究的数据表明，新辅助ICB与DDLPS和UPS肿瘤微环境内复杂的免疫变化相关，并且新辅助ICB联合放疗在UPS中具有显著的疗效。

6.Lung endothelium exploits susceptible tumor cell states to instruct metastatic latency

肺内皮利用易感肿瘤细胞状态来指导转移潜伏期

德国海德堡大学

Abstract：

In metastasis, cancer cells travel around the circulation to colonize distant sites. Due to the rarity of these events, the immediate fates of metastasizing tumor cells (mTCs) are poorly understood while the role of the endothelium as a dissemination interface remains elusive. Using a newly developed combinatorial mTC enrichment approach, we provide a transcriptional blueprint of the early colonization process. Following their arrest at the metastatic site, mTCs were found to either proliferate intravascularly or extravasate, thereby establishing metastatic latency. Endothelial-derived angiocrine Wnt factors drive this bifurcation, instructing mTCs to follow the extravasation–latency route. Surprisingly, mTC responsiveness towards niche-derived Wnt was established at the epigenetic level, which predetermined tumor cell behavior. Whereas hypomethylation enabled high Wnt activity leading to metastatic latency, methylated mTCs exhibited low activity and proliferated intravascularly. Collectively the data identify the predetermined methylation status of disseminated tumor cells as a key regulator of mTC behavior in the metastatic niche.

转移是指癌细胞通过血液循环到达远处器官定植的过程。由于这种事件的罕见性，我们对于转移性肿瘤细胞（mTCs）的即时命运了解甚少，同时内皮细胞作为癌症转移的传播界面在转移过程中的作用也尚不清楚。在此，该研究通过一种新开发的组合式mTC富集方法，提供了早期肿瘤定植过程的基因转录图谱。研究发现，在肿瘤到达转移部位后，mTCs要么在血管内增殖，要么从血管壁穿透至组织间隙，建立起转移性的潜伏期。内皮细胞分泌的Wnt因子在这一过程中起到了关键作用，指导mTCs完成外渗-潜伏的路径。令人意外的是，mTC对来自转移灶的Wnt因子的反应性是在表观遗传水平上建立的，这意味着肿瘤细胞的行为已经被预先决定了。另外，研究发现低甲基化状态使mTC对Wnt的活性增高，导致了转移性潜伏，而高甲基化的mTC则表现出对Wnt的活性较低，并在血管内持续增殖。总的来说，这些数据表明了预先确定的甲基化状态是mTCs在转移灶中行为模式的关键调节因子。

7、Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance

通过LGR4靶向激活结直肠癌中的铁死亡可克服获得性耐药

南开大学，北京干细胞与再生医学研究所

Abstract：

Acquired drug resistance is a major challenge for cancer therapy and is the leading cause of cancer mortality; however, the mechanisms of drug resistance are diverse and the strategy to specifically target drug-resistant cancer cells remains an unmet clinical issue. Here, we established a colorectal cancer-derived organoid biobank and induced acquired drug resistance by repeated low-level exposures of chemo-agents. Chemosensitivity profiling and transcriptomic analysis studies revealed that chemoresistant cancer-derived organoids exhibited elevated expression of LGR4 and activation of the Wnt signaling pathway. Further, we generated a monoclonal antibody (LGR4-mAb) that potently inhibited LGR4–Wnt signaling and found that treatment with LGR4-mAb notably sensitized drug-induced ferroptosis. Mechanistically, LGR4-dependent Wnt signaling transcriptionally upregulated SLC7A11, a key inhibitor of ferroptosis, to confer acquired drug resistance. Our findings reveal that targeting of Wnt signaling by LGR4-mAb augments ferroptosis when co-administrated with chemotherapeutic agents, demonstrating a potential opportunity to fight refractory and recurrent cancers.

获得性药物耐药是癌症治疗的主要挑战，也是癌症死亡的主要原因；然而，耐药的机制多种多样，而如何特异性靶向耐药癌细胞仍然是一个未解决的临床问题。在这里，该研究建立了一个结肠癌来源的类器官样体库，并通过反复低剂量暴露于化疗药物诱导获得性耐药。化疗敏感性分析和转录组分析研究显示，化疗耐药的类器官表现出LGR4的高表达和Wnt信号通路的激活。此外，研究合成了一种单克隆抗体（LGR4-mAb），能有效抑制LGR4-Wnt信号通路，并发现使用LGR4-mAb治疗显著增强了药物诱导的癌细胞铁死亡敏感性。机制上，LGR4依赖的Wnt信号能通过转录上调SLC7A11，SLC7A11是一个铁死亡的关键抑制因子，从而引起获得性耐药。总的来说，上述发现表明，LGR4-mAb通过靶向Wnt信号通路，与化疗药物联合使用时促进了癌细胞铁死亡，为难治性和复发性癌症提供了潜在的治疗机会。

8.Mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade response in melanoma

线粒体 DNA 突变驱动有氧糖酵解以增强黑色素瘤的检查点阻断反应

美国纽约纪念-斯隆-凯特琳癌症中心

Abstract：

The mitochondrial genome (mtDNA) encodes essential machinery for oxidative phosphorylation and metabolic homeostasis. Tumor mtDNA is among the most somatically mutated regions of the cancer genome, but whether these mutations impact tumor biology is debated. We engineered truncating mutations of the mtDNA-encoded complex I gene, Mt-Nd5, into several murine models of melanoma. These mutations promoted a Warburg-like metabolic shift that reshaped tumor microenvironments in both mice and humans, consistently eliciting an anti-tumor immune response characterized by loss of resident neutrophils. Tumors bearing mtDNA mutations were sensitized to checkpoint blockade in a neutrophil-dependent manner, with induction of redox imbalance being sufficient to induce this effect in mtDNA wild-type tumors. Patient lesions bearing >50% mtDNA mutation heteroplasmy demonstrated a response rate to checkpoint blockade that was improved by ~2.5-fold over mtDNA wild-type cancer. These data nominate mtDNA mutations as functional regulators of cancer metabolism and tumor biology, with potential for therapeutic exploitation and treatment stratification.

