肿瘤转移是造成癌症患者死亡的主要原因。中国科学院分子细胞科学卓越创新中心的王广川研究团 队联合相关合作团队建立了一种新型技术平台——CLIM-TIME，以小鼠为动物模型，揭示了肿瘤遗传 突变"改造"微环境进而导致免疫治疗耐药的基本规律。 王广川表示，研究首次在高通量（同时开展大规模分析）尺度上建立了"肿瘤内在遗传扰动-微环境 结构-免疫治疗效果"之间的因果联系。目前相关研究基于动物模型，临床场景更为复杂，需开展更多安 全性及疗效的评价。 0:00 / 3:56 肿瘤微环境导致免疫治疗耐药 科研人员破解其中密码 相关论文于北京时间12日在线发表于国际学术期刊《细胞》（Cell）。 近年来的研究发现，肿瘤微环境的特征和类型，与免疫治疗的效果密切相关。研究团队初步分析了 391种常见抑癌基因形成的转移瘤微环境如何影响免疫治疗，并将这些微环境分为七大类，对其中一类 进行了深入研究。 中国科学院分子细胞科学卓越创新中心研究员王广川当天在沪受访时介绍，团队深入研究的这一类 微环境里沉积了大量的胶原蛋白，微环境里的肿瘤细胞像蜘蛛，它们织了网，不仅给自身提供支撑， 还"猎捕"了更多免疫细胞，形成致密的屏障。这样的屏障，让免疫 ...

进一步研究发现，对免疫药物"无动于衷"的肿瘤转移微环境中，胶原蛋白的沉积显著增加。"这种 微环境的形成过程就像蜘蛛结了一个网，不仅保护了蜘蛛，T细胞也成为了这个网的猎物，从而大大削 弱了这支'特种部队'的战斗力。"王广川说。 为解决耐药难题提供新策略 如何"攻破"这道致密的"蜘蛛网"？研究团队锁定了一个关键分子——赖氨酸氧化酶样蛋白2。通过 抑制它，可显著减少肿瘤中的胶原沉积，使被阻挡的T细胞能够成功突破"屏障"，顺利进入肿瘤内部执 行任务。这一策略在多种小鼠以及肺转移肿瘤动物模型中都增强了免疫治疗的抗肿瘤效果。 与此同时，团队利用AI算法找到了肿瘤微环境免疫状态的因果基因，构建了凭借"30个特征基因"可 准确预测免疫治疗效果的模型。 T细胞具有免疫活性，好比人体内的特种部队，专门抵抗外来入侵者。但早在1968年，瑞典肿瘤免 疫学家就提出过一个经典悖论——为什么有些实体瘤中的T细胞不能有效阻止肿瘤生长？ 近年来的研究发现，肿瘤微环境特别是转移过程中形成的微环境，与免疫治疗的效果密切相关。肿 瘤可以通过遗传突变改造微环境，并形成免疫"屏障"，导致免疫治疗受限。 为破解"屏障"形成的机制，中国科学院分子细胞科学卓 ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 肿瘤微环境 （TME） 是有效免疫治疗的主要障碍，然而，用于剖析肿瘤微环境空间复杂性及其背景免疫调 节剂的高通量扰动图谱方法，目前仍显不足。 在这项最新研究中，研究团队开发了肿瘤免疫微环境的 CRISPR-激光捕获显微切割整合图谱—— CLIM- TIME （ C RISPR- L aser-captured microdissection I ntegration M apping of T umor I mmune M icro e nvironment ） ，这是一个可扩展平台，将 CRISPR 筛选与转移性肿瘤的 激光显微切割 （ LCM ） 相结合，用于转录组学、去卷积和免疫荧光分析。 CLIM-TIME 能够实现空间分辨的 肿瘤抑制基因 （ tumor suppressor gene， TSG） 缺失如何重塑肿 瘤微环境 （TME） 并调控免疫反应的图谱绘制。利用 CLIM-TIME ，研究团队确定了 七种 不同的肿瘤微 环境 （TME） 亚型，揭示出 DNA 修复和多梳抑制复合物 （PRC） 肿瘤抑制基因 （TSG） 的缺失与对 T 细胞疗法敏感的免疫浸润 ...

