撰文丨王聪 编辑丨王多鱼 排版丨水成文 胶质母细胞瘤 （GBM） 是成年人中最常见、最具侵袭性的恶性脑肿瘤。胶质母细胞瘤 表现出显著的异质 性， 患者在确诊后通常只能存活 12-18 个月。 尽管经过了几十年的研究，但该疾病尚无治愈方法，而且 已批准的治疗方法 （例如手术、放疗和化疗） 在延长预期寿命方面效果有限。 胶质母细胞瘤的 肿瘤微环境 （TME） 复杂，以 胶质母细胞瘤干细胞 （GSC） 为主，并有 肿瘤相关巨噬 细胞 （TAM） 浸润，且存在异常的代谢途径。 乳酸 （ Lactate ） 是一种关键的糖酵解代谢物，可促进 肿瘤进展；然而，胶质母细胞瘤的肿瘤微环境中 乳酸转运 和 乳酸化修饰 的作用机制仍不清楚。 2026 年 1 月 6 日，南京医科大学基础医学院 汪秀星 教授、北卡罗来纳大学教堂山分校 Jeremy N. Rich 教授、南京医科大学基础医学院 张茜 副教授、南京医科大学公共卫生学院 钱旭 教授、南京医科大学第一 附属医院 张军霞 教授作为共同通讯作者 （ 李大奇 、 崔高源 、 Kailin Yang 、 陆晨飞 、 江雨韩 、 张乐 为论文共同第一作者） ，在 Nature 子 ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 免疫疗法 已改善了越来越多种恶性肿瘤患者的生存率，但在 胰腺导管腺癌 （PDAC） 患者中引发有效的抗肿瘤 T 细胞免疫反应却一直颇具挑战性。 胰腺导管腺癌 （PDAC） 对免疫疗法产生耐药性的因素众多，包括靶抗原表达较弱以及免疫抑制分子的频繁产生或上调，从而导致肿瘤微环境 （TME） 呈现"冷 肿瘤"状态。即使存在可靶向的抗原，其异质性表达也可能导致快速适应和靶抗原调节，从而阻碍 T 细胞单药疗法的抗肿瘤潜力。 2026 年 1 月 2 日，得克萨斯州儿童医院/休斯顿卫理公会医院/贝勒医学院的研究人员在 Nature Medicine 期刊发表了题为： Autologous multiantigen- targeted T cell therapy for pancreatic cancer: a phase 1/2 trial 的研究论文。 该论文报道了 自体多抗原靶向的 T 细胞疗法 治疗 胰腺导管腺癌 （PDAC） 的 1/2 期临床试验数据，显示出良好的安全性和可行性。 研究团队推测，即使是在经过大量前期治疗的患者中，制备靶向 PRAME、SSX2、MAGEA ...

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].

Core Viewpoint - The study highlights the role of DNASE1L3-expressing dendritic cells in enhancing CD8+ T cell function and improving the efficacy of anti-PD-1/PD-L1 therapies by degrading neutrophil extracellular traps (NETs) [2][3][5]. Group 1: Research Findings - The expression of DNASE1L3 in tumor-infiltrating dendritic cells is positively correlated with better prognosis in cancer patients undergoing anti-PD-1/PD-L1 therapy [5]. - Conditional knockout of DNASE1L3 in dendritic cells leads to accelerated tumor growth and reduced efficacy of anti-PD-L1 therapy due to impaired CD8+ T cell infiltration and function [5]. - Exogenous supplementation of DNASE1L3 enhances CD8+ T cell infiltration into the tumor microenvironment, reduces T cell exhaustion, significantly inhibits tumor growth, and improves responses to anti-PD-L1 therapy [5]. Group 2: Mechanistic Insights - DNASE1L3+ dendritic cells maintain a cytotoxic CD8+ T cell hub by degrading NETs, which inhibit the spatial distribution of CD8+ T cells within tumors [5][8]. - The absence of DNASE1L3 in dendritic cells promotes tumor growth through CD8+ T cell dysfunction [5][8]. Group 3: Implications for Therapy - DNASE1L3 is identified as a promising new target for improving the effectiveness of anti-PD-1/PD-L1 therapies [8].