线粒体基因组（mtDNA）编码细胞内的参与氧化磷酸化和代谢稳态的重要组分。肿瘤mtDNA是癌症基因组中最常见的体细胞突变区域之一，但关于它的突变是否会对肿瘤生物学产生影响，目前还存在争议。因此，该研究将mtDNA编码的复合物I的基因—Mt-Nd5的截断突变引入到几种黑色素瘤的小鼠模型中。这些突变促进了类似Warburg效应的代谢转变，重塑了小鼠和人体内的肿瘤微环境，并一致地引发了以中性粒细胞丧失为特征的抗肿瘤免疫反应。携带mtDNA突变的肿瘤以中性粒细胞依赖性方式对检查点阻断疗法敏感，氧化还原失衡的诱导足以在mtDNA野生型肿瘤中诱导此效应。具有>50%的mtDNA突变异质性患者的病变对检查点阻断疗法的反应率比mtDNA野生型患者提高了2.5倍。总的来说，这些数据提出mtDNA突变是癌症代谢和肿瘤生物学的功能调节器，具有潜在的治疗应用和治疗分层的可能性。

9.Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation.

Pip4k2c的缺失通过胰岛素依赖性PI3K-AKT通路激活赋予肝转移器官倾向

美国哥伦比亚大学

Abstract：

Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR–Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms.

肝转移（LM）在各种癌症类型中均表现出生存率低和对治疗的抵抗性，但癌症肝转移器官选择性的机制仍然未知。在此，通过体内CRISPR-Cas9筛选，该研究发现Pip4k2c缺失会导致LM，但对肺转移或原发肿瘤的生长没有影响。Pip4k2c缺陷的细胞对会胰岛素介导的PI3K/AKT信号通路过度敏感，因此会对富含胰岛素的肝脏环境实现器官特异性转移。研究还观察到在3,511例黑色素瘤的患者中（包括原发肿瘤、LM和肺转移），PIP4K2C表达和不同代谢变化的一致性。另外，通过系统性PI3K抑制会通过宿主介导的肝脏胰岛素水平的增加加重Pip4k2c缺陷癌细胞注射小鼠的肝转移负担。然而，这一回路可以通过同时使用SGLT2抑制剂或通过生酮饮食来打破。总之，这项研究工作阐释了一个罕见的通过生理代谢信号实现器官选择性的癌症转移的例子，并提出了对抗这些机制的治疗途径。

10.The efficacy of chemotherapy is limited by intratumoral senescent cells expressing.

化疗的疗效受到表达PD-L2的肿瘤内衰老细胞的限制

西班牙巴塞罗那科学技术研究所

Abstract：

Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally. Indeed, after chemotherapy, PD-L2-deficient senescent cancer cells are rapidly eliminated and tumors do not produce the senescence-associated chemokines CXCL1 and CXCL2. Accordingly, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Finally, antibody-mediated blockade of PD-L2 strongly synergizes with chemotherapy causing remission of mammary tumors in mice. The combination of chemotherapy with anti-PD-L2 provides a therapeutic strategy that exploits vulnerabilities arising from therapy-induced senescence.

化疗通常会引发肿瘤内产生老化的癌细胞，这些细胞会显著改变肿瘤微环境，促进免疫抑制和肿瘤生长。在此，通过无偏倚的蛋白质组学筛选，该研究发现在不同类型的癌细胞中诱导老化后，免疫检查点抑制剂程序性细胞死亡配体2（PD-L2）的表达明显上调。PD-L2并不是细胞老化并所必需，但能帮助老化肿瘤细胞实现免疫逃逸和在肿瘤内持续存在。事实上，经过化疗后，PD-L2缺乏的老化癌细胞会被迅速清除，肿瘤不再产生与老化相关的趋化因子CXCL1和CXCL2。因此，PD-L2缺乏的胰腺肿瘤不能招募骨髓来源的抑制性细胞，并在化疗后由CD8T细胞驱动肿瘤消退。最后，通过抗PD-L2的抗体介导的阻断与化疗有强烈协同作用，能有效缓解小鼠乳腺肿瘤。总之，利用化疗后老化癌细胞对抗PD-L2产生的易感性，将化疗与抗PD-L2的联合应用是一种新的治疗策略。

11.Inhibition of ADAM9 promotes the selective degradation of KRAS and sensitizes pancreatic cancers to chemotherapy.

台湾台中中国医科大学

Abstract：

Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.

鼠类肉瘤病毒癌基因（KRAS）信号转导在驱动胰腺导管腺癌（PDAC）的恶变中具有重要作用，这也是目前还未解决的临床问题。在这里，该研究鉴定出一个解整合素样金属蛋白酶9（ADAM）9，作为与PDAC患者预后不良相关的KRAS信号调控因子，通过稳定野生型和突变型KRAS蛋白来调节PDAC进程。从机制上讲，ADAM9的缺失增加了KRAS与纤溶酶原激活物抑制剂1（PAI-1）的相互作用，PAI-1可与轻链3（LC3）一起作为选择性自噬受体发挥作用，触发KRAS的溶酶体降解。小分子抑制剂对ADAM9的抑制可限制模型中的疾病进展，并且与吉西他滨联合使用可使患者来源肿瘤显著好转。总之，该研究结果明确了ADAM9作为PDAC治疗的药物靶点，为提高PDAC的化疗敏感性提供了一种新的治疗策略。

12.The Molecular Twin artificial-intelligence platform integrates multi-omic data to predict outcomes for pancreatic adenocarcinoma patients.

分子孪生人工智能平台整合多组学数据来预测胰腺腺癌患者的结果

美国加利福尼亚洛杉矶医疗中心，约翰霍普金斯大学

Abstract：

Contemporary analyses focused on a limited number of clinical and molecular biomarkers have been unable to accurately predict clinical outcomes in pancreatic ductal adenocarcinoma. Here we describe a precision medicine platform known as the Molecular Twin consisting of advanced machine-learning models and use it to analyze a dataset of 6,363 clinical and multi-omic molecular features from patients with resected pancreatic ductal adenocarcinoma to accurately predict disease survival (DS). We show that a full multi-omic model predicts DS with the highest accuracy and that plasma protein is the top single-omic predictor of DS. A parsimonious model learning only 589 multi-omic features demonstrated similar predictive performance as the full multi-omic model. Our platform enables discovery of parsimonious biomarker panels and performance assessment of outcome prediction models learning from resource-intensive panels. This approach has considerable potential to impact clinical care and democratize precision cancer medicine worldwide.

目前针对有限数量的临床和分子生物标志物的分析很难精准预测胰腺癌的临床结局。在这里，该研究提出了一个称为“分子双胞胎”的精准医学平台，它由机器学习模型组成，研究使用它分析了来自已切除胰腺导管腺癌患者的6,363个临床和多组学分子特征的数据集，以准确预测疾病存活率（DS）。研究表明，完整的多组学模型预测DS的准确性最高，而血浆蛋白是DS的最佳单组学预测因子。此外，研究还提出了一个简约的多组学模型，它仅使用589个特征就能达到类似的预测性能。该平台具有利用多组学数据开发高效且简约的生物标志物的潜力。总之，这项研究不仅对胰腺导管腺癌的诊断和治疗提供了新的见解，而且对精准医疗领域有着重要的意义。

13.INPP5A phosphatase is a synthetic lethal target in GNAQ and GNA11-mutant melanomas.