Core Viewpoint - The article discusses the complex interactions between cancer cells and the tumor microenvironment (TME), emphasizing the potential of targeted cancer immunotherapies to disrupt immunosuppressive interactions, although many therapies show limited durability due to a lack of understanding of these interactions [2][3]. Group 1: Research Findings - A study published by a team from the University of Chicago reveals that tumor-initiating stem cells (tSC) regulate the plasticity of neutrophils through metabolic reprogramming, creating a protective niche that allows them to survive cancer immunotherapy, leading to cancer recurrence [4]. - The research indicates that targeting the SOX2-FADS1-PGE2 signaling axis could serve as a novel combination therapy strategy to prevent immunotherapy resistance and tumor recurrence [4]. Group 2: Mechanisms of Immune Evasion - The study highlights the heterogeneity of tumor-associated neutrophils (TAN) and how different states of TAN arise and evolve, impacting the effectiveness of cancer immunotherapy [8]. - It was found that anti-PDL1 + CD40 agonist immunotherapy can induce TAN to regain anti-tumor activity in squamous cell carcinoma (SCC), while TAN at the tumor-stroma interface maintain their immunosuppressive state [8]. Group 3: Key Pathways and Implications - The SOX2 high-expressing tSCs enhance PGE2 signaling in TAN, which may disrupt interferon responses and inhibit the anti-tumor functions of TAN [9]. - Specific knockout of PGE2 receptors in neutrophils or using COX-2 inhibitors to block PGE2 synthesis can effectively restore the anti-tumor functions of neutrophils, enhancing the efficacy of immunotherapy and significantly reducing tumor recurrence rates [9]. Group 4: Overall Conclusions - The research explores how effective immunotherapies influence the plasticity of TAN, revealing how tSCs evade TAN-mediated anti-tumor immunity, allowing them to survive cancer immunotherapy and promote recurrence [12].

Core Viewpoint - Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults, with a median survival of only 12-18 months post-diagnosis, and current treatments have limited efficacy in extending life expectancy [3] Group 1: Research Findings - A recent study published in Nature Cell Biology indicates that inhibiting lactate transport derived from tumor-associated macrophages (TAM) can restore cGAS-STING signaling and enhance antitumor immunity in glioblastoma [4] - The research team discovered that lactate is transported from TAM to glioblastoma stem cells (GSC) via MCT4-MCT1, promoting GSC proliferation and inducing lactylation modification of the non-homologous end joining protein KU70 at lysine 317 (K317), which inhibits cGAS-STING signaling and remodels the immunosuppressive tumor microenvironment [7] - Overall, the study reveals that lactate and lactylation modifications produced by TAM are key regulatory factors in maintaining the immunosuppressive tumor microenvironment in GSC, opening new avenues for combination therapies in glioblastoma [9]

Core Viewpoint - The article discusses the challenges and advancements in immunotherapy for pancreatic ductal adenocarcinoma (PDAC), highlighting a recent phase 1/2 clinical trial that demonstrates the safety and feasibility of autologous multiantigen-targeted T cell therapy for PDAC patients [2][3]. Summary by Sections Immunotherapy Challenges - PDAC presents significant challenges for effective immunotherapy due to weak expression of target antigens and frequent upregulation of immunosuppressive molecules, leading to a "cold tumor" microenvironment [2]. - The heterogeneity of tumor antigen expression can result in rapid adaptation and modulation of target antigens, hindering the potential of T cell monotherapy [2]. Clinical Trial Overview - A phase 1/2 clinical trial named TACTOPS was conducted to evaluate the safety and feasibility of an autologous non-engineered T cell product administered monthly at a dose of 1×10^7 cells/m² [7]. - The trial included three arms: patients responsive to first-line chemotherapy (Group A, n=13), patients resistant to first-line chemotherapy (Group B, n=12), and patients with resectable disease (Group C, n=12) [7]. Trial Results - Among 56 participants, 37 received the infusion with only one treatment-related serious adverse event reported [8]. - Disease control rates were 84.6% for Group A and 25% for Group B, while 2 out of 9 patients in Group C remained disease-free after 66 months of follow-up [8]. - The infused cells persisted for 12 months post-treatment, with responders showing higher levels of tumor-directed T cells compared to non-responders [8]. Conclusion and Future Directions - The study confirms the feasibility of generating autologous multi-tumor-associated antigen (mTAA) T cells for patients at all stages of pancreatic cancer, with a maximum of six infusions at a dose of 1×10^7 cells/m² being safe [8]. - The clinical outcomes are associated with the peripheral expansion of mTAA-targeted T cell clones and the emergence of antigen spreading during treatment, suggesting further research into TAA T cells as a standalone therapy or in combination with other novel immunotherapies or standard treatments [8].

