高级别浆液性卵巢癌（HGSC）是一种侵袭性疾病，占所有卵巢癌死亡率的70％。然而，15％的经诊断为晚期HGSC的患者可以存活10年以上。揭示这些长期存活者（LTS）预测性标志物可以帮助确定该疾病的治疗靶点，从而提高患者的生存率。为了研究卵巢癌的肿瘤微环境中间质异质性，我们使用空间转录组学在治疗前的晚期HGSC的LTS和短期存活者（STS）中生成了空间分辨的转录表达谱，并确定了癌症相关成纤维细胞（CAF）的异质性与晚期HGSC患者的生存之间的关联。结合了单细胞RNA测序数据和空间转录组学技术来区分肿瘤和基质区域，并开发了一种计算方法来研究TME中各种肿瘤和CAF亚型之间空间分辨的配体受体相互作用。TME中一种特定的CAF亚型及其与特定卵巢癌细胞亚型的空间位置相关联，可以影响晚期HGSC患者的长期生存。此外，与LTS相比，STS的肿瘤组织中基质和肿瘤之间的APOE-LRP5共同作用增加。这些发现通过多重免疫组织化学验证。总的来说，这种空间转录组学分析揭示了卵巢TME中空间分辨的CAF-肿瘤相互作用信号网络，与HGSC患者的长期生存有关。进一步的研究将证实这种相互作用是否在调节HGSC的恶性表型方面发挥作用，并可作为预测生存的生物标志物。

Advanced high-grade serous ovarian cancer (HGSC) is an aggressive disease that accounts for 70% of all ovarian cancer deaths. Nevertheless, 15% of patients diagnosed with advanced HGSC survive more than 10 years. The elucidation of predictive markers of these long-term survivors (LTS) could help identify therapeutic targets for the disease, and thus improve patient survival rates. To investigate the stromal heterogeneity of the tumor microenvironment (TME) in ovarian cancer, we used spatial transcriptomics to generate spatially resolved transcript profiles in treatment naïve advanced HGSC from LTS and short-term survivors (STS) and determined the association between cancer-associated fibroblasts (CAF) heterogeneity and survival in patients with advanced HGSC. Spatial transcriptomics and single-cell RNA sequencing data were integrated to distinguish tumor and stroma regions, and a computational method was developed to investigate spatially resolved ligand-receptor interactions between various tumor and CAF subtypes in the TME. A specific subtype of CAFs and its spatial location relative to a particular ovarian cancer cell subtype in the TME correlated with long-term survival in advanced HGSC patients. Also, increased APOE-LRP5 crosstalk occurred at the stroma-tumor interface in tumor tissues from STS compared to LTS. These findings were validated using multiplex immunohistochemistry. Overall, this spatial transcriptomics analysis revealed spatially resolved CAF-tumor crosstalk signaling networks in the ovarian TME that are associated with long-term survival of HGSC patients. Further studies to confirm whether such crosstalk plays a role in modulating the malignant phenotype of HGSC and could serve as a predictive biomarker of patient survival are warranted.