瑞士诺华生物医学研究所

Abstract：

Activating mutations in GNAQ/GNA11 occur in over 90% of uveal melanomas (UMs), the most lethal melanoma subtype; however, targeting these oncogenes has proven challenging and inhibiting their downstream effectors show limited clinical efficacy. Here, we performed genome-scale CRISPR screens along with computational analyses of cancer dependency and gene expression datasets to identify the inositol-metabolizing phosphatase INPP5A as a selective dependency in GNAQ/11-mutant UM cells in vitro and in vivo. Mutant cells intrinsically produce high levels of the second messenger inositol 1,4,5 trisphosphate (IP3) that accumulate upon suppression of INPP5A, resulting in hyperactivation of IP3-receptor signaling, increased cytosolic calcium and p53-dependent apoptosis. Finally, we show that GNAQ/11-mutant UM cells and patients’ tumors exhibit elevated levels of IP4, a biomarker of enhanced IP3 production; these high levels are abolished by GNAQ/11 inhibition and correlate with sensitivity to INPP5A depletion. Our findings uncover INPP5A as a synthetic lethal vulnerability and a potential therapeutic target for GNAQ/11-mutant-driven cancers.

GNAQ/GNA11的激活突变发生在90%以上的葡萄膜黑色素瘤（UM）中，这是致死率最高的黑色素瘤亚型。然而，靶向这些癌基因十分具有挑战性，并且抑制其下游效应物的临床疗效也非常有限。在此，该研究进行了全基因组CRISPR筛选，同时对癌症依赖性和基因表达数据集进行了计算分析，发现肌醇代谢磷酸酶INPP5A在体外和体内的GNAQ/11突变UM细胞中具有选择性依赖性。突变UM细胞的第二信使肌醇三磷酸(IP3)在INPP5A抑制的基础上积累，使胞内IP3保持高水平状态，导致IP3受体信号的过度激活，增加了细胞溶质钙并促进p53依赖性凋亡。最后，研究发现GNAQ/11突变的UM细胞和患者的肿瘤组织显示出IP4水平的升高，IP4是IP3生成增强的生物标志物。这些现象可以被GNAQ/11抑制消除，并与对INPP5A缺失的敏感性相关。总之，该研究结果发现，INPP5A是GNAQ/11突变型癌症的合成致死性易感性基因，是该类癌症潜在的治疗靶点。

14.Repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab show no efficacy in glioblastoma: a phase 1 trial.

重复外周输注抗EGFRvIII CAR T细胞与帕博利珠单联合治疗对胶质母细胞瘤没有疗效：一项1期试验

美国宾夕法尼亚大学

Abstract：

We previously showed that chimeric antigen receptor (CAR) T-cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces upregulation of programmed death-ligand 1 (PD-L1) in the tumor microenvironment (TME). Here we conducted a phase 1 trial (NCT03726515) of CAR T-EGFRvIII cells administered concomitantly with the anti-PD1 (aPD1) monoclonal antibody pembrolizumab in patients with newly diagnosed, EGFRvIII+ glioblastoma (GBM) (n = 7). The primary outcome was safety, and no dose-limiting toxicity was observed. Secondary outcomes included median progression-free survival (5.2 months; 90% confidence interval (CI), 2.9–6.0 months) and median overall survival (11.8 months; 90% CI, 9.2–14.2 months). In exploratory analyses, comparison of the TME in tumors harvested before versus after CAR + aPD1 administration demonstrated substantial evolution of the infiltrating myeloid and T cells, with more exhausted, regulatory, and interferon (IFN)-stimulated T cells at relapse. Our study suggests that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicates a need to consider alternative strategies.

既往研究表明，靶向表皮生长因子受体变体III（EGFRvIII）的嵌合抗原受体（CAR）T细胞治疗会在肿瘤微环境（TME）中导致程序性死亡配体1（PD-L1）上调。在此，该研究团队进行了一项1期临床试验（NCT03726515），对新诊断的EGFRvIII+的胶质母细胞瘤（GBM）患者（n=7）进行了CART-EGFRvIII细胞治疗，同时联合使用抗PD1（aPD1）单克隆抗体帕博利珠单抗。主要结局指标为安全性，结果显示未观察到剂量限制性毒性。次要结局指标包括中位无进展生存期（5.2个月；90%CI，2.9-6.0个月）和中位总生存期（11.8个月；90%CI，9.2-14.2个月）。探索性分析比较CAR+aPD1给药前后采集的肿瘤的TME，结果显示，浸润的髓系和T细胞发生了显著的变化，并且复发时TME中出现更多的耗竭型、调节型和干扰素（IFN）激活的T细胞。总的来说，该研究表明，在GBM中联合使用CAR-T细胞和PD-1抑制剂是安全并且具有生物活性的，但考虑到缺乏疗效，未来也需要替代的治疗策略。

15.Sirpα on tumor-associated myeloid cells restrains antitumor immunity in colorectal cancer independent of its interaction with CD47. 

肿瘤相关骨髓细胞上的Sirpα抑制结直肠癌的抗肿瘤免疫，其与CD47的相互作用无关

南方科技大学，中山大学，厦门大学

Abstract：

Immunosuppressive myeloid cells hinder immunotherapeutic efficacy in tumors, but the precise mechanisms remain undefined. Here, by performing single-cell RNA sequencing in colorectal cancer tissues, we found tumor-associated macrophages and granulocytic myeloid-derived suppressor cells increased most compared to their counterparts in normal tissue and displayed the highest immune-inhibitory signatures among all immunocytes. These cells exhibited significantly increased expression of immunoreceptor tyrosine-based inhibitory motif-bearing receptors, including SIRPA. Notably, Sirpa−/− mice were more resistant to tumor progression than wild-type mice. Moreover, Sirpα deficiency reprogramed the tumor microenvironment through expansion of TAM_Ccl8hi and gMDSC_H2-Q10hi subsets showing strong antitumor activity. Sirpa−/− macrophages presented strong phagocytosis and antigen presentation to enhance T cell activation and proliferation. Furthermore, Sirpa−/− macrophages facilitated T cell recruitment via Syk/Btk-dependent Ccl8 secretion. Therefore, Sirpα deficiency enhances innate and adaptive immune activation independent of expression of CD47 and Sirpα blockade could be a promising strategy to improve cancer.