Core Viewpoint - Kewang Pharmaceutical Group has submitted an application for listing on the Hong Kong Stock Exchange, with CITIC Securities as the sole sponsor. The company aims to develop next-generation cancer therapies globally, focusing on its core product ES102, an advanced six-valent OX40 agonist currently in clinical development [1][6]. Company Overview - Kewang Pharmaceutical, established in 2017, is a clinical-stage biopharmaceutical company dedicated to developing innovative cancer therapies by understanding the tumor microenvironment (TME) [6]. - The core product, ES102, is designed to treat cancer patients who respond poorly to immune checkpoint inhibitors (ICIs) and has shown controllable safety and anti-tumor activity in clinical trials [6][7]. Clinical Development - Since acquiring ES102 from Inhibrx in 2018, Kewang has completed two Phase 1 clinical trials in China for advanced solid tumor patients and has initiated a Phase 2 trial combining ES102 with a PD-1 inhibitor for advanced NSCLC patients [7]. - The company has a differentiated pipeline with five major assets, three of which are in clinical stages, targeting unmet medical needs in major tumor types [7]. Research and Development Capabilities - Kewang has established a comprehensive drug development engine, equipped with proprietary technologies covering the entire R&D cycle from drug discovery to clinical development [8]. - The company has developed multiple proprietary antibody discovery platforms, which are crucial for accelerating drug discovery and improving cost-effectiveness [8]. Strategic Partnerships - Kewang has formed a strategic partnership with AstraZeneca to collaborate on a new bispecific macrophage connector project, potentially earning over $1.7 billion in milestone payments [9]. - The company has also partnered with Partex N.V. to develop a platform for designing new therapeutic antibodies, leveraging AI technology [8]. Financial Overview - For the year 2024, Kewang is projected to generate revenue of RMB 106.566 million from its collaboration with AstraZeneca [10]. - The company reported a loss of RMB 729.508 million for the year 2023, with a significant reduction in losses expected in subsequent periods [10].

Core Insights - Tumor-infiltrating bacteria, particularly Fusobacterium nucleatum, are increasingly recognized as key components of the tumor microenvironment (TME) and are linked to cancer recurrence and treatment resistance [2][5] - The recent study published in Cancer Cell highlights a new mechanism by which these bacteria disrupt interactions between cancer epithelial cells and induce cell-cycle arrest, leading to resistance against chemotherapy drug 5-fluorouracil (5-FU) [3][10] Summary by Sections Tumor-Infiltrating Bacteria and Cancer - Tumor-infiltrating bacteria, especially in mucosal sites, are being viewed as critical elements of TME [2] - Specific bacteria have been associated with cancer progression and poor prognosis, such as the enrichment of Fusobacterium nucleatum in colorectal cancer (CRC) tissues [2] Mechanism of Action - The study describes how extracellular bacteria, including Fusobacterium nucleatum, regulate the behavior of cancer epithelial cells [6] - These bacteria are primarily found in the extracellular regions of the TME in colorectal and oral cancers, where cell density, transcriptional activity, and proliferation are reduced [6] Experimental Findings - In vitro experiments show that Fusobacterium nucleatum disrupts epithelial cell contact, causing cells to enter a G0-G1 phase and inhibiting transcriptional activity [6] - This state confers resistance to the chemotherapy drug 5-FU and remodels the tumor microenvironment [6] - The findings were validated through live-cell imaging, spatial analysis, mouse models, and a cohort of 52 colorectal cancer patients [6] Clinical Implications - High loads of Fusobacterium nucleatum in tumors correlate with reduced treatment response [8] - The study emphasizes the potential of targeting microbial-tumor interactions as a therapeutic strategy [10]

Core Viewpoint - The study highlights the dynamic changes in the tumor microenvironment (TME) across various cancer types and stages, emphasizing the importance of understanding cellular interactions within the TME as a promising therapeutic target [3][7]. Group 1: Research Overview - The research published in Nature Cancer integrates data from 36 cancer types and 746 samples, analyzing over 4 million single cells and spatial transcriptomics data from 6 cancer types [4][5]. - A comprehensive atlas of TME heterogeneity, named TabulaTIME, was established, detailing six major cell lineages and 56 cell subtypes within the TME [7][9]. Group 2: Key Findings - The study identified CTHRC1 as a marker for cancer-associated fibroblasts (CAFs) that are enriched in various cancer types, indicating their role in immune cell infiltration prevention [9]. - The research demonstrated that TabulaTIME can be utilized for analyzing tumor ecotype composition and serves as a reference for cell type annotation, providing insights into potential therapeutic strategies targeting profibrotic ecotypes [9].

Core Viewpoint - Aging significantly increases the risk of cancer and profoundly affects the immune system, leading to impaired immune responses to chronic and acute infections, as well as a higher susceptibility to autoimmune diseases [2]. Group 1: Research Findings - A study published by researchers at the Moffitt Cancer Center indicates that lymphoma accelerates T cell and tissue aging [3][4]. - The research shows that lymphoma induces transcriptional, epigenetic, and phenotypic changes in young T cells, which are also reflected in older T cells [8]. - Aging T cells exhibit strong resistance to changes induced by lymphoma, while lymphoma itself accelerates aging in young T cells and tissues [9]. Group 2: Immune System Changes - Aging leads to numerous changes in the immune system, including an imbalance of inflammatory cytokines and chemokines, a shift in hematopoietic stem cells towards monocyte generation, and a reduction in lymphocyte populations [6]. - Tumors escape immune surveillance by creating various pressures, such as an acidic environment that damages CD8+ T cells while promoting the expansion of regulatory T cells (Tregs) [7]. - The study highlights that lymphoma drives age-related inflammation and alters protein and iron homeostasis in T cells [9].