撰文丨王聪 编辑丨王多鱼 排版丨水成文 癌症 的发展是一个多步骤的过程，在此过程中癌细胞获得了克服复制潜能限制以及逃避免疫系统破坏的能 力。与此同时，非癌细胞 （比如基质细胞） 逐渐被重新编程以支持肿瘤生长。 肿瘤发生的器官因其独特的组织驻留细胞类型，造就了肿瘤微环境 （TME） 的显著差异，并塑造了肿瘤不 同的临床特性，例如分子亚型、侵袭能力和对靶向治疗或免疫治疗的反应。单细胞 RNA 测序 （scRNA- seq） 和空间转录组学 （ST） 的最新进展已成为探索肿瘤微环境多样性的强大工具。然而，表型相关的细 胞类型是否普遍存在于不同癌症类型和阶段中仍不清楚。此外，构成肿瘤微环境内特定生态型的不同细胞 类型之间的相互作用尚不明确。 因此，从泛癌角度探究肿瘤微环境成分的动态变化以及细胞间相互作用，对于阐明癌症的发病机制至关重 要，并且是一个很有前景的治疗靶点。 2025 年 8 月 25 日 ，同济大学生命科学与技术学院 王晨飞 教授、 吴秋 助理教授作为共同通讯作者 （ 博士 后 韩雅 为第一作者 ） 在 Nature 子刊 Nature Cancer 上发表了题为： Spatiotemporal anal ...

撰文丨王聪 编辑丨王多鱼 排版丨水成文 衰老 会大大增加 癌症 患病风险，并对免疫系统的功能和构成产生深远影响，导致对慢性及急性感染的免疫反应受损，以及易患自身免疫疾病。 那么， 癌症本身会加速衰老吗？ 2025 年 8 月 21 日， 莫菲特癌症中心及研究所的研究人 员在 Cancer Cell 上发表了题为： Lymphoma accelerates T cell and tissue aging 的研究论文。 该研究在小鼠和人类中研究发现， 淋巴瘤会加速 T 细胞和组织衰老。 衰老导致的免疫系统变化众多，包括炎症细胞因子和趋化因子失衡 （炎症衰老） 以及分泌表型的变化、造血干细胞向单核细胞群生成的倾斜以及淋巴细胞群的减 少、巨噬细胞向促炎极化的转变，以及 NK 细胞和 CD8 + 和 CD4 + T 细胞数量的减少以及成熟度的改变，其中 CD8 + 和 CD4 + T 细胞向功能减弱或免疫抑制性 细胞 （例如 Treg） 转变。 与这些衰老变化相关的是，T 细胞表现出衰老标志物 （例如 KLRG1、细胞周期抑制剂 p16 INK4a / CDKN2A 以及某些促炎细胞因子） 表达增加 。最后，衰老的 T ...

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].

Core Viewpoint - The article discusses a groundbreaking study published in Nature by a team led by Academician Zhang Zemin, focusing on the concept of "cross-tissue cellular modules" and their role in multicellular coordination within human tissues, particularly in the context of cancer progression [2][16]. Group 1: Research Background - The study integrates single-cell transcriptomic data from 706 healthy samples across 35 human tissues, creating the most comprehensive cross-tissue single-cell atlas to date, covering 2.29 million cells [8][16]. - The research identifies significant differences in cellular composition across various healthy tissues, revealing 12 distinct cross-tissue cellular modules (CMs) with unique cellular compositions and distributions [9][16]. Group 2: Cellular Modules and Their Functions - The identified cellular modules include CM04, CM05, CM06, and CM09, which are abundant in primary and secondary immune organs, indicating their roles in immune cell production and maturation [10][13]. - Other modules, such as CM02 and CM03, are primarily found in the urinary system and gastrointestinal tract, while CM08 is enriched in barrier tissues like skin and mucosal surfaces, suggesting their specific functional roles [10][11]. Group 3: Spatial Dynamics and Aging - The study employs spatial transcriptomics to illustrate how these cellular modules are spatially organized within tissues, highlighting their functional roles in maintaining tissue homeostasis [14][16]. - Notably, the immune cell modules CM05 and CM06 exhibit contrasting temporal dynamics with aging, where CM05 increases while CM06 decreases, indicating their potential as biomarkers for age-related changes [14][16]. Group 4: Implications for Cancer Research - The research extends to the tumor microenvironment (TME), analyzing single-cell transcriptomic data from 1,062 clinical samples across 29 cancer types, identifying 91 cell subpopulations [15][16]. - It reveals a dual remodeling of cellular modules during tumor progression, where healthy tissue-specific modules are lost, and cancer-associated modules emerge, providing insights into the fundamental organizational principles of multicellular ecosystems in health and disease [15][16].