免疫抑制性髓系细胞抑制了肿瘤的免疫治疗效果，但确切的机制仍未确定。在这里，该研究通过对结直肠癌组织进行单细胞RNA测序，发现肿瘤相关巨噬细胞（TAMs）和粒细胞样髓源性抑制细胞（gMDSCs）在肿瘤组织中显著富集，且呈现出最强的免疫抑制性，同时高表达免疫受体SIRPA等。为进一步探索SIRPA等免疫抑制性受体对肿瘤的影响，研究团队利用CRISPR-Cas9技术建立了多种基因敲除小鼠（SirpKO、Clec4aKO和Siglec-EKO），结果显示，基因敲除小鼠中的肿瘤进展被显著抑制，小鼠生存率提高。敲除Sirp可使得TAMs和gMDSCs向具有更强的抗原呈递能力、细胞吞噬能力、炎症应答能力和趋化作用的TAM_Ccl8hi和gMDSC_H2-Q10hi亚群转化，并可促进T细胞的活化与增殖，从而重塑TME使其呈现出更强的抗肿瘤作用。体外实验表明，Sirp敲除鼠中的巨噬细胞可通过脾酪氨酸激酶/布鲁顿酪氨酸激酶（Syk/Btk）激酶依赖的趋化因子Ccl8分泌而促进T细胞募集发挥抗肿瘤免疫作用。因此，靶向Sirp可以同时调节先天免疫和适应性免疫，重塑肿瘤免疫微环境使其呈现出更强的抗肿瘤免疫效应，从而阻止实体肿瘤的进展。Sirp阻断有望成为实体肿瘤免疫治疗的新靶点，攻克实体肿瘤免疫治疗耐受的困境。

哥伦比亚大学

Abstract：

The contribution of antitumor immunity to metastatic dormancy is poorly understood. Here we show that the long noncoding RNA Malat1 is required for tumor initiation and metastatic reactivation in mouse models of breast cancer and other tumor types. Malat1 localizes to nuclear speckles to couple transcription, splicing and mRNA maturation. In metastatic cells, Malat1 induces WNT ligands, autocrine loops to promote self-renewal and the expression of Serpin protease inhibitors. Through inhibition of caspase-1 and cathepsin G, SERPINB6B prevents gasdermin D-mediated induction of pyroptosis. In this way, SERPINB6B suppresses immunogenic cell death and confers evasion of T cell-mediated tumor lysis of incipient metastatic cells. On-target inhibition of Malat1 using therapeutic antisense nucleotides suppresses metastasis in a SERPINB6B-dependent manner. These results suggest that Malat1-induced expression of SERPINB6B can titrate pyroptosis and immune recognition at metastatic sites. Thus, Malat1 is at the nexus of tumor initiation, reactivation and immune evasion and represents a tractable and clinically relevant drug target.

癌细胞扩散后会在转移部位进入休眠状态，直到适应新环境并构建支持性生态位才会重新分裂，但目前癌细胞转移性休眠的免疫逃避机制仍不完全明确。在这里，该研究发现，在乳腺癌和其他肿瘤类型的小鼠模型中，长链非编码RNAMalat1是肿瘤起始和转移再激活所必需的。在转移细胞中，Malat1诱导WNT配体、自分泌环以促进自我更新和丝氨酸蛋白酶抑制剂的表达。通过抑制半胱氨酸蛋白酶1（caspase-1）和组织蛋白酶G，丝氨酸蛋白酶抑制剂（SERPINB6B）阻止消皮素D（gasderminD）介导的细胞焦亡，并逃避T细胞介导的早期转移细胞的肿瘤裂解。使用治疗性反义核苷酸靶向抑制Malat1可以以SERPINB6B依赖性的方式抑制肿瘤转移。这些结果表明，Malat1诱导的SERPINB6B的表达可以调节转移部位的细胞焦亡和免疫识别。因此，靶向MALAT1可能为治疗转移性乳腺癌提供新途径。

17.Autotaxin–lysolipid signaling suppresses a CCL11–eosinophil axis to promote pancreatic cancer progression.

美国俄勒冈健康与科学大学，纪念斯隆-凯特琳癌症中心

Abstract：

Lipids and their modifying enzymes regulate diverse features of the tumor microenvironment and cancer progression. The secreted enzyme autotaxin (ATX) hydrolyzes extracellular lysophosphatidylcholine to generate the multifunctional lipid mediator lysophosphatidic acid (LPA) and supports the growth of several tumor types, including pancreatic ductal adenocarcinoma (PDAC). Here we show that ATX suppresses the accumulation of eosinophils in the PDAC microenvironment. Genetic or pharmacologic ATX inhibition increased the number of intratumor eosinophils, which promote tumor cell apoptosis locally and suppress tumor progression. Mechanistically, ATX suppresses eosinophil accumulation via an autocrine feedback loop, wherein ATX–LPA signaling negatively regulates the activity of the AP-1 transcription factor c-Jun, in turn suppressing the expression of the potent eosinophil chemoattractant CCL11 (eotaxin-1). Eosinophils were identified in human PDAC specimens, and rare individuals with high intratumor eosinophil abundance had the longest overall survival. Together with recent findings, this study reveals the context-dependent, immune-modulatory potential of ATX–LPA signaling in cancer.

脂质及其修饰酶会调节肿瘤微环境和癌症进展的不同特征。分泌的自体化酶（ATX）会水解细胞外溶血磷脂酰胆碱，生成多功能脂质介质溶血磷脂酸（LPA），并支持多种肿瘤类型的生长，包括胰腺导管腺癌（PDAC）。在这里，该研究表明ATX抑制了PDAC微环境中嗜酸性粒细胞的积累，通过基因或药理学方法抑制ATX可以增加肿瘤内嗜酸性粒细胞的数量，从而促进肿瘤细胞局部凋亡并抑制肿瘤进展。从机制上讲，ATX通过自分泌反馈回路抑制嗜酸性粒细胞积累，其中ATX-LPA信号转导负调控AP-1转录因子c-Jun的活性，进而抑制强效嗜酸性粒细胞化学引诱剂CCL11（eotaxin-1）的表达。该研究还在人类PDAC标本中鉴定出嗜酸性粒细胞，并且发现，极少数的肿瘤内嗜酸性粒细胞丰度高的患者总生存期最长。结合最近的研究结果，这项研究揭示了ATX-LPA信号转导在癌症中的免疫调节潜力。

18.Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease.

