空间受限的免疫进入在肝细胞癌中形成肿瘤避难所
Spatially Limited Immune Access Creates Tumour Refugia in Hepatocellular Carcinoma
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中文总结 AI 辅助
本研究建立肝细胞癌反应-扩散-趋化模型，揭示空间受限的免疫进入（而非总体免疫丰度）可导致肿瘤避难所形成，即使平均募集充足也可能无法完全控制肿瘤。
中文摘要 AI 辅助
空间受限的免疫进入可能削弱肿瘤控制，即使总体免疫募集看似充足。我们为肝细胞癌建立了一个无量纲的反应-扩散-趋化模型，该模型将肿瘤生长和免疫介导的杀伤与效应物扩散、饱和趋化因子依赖性募集以及沿有效CXCL9/CXCL10/CXCL11-CXCR3信号的迁移耦合在一起。我们在一维空间中建立了非负性、均匀肿瘤和质量界以及经典解的全局有界性，并在任意维度中（当趋化因子产生由肿瘤驱动时）也建立了这些性质。对均匀动力学的分析表明，阈值σ0>δ仅是局部的，并不排除双稳态肿瘤持续存在。一种模式色散关系识别出静态有限波长和振荡不稳定性，其临界敏感性、主导模式、增长率和频率通过保守有限体积模拟定量恢复。使用匹配的初始状态和相同的平均募集，我们表明充分混合的模型可能预测清除，而边缘限制的募集则维持稳定的内部肿瘤避难所。趋化性改善了内部效应物进入并减少了（但不必消除）这种避难所。空间重叠生物标志物进一步将模型生成的表型与病理学和空间组学可观测数据联系起来。这些结果区分了免疫丰度与有效空间进入，并将进入受限的募集确定为不完全肿瘤控制的机制。
英文摘要
Spatially restricted immune access can undermine tumour control even when total immune recruitment appears sufficient. We develop a nondimensional reaction--diffusion--chemotaxis model for hepatocellular carcinoma that couples tumour growth and immune-mediated killing with effector diffusion, saturating chemokine-dependent recruitment, and migration along an effective CXCL9/CXCL10/CXCL11--CXCR3 signal. We establish nonnegativity, uniform tumour and mass bounds, and global boundedness of classical solutions in one dimension and, in arbitrary dimensions, when chemokine production is tumour-driven. Analysis of the homogeneous dynamics shows that the threshold $σ_0>δ$ is only local and does not preclude bistable tumour persistence. A mode-wise dispersion relation identifies stationary finite-wavelength and oscillatory instabilities, whose critical sensitivities, dominant modes, growth rates, and frequencies are quantitatively recovered by conservative finite-volume simulations. Using matched initial states and identical mean recruitment, we show that a well-mixed model may predict clearance while margin-limited recruitment preserves a stable interior tumour refuge. Chemotaxis improves interior effector access and reduces, but need not eliminate, this refuge. Spatial-overlap biomarkers further connect model-generated phenotypes to pathology and spatial-omics observables. These results distinguish immune abundance from effective spatial access and identify access-limited recruitment as a mechanism of incomplete tumour control.