Core Viewpoint - Lung cancer remains the leading cause of cancer-related deaths globally, primarily due to late-stage diagnosis, emphasizing the critical need for early detection and intervention [1][11]. Group 1: Importance of Early Detection - Early diagnosis and intervention are crucial, with low-dose spiral CT screening significantly reducing lung cancer mortality rates [1]. - Understanding the molecular mechanisms of early lung cancer is vital for precise screening, diagnosis, prevention, and treatment [1]. Group 2: Challenges in Research - The study of early cancer development, particularly lung adenocarcinoma (LUAD), faces significant challenges due to the scarcity of precursor lesion specimens [1]. - Atypical adenomatous hyperplasia (AAH) is recognized as the only precursor lesion for lung adenocarcinoma, with potential progression to non-invasive adenocarcinoma in situ (AIS) and invasive adenocarcinoma (IAC) [1]. Group 3: Recent Research Findings - A recent study published in Cancer Cell identified TIM-3 as a potential target for lung cancer "precancer interception" through spatial and multiomics analysis of human and mouse lung adenocarcinoma precursors [2]. - The research revealed a significant upregulation of TIM-3 in myeloid immune cells during the precancerous stage, suggesting its role in immune regulation within the tumor microenvironment [6][7]. Group 4: Immune Response Dynamics - The transition from precancerous lesions to invasive cancer is associated with changes in macrophage polarization and T cell functionality, indicating a shift from innate to adaptive immune responses [6]. - The study identified 818 spatial features related to immune checkpoint TIM-3, highlighting its central regulatory role in early tumor evolution [6]. Group 5: Therapeutic Implications - Blocking TIM-3 demonstrated significant potential for "precancer interception," effectively inhibiting the progression from precancerous lesions to invasive cancer in mouse models [8]. - The treatment not only reduced the proportion of pro-tumor M2 macrophages but also improved the immune surveillance of the precancerous microenvironment [8]. Group 6: Conclusion - The findings provide a crucial mechanistic basis for targeting immune suppression in precancerous stages and lay a solid foundation for early intervention strategies [11].

本文为IPO早知道原创 作者｜罗宾 微信公众号｜ipozaozhidao 已启动C2轮融资。 礼新医药创始人、董事长兼首席执行官秦莹博士表示："礼新医药自创立以来，一直坚持源头自主创 新，聚焦肿瘤微环境，专注于开发研发肿瘤特异性靶向ADC和免疫调节大分子创新药物，已建立了 一套完整覆盖从临床前直至临床III期的拥有自主知识产权并具有全球竞争力的差异化创新药管线。我 们将不负众望，加快推进LM-302和LM-108两个后期临床管线，争取早日实现产品上市。同时， 持续产出聚焦于肿瘤免疫及肿瘤微环境领域内尚未满足的治疗需求的早期源头创新管线，并继续积极 探索与各种伙伴以及各界展开多元化的紧密合作，通过BD合作进一步提升公司自我造血能力。" 中国生物制药有限公司董事会主席谢其润表示："中国生物制药已上市了安罗替尼等众多重要的肿瘤 产品，并且正持续不断地投入创新药研发与合作。我们一直关注肿瘤免疫治疗和ADC药物的研发进 展，礼新医药是一家聚焦于肿瘤免疫及肿瘤微环境领域的创新药公司，其差异化的创新管线布局、扎 实的GPCR多次跨膜蛋白抗体发现平台、双抗技术平台和ADC技术平台、都给我们留下了深刻的印 象。我们坚定看好礼新 ...