美国纪念斯隆-凯特琳癌症中心，德国图宾根大学

Abstract：

Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models. Here we developed methods to somatically introduce different oncogenic lesions directly into the murine gastric epithelium. Genotypic configurations observed in patients produced metastatic gastric cancers that recapitulated the histological, molecular and clinical features of all nonviral molecular subtypes of the human disease. Applying this platform to both wild-type and immunodeficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells, which produced distinct patterns of metastasis that were mirrored in patients. Our results establish a highly portable platform for generating autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts.

转移性胃癌是一种高致死性癌症，对常规和分子靶向治疗反应不佳，尽管其临床相关性很高，但由于可追溯的模型数量不足，该疾病的行为和治疗反应机制尚不明确。在此，该研究开发了将不同致癌病变体细胞引入小鼠胃上皮的方法，并开发了适用于具有一系列癌症基因型的胃癌小鼠的手术方法和电穿孔条件，可以模拟人类疾病的所有的非病毒亚型。此外，该研究还将这种方法与不同遗传背景的小鼠相结合，以探索转移扩散相关的肿瘤与宿主之前的相互作用。这些基于电穿孔的基因小鼠模型（EPO-GEMM）为探索胃癌如何在复杂的体内环境中演变、扩散和对治疗做出反应创造了新的可能性。

19.Multiregion sampling of de novo metastatic prostate cancer reveals complex polyclonality and augments clinical genotyping.

加拿大大不列颠哥伦比亚大学

Abstract：

新发转移性前列腺癌具有高度侵袭性，但常规收集组织的不足阻碍了基因组分层和精准肿瘤学的发展。在这项罕见的研究中，研究者对43例新发转移性前列腺癌患者进行了手术干预，评估了607个同步原发和转移组织区域以及循环肿瘤中的体细胞基因型。前列腺内部异质性普遍存在并影响临床相关基因，导致选定的原发限制区域和同步转移之间的基因型不一致。额外的复杂性来源于与原发肿瘤相关的多克隆性转移性播种。在模拟临床实践时，仅依赖单一组织区域的基因组学分析存在困难，因为基因型的异质性以及样本中肿瘤细胞的比例不一致可能导致对主要疾病的基因型分析错误。但在测序之前，从多个活检核心中提取DNA可以纠正错误的体细胞基因型。该研究的结果定义了患有新发转移性前列腺癌的男性中同步治疗敏感的原发性和转移性病变之间的关系，并为实施基因组学导向的患者管理提供了框架。

20.Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism.

美国匹兹堡大学

Abstract：

Glioblastoma is the most lethal primary brain tumor with glioblastoma stem cells (GSCs) atop a cellular hierarchy. GSCs often reside in a perivascular niche, where they receive maintenance cues from endothelial cells, but the role of heterogeneous endothelial cell populations remains unresolved. Here, we show that lymphatic endothelial-like cells (LECs), while previously unrecognized in brain parenchyma, are present in glioblastomas and promote growth of CCR7-positive GSCs through CCL21 secretion. Disruption of CCL21–CCR7 paracrine communication between LECs and GSCs inhibited GSC proliferation and growth. LEC-derived CCL21 induced KAT5-mediated acetylation of HMGCS1 on K273 in GSCs to enhance HMGCS1 protein stability. HMGCS1 promoted cholesterol synthesis in GSCs, favorable for tumor growth. Expression of the CCL21–CCR7 axis correlated with KAT5 expression and HMGCS1K273 acetylation in glioblastoma specimens, informing patient outcome. Collectively, glioblastomas contain previously unrecognized LECs that promote the molecular crosstalk between endothelial and tumor cells, offering potentially alternative therapeutic strategies.

胶质母细胞瘤是最致命的原发性脑肿瘤，其中胶质母细胞瘤干细胞（GSCs）位于细胞层次结构的顶端。GSC通常位于血管周围的微环境中，在那里它们接收来自内皮细胞的维持信号，但异质内皮细胞群对它的影响仍未解决。在这里，该研究发现淋巴管内皮样细胞（LEC）虽然以前在脑实质中未被识别，但存在于胶质母细胞瘤中，并通过CCL21分泌促进CCR7阳性GSC的生长。破坏LEC和GSC之间CCL21-CCR7旁分泌通讯能抑制GSC的增殖和生长。LEC来源的CCL21诱导GSC中KAT5介导的HMGCS1在K273上的乙酰化，以增强HMGCS1蛋白的稳定性。HMGCS1促进GSC中胆固醇的合成，有利于肿瘤生长。胶质母细胞瘤标本中CCL21-CCR7轴的表达与KAT5的表达和HMGCS1K273乙酰化呈正相关，可用于预测患者的预后。总的来说，胶质母细胞瘤含有以前未被识别的LEC，这些细胞促进了内皮和肿瘤细胞之间的分子相互作用，为寻找潜在的替代治疗策略提供了新思路。

21.Bacteria and bacteriophage consortia are associated with protective intestinal metabolites in patients receiving stem cell transplantation.

细菌和噬菌体菌群与接受干细胞移植的患者的肠道保护性代谢物有关

德国雷根斯堡大学

Abstract：

The microbiome is a predictor of clinical outcome in patients receiving allogeneic hematopoietic stem cell transplantation (allo-SCT). Microbiota-derived metabolites can modulate these outcomes. How bacteria, fungi and viruses contribute to the production of intestinal metabolites is still unclear. We combined amplicon sequencing, viral metagenomics and targeted metabolomics from stool samples of patients receiving allo-SCT (n = 78) and uncovered a microbiome signature of Lachnospiraceae and Oscillospiraceae and their associated bacteriophages, correlating with the production of immunomodulatory metabolites (IMMs). Moreover, we established the IMM risk index (IMM-RI), which was associated with improved survival and reduced relapse. A high abundance of short-chain fatty acid-biosynthesis pathways, specifically butyric acid via butyryl-coenzyme A (CoA):acetate CoA-transferase (BCoAT, which catalyzes EC 2.8.3.8) was detected in IMM-RI low-risk patients, and virome genome assembly identified two bacteriophages encoding BCoAT as an auxiliary metabolic gene. In conclusion, our study identifies a microbiome signature associated with protective IMMs and provides a rationale for considering metabolite-producing consortia and metabolite formulations as microbiome-based therapies.

