新型的免疫疗法组合治疗方案已经改善了肝细胞癌（HCC）患者的预后，但是其反应仅限于部分患者。我们对HCC肿瘤微环境中细胞信号网络的异质性进行了研究，该研究为现代全身治疗导致的反应提供了基础。我们使用空间转录组学（ST）对来自新辅助卡博曲替尼（一种主要靶向VEGF的多重酪氨酸激酶抑制剂）和尼伐替尼（一种PD-1抑制剂）的临床试验的HCC切除标本进行谱系分析。结果显示，在切除术时，有5个患者在病理学上表现出反应.ST谱系分析表明，反应肿瘤的微环境富含免疫细胞和癌相关成纤维细胞（CAF），相对于无反应者而言，这些肿瘤具有促炎信号。其中，反应肿瘤富含与PAX5模块的活化相关的癌细胞-免疫细胞相互作用，PAX5模块是一种已知的B细胞成熟调控因子，这些活跃的相互作用呈点状分布，且伴有B细胞标志物的表达增加，说明这些细胞的功能活跃性。在反应肿瘤中，HCC-CAF相互作用也被富集，并且与细胞外基质（ECM）重塑有关，因为在肿瘤旁边的CAF中，FOS和JUN的活化程度较高。ECM重塑与免疫介导的肿瘤退缩相关的增殖性纤维化一致。在具有重大病理学反应的患者中，有一个患者出现了早期HCC复发。对该患者的ST分析显示明显的肿瘤异质性，有一个独特的免疫缺乏型肿瘤区域，类似于患者间没有反应的微环境，并且其中表达了癌干细胞标志物，这可能在该患者中介导了肿瘤早期的免疫逃逸和复发。这些数据表明，HCC对现代全身治疗的反应与特定的分子和细胞背景相关，并提供了增强和延长HCC全身治疗反应的新的靶点。© 2023. BioMed Central Ltd.部分权利已授予施普林格自然出版集团。

Novel immunotherapy combination therapies have improved outcomes for patients with hepatocellular carcinoma (HCC), but responses are limited to a subset of patients. Little is known about the inter- and intra-tumor heterogeneity in cellular signaling networks within the HCC tumor microenvironment (TME) that underlie responses to modern systemic therapy.We applied spatial transcriptomics (ST) profiling to characterize the tumor microenvironment in HCC resection specimens from a prospective clinical trial of neoadjuvant cabozantinib, a multi-tyrosine kinase inhibitor that primarily blocks VEGF, and nivolumab, a PD-1 inhibitor in which 5 out of 15 patients were found to have a pathologic response at the time of resection.ST profiling demonstrated that the TME of responding tumors was enriched for immune cells and cancer-associated fibroblasts (CAF) with pro-inflammatory signaling relative to the non-responders. The enriched cancer-immune interactions in responding tumors are characterized by activation of the PAX5 module, a known regulator of B cell maturation, which colocalized with spots with increased B cell marker expression suggesting strong activity of these cells. HCC-CAF interactions were also enriched in the responding tumors and were associated with extracellular matrix (ECM) remodeling as there was high activation of FOS and JUN in CAFs adjacent to the tumor. The ECM remodeling is consistent with proliferative fibrosis in association with immune-mediated tumor regression. Among the patients with major pathologic responses, a single patient experienced early HCC recurrence. ST analysis of this clinical outlier demonstrated marked tumor heterogeneity, with a distinctive immune-poor tumor region that resembles the non-responding TME across patients and was characterized by HCC-CAF interactions and expression of cancer stem cell markers, potentially mediating early tumor immune escape and recurrence in this patient.These data show that responses to modern systemic therapy in HCC are associated with distinctive molecular and cellular landscapes and provide new targets to enhance and prolong responses to systemic therapy in HCC.© 2023. BioMed Central Ltd., part of Springer Nature.