Background/Objectives: Subcutaneous tumor models are widely used in colorectal cancer (CRC) research due to their experimental accessibility; however, the spatial organization and regulatory mechanisms of their tumor microenvironment remain poorly understood.Methods: Here, we applied spatial transcriptomics to systematically characterize spatial heterogeneity within MC38 subcutaneous tumors in a syngeneic mouse model.Results: We identified two spatially distinct tumor zones, partitioned by cancer-associated fibroblasts (CAFs), that differ markedly in cellular composition, oncogenic signaling, immune infiltration, and metabolic states. One zone exhibited features of TGF-β-driven extracellular matrix remodeling, immune exclusion, and hyperproliferative metabolism, while the other was enriched for immunosuppressive macrophages, metabolic reprogramming via PPAR and AMPK pathways, and high-risk cell populations. Spatially resolved cell–cell communication networks further revealed zone-specific ligand–receptor interactions—such as ANGPTL4–SDC2 and PROS1–AXL—that underpin stromal remodeling and immune evasion and are associated with patient prognosis.Conclusions: Collectively, our study uncovers how region-specific cellular ecosystems and intercellular crosstalk establish prognostically divergent niches within subcutaneous CRC tumors, offering insights into spatially guided therapeutic strategies.
**背景/目的：** 皮下肿瘤模型因其实验操作便捷性，在结直肠癌研究中被广泛应用；然而，其肿瘤微环境的空间组织结构与调控机制仍不甚明晰。 **方法：** 本研究在同系小鼠模型中，应用空间转录组学技术，系统性地描绘了MC38皮下肿瘤的空间异质性特征。 **结果：** 我们鉴定出两个由癌症相关成纤维细胞分隔、空间分布截然不同的肿瘤区域。这两个区域在细胞组成、致癌信号传导、免疫浸润及代谢状态方面存在显著差异。其中一个区域表现出TGF-β驱动的细胞外基质重塑、免疫排斥及高增殖代谢特征；而另一个区域则富含免疫抑制性巨噬细胞，呈现通过PPAR和AMPK通路介导的代谢重编程，并存在高风险细胞群体。空间解析的细胞间通讯网络进一步揭示了区域特异性的配体-受体相互作用（如ANGPTL4–SDC2和PROS1–AXL），这些相互作用支撑了基质重塑与免疫逃逸，并与患者预后相关。 **结论：** 综上所述，本研究揭示了皮下结直肠癌肿瘤内部如何通过区域特异的细胞生态系统及细胞间交互作用，形成预后迥异的微环境生态位，为空间引导的治疗策略提供了新的见解。
肿瘤(癌症)患者之家