在接受异基因造血干细胞移植（allo-SCT）的患者中，微生物组被认为是临床结局的预测因素。微生物群落衍生的代谢产物可以影响这些结果。然而，细菌、真菌和病毒在促进肠道代谢产物生成方面的具体贡献仍然不清楚。我们将接受allo-SCT患者的粪便样本（n=78）的扩增子测序、病毒宏基因组学和靶向代谢组学结合起来，发现了与免疫调节代谢产物（IMMs）生成相关的Lachnospiraceae和Oscillospiraceae的微生物组特征及其相关的噬菌体。此外，研究还建立了IMM风险指数（IMM-RI），该指数与提高生存率和减少复发相关。并且，研究在IMM-RI低风险患者中检测到大量的短链脂肪酸生物合成途径，特别是通过丁酰辅酶A（CoA）:乙酸CoA转移酶（BCoAT，催化EC2.8.3.8）产生的丁酸，此外，病毒组的基因组组装还识别出两种噬菌体编码BCoAT的基因作为辅助代谢基因。总之，该研究确定了与保护性IMM相关的微生物组特征，并为将产生代谢物的联合体和代谢物制剂作为基于微生物组的疗法提供了理由。

22.PD-1 defines a distinct, functional, tissue-adapted state in Vδ1+ T cells with implications for cancer immunotherapy.

英国伦敦国王学院

Abstract：

Checkpoint inhibition (CPI), particularly that targeting the inhibitory coreceptor programmed cell death protein 1 (PD-1), has transformed oncology. Although CPI can derepress cancer (neo)antigen-specific αβ T cells that ordinarily show PD-1-dependent exhaustion, it can also be efficacious against cancers evading αβ T cell recognition. In such settings, γδ T cells have been implicated, but the functional relevance of PD-1 expression by these cells is unclear. Here we demonstrate that intratumoral TRDV1 transcripts (encoding the TCRδ chain of Vδ1+ γδ T cells) predict anti-PD-1 CPI response in patients with melanoma, particularly those harboring below average neoantigens. Moreover, using a protocol yielding substantial numbers of tissue-derived Vδ1+ cells, we show that PD-1+Vδ1+ cells display a transcriptomic program similar to, but distinct from, the canonical exhaustion program of colocated PD-1+CD8+ αβ T cells. In particular, PD-1+Vδ1+ cells retained effector responses to TCR signaling that were inhibitable by PD-1 engagement and derepressed by CPI.

检查点抑制（CPI），特别是靶向抑制性共受体程序性细胞死亡蛋白1（PD-1）的检查点抑制，已经改变了肿瘤学。虽然CPI可以抑制表现出PD-1依赖性耗竭的癌症（新）抗原特异性αβT细胞，但它也可以有效对抗逃避αβT细胞识别的癌症。在这种情况下，γδT细胞与此有关，但这些细胞表达PD-1的功能相关性尚不清楚。在这里，该研究证明肿瘤内TRDV1转录本（编码Vδ1+γδT细胞的TCRδ链）可以预测黑色素瘤患者对抗PD-1CPI的反应，特别是那些新抗原低于平均水平的患者。此外，使用产生大量组织来源的Vδ1+细胞的方案，研究发现PD-1+Vδ1细胞表现出与共存PD-1+CD8+αβT细胞的典型衰竭程序相似但不同的转录组程序。特别是，PD-1+Vδ1+细胞保留了对TCR信号的效应子反应，这些反应可以通过与PD-1结合而受到抑制，同时也可以通过CPI而解除抑制。

23.Presence of onco-fetal neighborhoods in hepatocellular carcinoma is associated with relapse and response to immunotherapy.

肝细胞癌中癌-胚邻域的存在与复发和对免疫治疗的反应有关

上海交通大学，新加坡国立大学，澳大利亚科廷大学

Abstract：

Onco-fetal reprogramming of the tumor ecosystem induces fetal developmental signatures in the tumor microenvironment, leading to immunosuppressive features. Here, we employed single-cell RNA sequencing, spatial transcriptomics and bulk RNA sequencing to delineate specific cell subsets involved in hepatocellular carcinoma (HCC) relapse and response to immunotherapy. We identified POSTN+ extracellular matrix cancer-associated fibroblasts (EM CAFs) as a prominent onco-fetal interacting hub, promoting tumor progression. Cell–cell communication and spatial transcriptomics analysis revealed crosstalk and co-localization of onco-fetal cells, including POSTN+ CAFs, FOLR2+ macrophages and PLVAP+ endothelial cells. Further analyses suggest an association between onco-fetal reprogramming and epithelial–mesenchymal transition (EMT), tumor cell proliferation and recruitment of Treg cells, ultimately influencing early relapse and response to immunotherapy. In summary, our study identifies POSTN+ CAFs as part of the HCC onco-fetal niche and highlights its potential influence in EMT, relapse and immunotherapy response, paving the way for the use of onco-fetal signatures for therapeutic stratification.

肿瘤生态系统的瘤胚重编程会诱导肿瘤微环境中产生具有胚胎特征的癌症干细胞，从而导致免疫抑制。在这里，该研究采用单细胞RNA测序、空间转录组学和批量RNA测序来描绘与肝细胞癌（HCC）复发和免疫治疗反应有关的特定细胞亚群。研究认为POSTN+细胞外基质癌症相关成纤维细胞（EMCAF）是一个重要的癌胚相互作用中心，促进肿瘤进展。细胞间通讯和空间转录组学分析揭示了癌胚细胞的串扰和共定位，包括POSTN+CAFs、FOLR2+巨噬细胞和PLVAP+内皮细胞。进一步的分析表明，癌胚重编程与上皮间质转化（EMT）、肿瘤细胞增殖和Treg细胞募集之间存在关联，最终影响肿瘤的早期复发和对免疫治疗的反应。总的来说，该研究表明POSTN+CAFs是HCC癌胎巢的一部分，并突显了其对EMT、复发和免疫治疗反应的潜在影响，为利用癌胎特征进行治疗分层提供了基础。

24.Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer.

复旦大学，美国宾夕法尼亚大学

Abstract：

Availability of the essential amino acid methionine affects cellular metabolism and growth, and dietary methionine restriction has been implicated as a cancer therapeutic strategy. Nevertheless, how liver cancer cells respond to methionine deprivation and underlying mechanisms remain unclear. Here we find that human liver cancer cells undergo irreversible cell cycle arrest upon methionine deprivation in vitro. Blocking methionine adenosyl transferase 2A (MAT2A)-dependent methionine catabolism induces cell cycle arrest and DNA damage in liver cancer cells, resulting in cellular senescence. A pharmacological screen further identified GSK3 inhibitors as senolytics that selectively kill MAT2A-inhibited senescent liver cancer cells. Importantly, combined treatment with MAT2A and GSK3 inhibitors therapeutically blunts liver tumor growth in vitro and in vivo across multiple models. Together, methionine catabolism is essential for liver tumor growth, and its inhibition can be exploited as an improved pro-senescence strategy for combination with senolytic agents to treat liver cancer.

