| 摘要: |
| 肿瘤免疫治疗的临床获益显著受限于肿瘤微环境(Tumor Microenvironment, TME)的高度空间异质性,尤其是免疫“冷区”——包括由于趋化信号缺失导致的“荒漠型”以及由于物理或代谢屏障导致的“排斥型”生态位。空间转录组学(Spatial Transcriptomics, ST)技术的突破及应用,使得在亚细胞及单细胞分辨率下解析免疫逃逸的空间拓扑构架成为可能。通过系统整合最新临床证据与多组学数据发现,三级淋巴结构(Tertiary Lymphoid Structures, TLS)的成熟度梯度及其空间分布是决定效应细胞浸润效率的核心变量。此外,调节性(Treg-rich)及纤维化相关(Fibrosis-associated)TLSs的空间演变,是驱动肿瘤从免疫排斥向免疫“冷区”转化的关键环节。基于此,我们提出剖析肿瘤免疫微环境应从单纯的“空间描述”向“功能性空间干预(Functional Spatial Intervention)”模式转变。通过重塑表观遗传、精准阻断代谢通路及诱导高内皮静脉(High Endothelial Venules, HEV)生成,重构免疫允许性微环境,为克服实体瘤免疫治疗抵抗提供基于空间生物学的科学理论依据。 |
| 关键词: 空间转录组学 肿瘤微环境 三级淋巴结构 免疫“冷区” 功能性空间干预 免疫治疗耐受 |
| DOI： |
| 分类号: |
| 基金项目:广西自然科学基金(2023GXNSFAA026033),国家自然科学(82560501,82073004) |
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| Decoding and Functional Remodeling Strategies for Tumor Immune |
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瞿梓泉
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College of Medical Technology, Chengdu University of Traditional Chinese Medicine
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| Abstract: |
| The clinical efficacy of cancer immunotherapy is profoundly constrained by the pronounced spatial heterogeneity of the tumor microenvironment (TME), particularly the presence of immune "cold" zones—encompassing "desert" niches characterized by a deficiency in chemotactic signaling and "excluded" niches sustained by physical or metabolic barriers. Advancements in spatial transcriptomics (ST) have empowered the resolution of the spatial topological architecture governing immune evasion at sub-cellular and single-cell scales. By systematically integrating recent clinical evidence with multi-omic datasets, it was found that the maturation gradient and spatial distribution of tertiary lymphoid structures (TLSs) serve as the core determinants of effector cell infiltration efficiency. In addition, the spatial evolution of regulatory (Treg-rich) and fibrosis-associated TLS constitutes a critical nexus driving the transition from immune-excluded to immune-cold phenotypes. Therefore, here we propose that characterization of the tumor immune microenvironment should shift from a simple "spatial description" to a "functional spatial intervention" model. By leveraging epigenetic remodeling, targeted metabolic blockade, and the induction of high endothelial venules (HEVs), it is expected to reconstruct an immuno-permissive microenvironment, thereby providing a scientific theoretical basis based on spatial biology to overcome resistance in solid tumor immunotherapy. |
| Key words: Spatial Transcriptomics Tumor Microenvironment (TME) Tertiary Lymphoid Structures (TLSs) Immune Cold Zones Functional Spatial Intervention Immunotherapy Resistance |