Core Viewpoint - Cancer-associated fibroblasts (CAF) play a critical role in supporting tumor growth and metastasis through extracellular matrix remodeling, paracrine signaling, and immune suppression, which limits the efficacy of immune checkpoint blockade (ICB) therapies [2][3]. Group 1 - The study published by researchers from the University of Chicago in the journal Nature reveals that NNMT promotes the recruitment of myeloid-derived suppressor cells (MDSC) into tumors via CAF, leading to the formation of an immunosuppressive tumor microenvironment (TME) [4]. - The research demonstrates that NNMT is expressed in all CAF subtypes and induces H3K27me3 hypomethylation, which facilitates the secretion of complement proteins that recruit MDSC into the tumor [7]. - The team developed a potent and specific NNMT inhibitor (NNMTi) that reduced tumor burden and metastasis in various mouse tumor models by decreasing CAF-mediated MDSC recruitment and reactivating CD8+ T cell activation, thereby restoring the efficacy of ICB therapy [9]. Group 2 - Overall, the study indicates that NNMT is a key regulatory factor of immunosuppression in the tumor microenvironment and represents a promising new target for alleviating immune suppression and enhancing cancer immunotherapy effectiveness [11].

Core Viewpoint - The study reveals a new mechanism by which lactate in the tumor microenvironment inhibits the anti-tumor function of natural killer (NK) cells through lactylation modification, providing new intervention targets and strategies to enhance NK cell cytotoxicity [1][3]. Group 1 - The research indicates that elevated levels of lysine lactylation (Kla) in NK cells are associated with impaired NAD metabolism, mitochondrial fragmentation, and reduced cytotoxicity [3]. - Supplementation with nicotinamide riboside (NR) and honokiol, a SIRT3 activator, enhances NK cell cytotoxicity by lowering intracellular Kla levels [3]. - The combination of NR and honokiol regulates Kla's effect on the protein kinase ROCK1, inhibiting the ROCK1-DRP1 signaling pathway to prevent mitochondrial fragmentation and restore NK cell activity against leukemia both in vivo and in vitro [3]. Group 2 - The study emphasizes that lactate-induced lactylation represents a new target for immunotherapy based on NK cells, aiming to enhance their tolerance to lactate within the tumor microenvironment [5]. - The research was conducted by a collaborative team from the University of Science and Technology of China and Fudan University, with key contributors including researchers Jin Jing, Yan Peidong, and Wang Dongyao [5].

Core Viewpoint - The research emphasizes the importance of understanding the interaction between tumor microenvironment and systemic immune macroenvironment for developing more effective cancer diagnosis and treatment strategies [2]. Group 1: Research Development - A novel organoid co-culture model, the Gel-Liquid Interface (GLI) co-culture model, was developed to explore systemic anti-tumor immunity in lung cancer [3]. - The research team established a lung cancer organoid (LCO) paired with peripheral blood mononuclear cells (PBMC) using the GLI model, enhancing the interaction between immune cells and tumor organoids to better simulate systemic anti-tumor immune responses in vivo [4]. Group 2: Findings and Implications - The study demonstrated that the GLI model's response under anti-PD-1 (αPD1) treatment accurately reflects the immune treatment outcomes of corresponding lung cancer patients [5]. - Functional multi-omics analysis in the GLI model revealed various tumor immune processes mediated by T cells derived from PBMC, characterizing circulating tumor-reactive T cells with an effector memory-like phenotype (GNLY+ CD44+ CD9+) as potential indicators of immunotherapy effectiveness [6]. - Key findings indicate that the GLI co-culture model reflects the immune treatment outcomes of lung cancer patients, reveals the infiltration and activation of peripheral T cells post immune checkpoint inhibitor (ICI) treatment, and shows that PBMC-derived T cells transform into more cytotoxic tumor-reactive T cells under ICI influence [7]. Group 3: Overall Conclusion - Overall, the research results suggest that the GLI co-culture model can be utilized for developing diagnostic strategies for precision immunotherapy and aids in understanding its underlying mechanisms [9].