蛋氨酸这种必需氨基酸的供应对细胞代谢和生长具有重要影响，而膳食中限制蛋氨酸的摄入被认为是一种癌症治疗策略。然而，肝癌细胞如何对蛋氨酸剥夺做出反应及其潜在机制仍不清楚。在这里，该研究发现人类肝癌细胞在体外剥夺蛋氨酸时会经历不可逆的细胞周期停滞。阻断蛋氨酸腺苷转移酶2A（MAT2A）依赖性蛋氨酸分解代谢会导致肝癌细胞的细胞周期停滞和DNA损伤，从而导致细胞衰老。研究通过药理学筛选进一步鉴定出GSK3抑制剂能选择性杀死MAT2A受抑制的衰老肝癌细胞。重要的是，MAT2A和GSK3抑制剂的联合治疗在多种模型中能治疗性地抑制体外和体内的肝肿瘤生长。总之，蛋氨酸分解代谢对肝肿瘤的生长至关重要，抑制蛋氨酸摄入可以作为一种改进的促肝癌细胞衰老策略，可以和抗衰老剂联合治疗肝癌。

25.Small-molecule inhibition of kinesin KIF18A reveals a mitotic vulnerability enriched in chromosomally unstable cancers.

驱动蛋白 KIF18A 的小分子抑制剂揭示了在染色体不稳定癌症中有丝分裂的易损性

意大利人文大学生物医学系

Abstract：

Chromosomal instability (CIN) is a hallmark of cancer, caused by persistent errors in chromosome segregation during mitosis. Aggressive cancers like high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) have a high frequency of CIN and TP53 mutations. Here, we show that inhibitors of the KIF18A motor protein activate the mitotic checkpoint and selectively kill chromosomally unstable cancer cells. Sensitivity to KIF18A inhibition is enriched in TP53-mutant HGSOC and TNBC cell lines with CIN features, including in a subset of CCNE1-amplified, CDK4–CDK6-inhibitor-resistant and BRCA1-altered cell line models. Our KIF18A inhibitors have minimal detrimental effects on human bone marrow cells in culture, distinct from other anti-mitotic agents. In mice, inhibition of KIF18A leads to robust anti-cancer effects with tumor regression observed in human HGSOC and TNBC models at well-tolerated doses. Collectively, our results provide a rational therapeutic strategy for selective targeting of CIN cancers via KIF18A inhibition.

染色体不稳定性（CIN）是癌症的一个标志，是由有丝分裂过程中染色体分离的持续出现错误引起的。高级别浆液性卵巢癌（HGSOC）和三阴性乳腺癌（TNBC）等侵袭性癌症具有高频率的CIN和TP53突变。在这里，该研究发现KIF18A运动蛋白的抑制剂激活有丝分裂检查点并选择性杀死染色体不稳定的癌细胞。具有CIN特征的并且TP53突变的HGSOC和TNBC细胞系对KIF18A抑制的敏感性会增强，包括一些CCNE1扩增、CDK4-CDK6抑制剂耐药和BRCA1改变的细胞系模型。与其他抗有丝分裂剂不同，KIF18A抑制剂对体外培养的人骨髓细胞的有害影响极小。在小鼠中，抑制KIF18A会产生强大的抗癌作用，在人类HGSOC和TNBC模型中以耐受良好的剂量治疗能观察到肿瘤消退。总的来说，该研究的结果为通过KIF18A抑制选择性靶向CIN癌症提供了合理的治疗策略。

26.Cytokine-armed dendritic cell progenitors for antigen-agnostic cancer immunotherapy.

瑞士癌症实验研究所，瑞士洛桑联邦理工学院

Abstract：

Dendritic cells (DCs) are antigen-presenting myeloid cells that regulate T cell activation, trafficking and function. Monocyte-derived DCs pulsed with tumor antigens have been tested extensively for therapeutic vaccination in cancer, with mixed clinical results. Here, we present a cell-therapy platform based on mouse or human DC progenitors (DCPs) engineered to produce two immunostimulatory cytokines, IL-12 and FLT3L. Cytokine-armed DCPs differentiated into conventional type-I DCs (cDC1) and suppressed tumor growth, including melanoma and autochthonous liver models, without the need for antigen loading or myeloablative host conditioning. Tumor response involved synergy between IL-12 and FLT3L and was associated with natural killer and T cell infiltration and activation, M1-like macrophage programming and ischemic tumor necrosis. Antitumor immunity was dependent on endogenous cDC1 expansion and interferon-γ signaling but did not require CD8+ T cell cytotoxicity. Cytokine-armed DCPs synergized effectively with anti-GD2 chimeric-antigen receptor (CAR) T cells in eradicating intracranial gliomas in mice, illustrating their potential in combination therapies.

树突状细胞（DC）是呈递抗原的髓样细胞，可调节T细胞的活化、运输和功能。用肿瘤抗原脉冲的单核细胞来源的DC已被用于癌症的治疗性疫苗接种，虽然已经广泛测试，但临床结果不一。在这里，该研究提出了一个基于小鼠或人类DC祖细胞（DCP）的细胞治疗平台，该平台经过改造可产生两种免疫刺激细胞因子，IL-12和FLT3L。携带细胞因子的DCP可以分化为传统的I型DC（cDC1）并抑制肿瘤生长，包括黑色素瘤和肝肿瘤模型，而不需要抗原装载或宿主的清髓性条件。肿瘤反应涉及IL-12和FLT3L之间的协同作用，并与自然杀伤和T细胞浸润和活化、M1样巨噬细胞程序性和缺血性肿瘤坏死有关。抗肿瘤免疫依赖于内源性cDC1扩增和干扰素-γ信号传导，但不需要CD8+T细胞的细胞毒性。携带细胞因子的DCP与抗GD2嵌合抗原受体（CAR）T细胞协同使用能有效根除小鼠颅内胶质瘤，说明了它们在联合疗法中的潜力。

27.Genomic and immune signatures predict clinical outcome in newly diagnosed multiple myeloma treated with immunotherapy regimens. 基因组和免疫特征预测新诊断的多发性骨髓瘤接受免疫治疗方案的临床结果.

美国迈阿密大学

Abstract：

Despite improving outcomes, 40% of patients with newly diagnosed multiple myeloma treated with regimens containing daratumumab, a CD38-targeted monoclonal antibody, progress prematurely. By integrating tumor whole-genome and microenvironment single-cell RNA sequencing from upfront phase 2 trials using carfilzomib, lenalidomide and dexamethasone with daratumumab (NCT03290950), we show how distinct genomic drivers including high APOBEC mutational activity, IKZF3 and RPL5 deletions and 8q gain affect clinical outcomes. Furthermore, evaluation of paired bone marrow profiles, taken before and after eight cycles of carfilzomib, lenalidomide and dexamethasone with daratumumab, shows that numbers of natural killer cells before treatment, high T cell receptor diversity before treatment, the disappearance of sustained immune activation (that is, B cells and T cells) and monocyte expansion over time are all predictive of sustained minimal residual disease negativity. Overall, this study provides strong evidence of a complex interplay between tumor cells and the immune microenvironment that is predictive of clinical outcome and depth of treatment response in patients with newly diagnosed multiple myeloma treated with highly effective combinations containing anti-CD38 antibodies.

尽管含达拉葛单抗（一种CD38靶向的单克隆抗体）的治疗方案改善了患者预后，但有40%的新诊断多发性骨髓瘤患者的肿瘤会提前进展。在此该研究通过整合来自使用卡非佐米、来那度胺和地塞米松与达雷妥尤单抗（NCT03290950）的前期2期试验的肿瘤全基因组和微环境单细胞RNA测序数据，展示了不同的基因组驱动因素，包括高APOBEC突变活性、IKZF3和RPL5缺失以及8q增益对临床结果的影响。此外，研究对配对的骨髓样本进行了评估，即在接受八个周期卡法替尼、来那度胺和地塞米松与达拉葛单抗治疗的前后进行评估，结果显示，治疗前的自然杀伤细胞数量、治疗前的T细胞受体多样性高、持续免疫激活（即B细胞和T细胞）的消失以及随时间推移单核细胞扩张都是持续无残余疾病状态的预测因子。总体而言，这项研究提供了强有力的证据，证明肿瘤细胞和免疫微环境之间复杂的相互作用，可以预测新诊断的多发性骨髓瘤患者接受含有抗CD38抗体的高效组合治疗的临床结果和治疗反应深度。

28.Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia.

伊美司他介导的脂肪酸代谢改变诱导铁死亡作为急性髓系白血病的治疗策略

美国德克萨斯大学西南医学中心病理学

Abstract：

Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML.

端粒酶可在大多数癌症中实现复制性永生，包括急性髓系白血病（AML）。Imetelstat是一种首创的端粒酶抑制剂，对骨髓纤维化和骨髓增生异常综合征具有临床疗效。在这项研究中，我们建立了一个AML患者来源的异种移植模型资源，并进行了综合的基因组学、转录组学和脂质组学分析，并结合功能基因学，以确定Imetelstat疗效的关键介导因子。在一项针对患者来源的异种移植物的随机II期类临床前试验中，imetelstat有效减轻了AML负担，并优先靶向含有突变NRAS和有氧化应激相关基因表达特征的亚型。另外，无偏倚的全基因组CRISPR/Cas9编辑将铁死亡调节因子确定为imetelstat疗效的关键介质。Imetelstat促进含多不饱和脂肪酸磷脂的形成，导致脂质过氧化和氧化应激水平过高。铁死亡的药理学抑制会降低imetelstat的疗效。总的来说，该研究利用目前对这些机制认识，来开发了一种优化的治疗策略，使用氧化应激诱导化疗增加患者样本对imetelstat的敏感性，从而使AML得到实质性的控制。

29.Structural surfaceomics reveals an AML-specific conformation of integrin β2 as a CAR T cellular therapy target.

结构表面组学揭示了整合素β2的AML特异性构象作为CAR T细胞治疗靶点

荷兰皇家艺术与科学学院

Abstract：

Safely expanding indications for cellular therapies has been challenging given a lack of highly cancer-specific surface markers. Here we explore the hypothesis that tumor cells express cancer-specific surface protein conformations that are invisible to standard target discovery pipelines evaluating gene or protein expression, and these conformations can be identified and immunotherapeutically targeted. We term this strategy integrating cross-linking mass spectrometry with glycoprotein surface capture ‘structural surfaceomics’. As a proof of principle, we apply this technology to acute myeloid leukemia (AML), a hematologic malignancy with dismal outcomes and no known optimal immunotherapy target. We identify the activated conformation of integrin β2 as a structurally defined, widely expressed AML-specific target. We develop and characterize recombinant antibodies to this protein conformation and show that chimeric antigen receptor T cells eliminate AML cells and patient-derived xenografts without notable toxicity toward normal hematopoietic cells. Our findings validate an AML conformation-specific target antigen and demonstrate a tool kit for applying these strategies more broadly.

由于缺乏高度癌症特异性的表面标志物，安全地扩大细胞疗法的适应症一直具有挑战性。在这里，该研究探讨了这样的假设：肿瘤细胞表达癌症特异性表面蛋白构象，但通过评估基因或蛋白质表达的标准靶标发现流程是无法发现这些构象的，而这些构象可以被识别并进行免疫治疗靶向。该研究将交联质谱与糖蛋白表面捕获相结合的策略称为“结构表面组学”。作为原理证明，研究将该技术应用于急性髓系白血病（AML），这是一种血液恶性肿瘤，且没有已知的最佳免疫治疗靶点。研究将整合素β2的激活构象确定为结构明确、广泛表达的AML特异性靶点，研究还开发、表征了针对这种蛋白质构象的重组抗体，并发现嵌合抗原受体T细胞消除了AML细胞和患者来源的异种移植物，而对正常造血细胞没有明显的毒性。该研究的方法发现了AML构象特异性靶标抗原，并展现了一个发现特异性肿瘤抗原的新策略。

30.Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia.

美国纽约纪念斯隆-凯特琳癌症中心

Abstract：

Despite recent advances in the treatment of acute myeloid leukemia (AML), there has been limited success in targeting surface antigens in AML, in part due to shared expression across malignant and normal cells. Here, high-density immunophenotyping of AML coupled with proteogenomics identified unique expression of a variety of antigens, including the RNA helicase U5 snRNP200, on the surface of AML cells but not on normal hematopoietic precursors and skewed Fc receptor distribution in the AML immune microenvironment. Cell membrane localization of U5 snRNP200 was linked to surface expression of the Fcγ receptor IIIA (FcγIIIA, also known as CD32A) and correlated with expression of interferon-regulated immune response genes. Anti-U5 snRNP200 antibodies engaging activating Fcγ receptors were efficacious across immunocompetent AML models and were augmented by combination with azacitidine. These data provide a roadmap of AML-associated antigens with Fc receptor distribution in AML and highlight the potential for targeting the AML cell surface using Fc-optimized therapeutics.