巨噬细胞在癌症生物学中发挥着多方面的作用，具有促肿瘤和抗肿瘤功能。了解巨噬细胞参与癌症进展的机制对于制定治疗策略至关重要。我们的研究分析了 12 名肝癌患者的单细胞 RNA 测序数据，并鉴定了一个以 SPP1 表达升高为特征的巨噬细胞亚群，这与肝癌患者的不良预后相关。这些 SPP1 巨噬细胞通过玻连蛋白 (VTN) 依赖性旁分泌机制诱导肿瘤干细胞的上调。从机制上讲，源自 SPP1 巨噬细胞的 VTN 促进整合素 αvβ5/腺苷 5'-单磷酸激活蛋白激酶 (AMPK)/Yes 相关蛋白 1 (YAP1)/SYR-box 转录因子 4 (SOX4) 信号传导，介导肝肿瘤干性和进展。相反，肝癌细胞产生的 CCL15 驱动 M0 巨噬细胞向 SPP1 巨噬细胞表型极化，建立巨噬细胞-肿瘤干性的正反馈回路。此外，SPP1巨噬细胞的存在赋予肝癌化疗耐药性，并且通过靶向整合素αvβ5/YAP1信号传导抑制巨噬细胞-肿瘤反馈环路使肝癌细胞对化疗敏感。我们的研究强调了 SPP1 巨噬细胞在肝癌进展中的关键作用，为临床肝癌治疗提供了新的见解。版权所有 © 2024。由 Elsevier B.V. 出版。

Macrophages play a multifaceted role in cancer biology, with both pro-tumorigenic and anti-tumorigenic functions. Understanding the mechanisms underlying macrophage involvement in cancer progression is essential for the development of therapeutic strategies. Our study analyzed single-cell RNA sequencing data from 12 patients with liver cancer and identified a subpopulation of macrophages characterized by elevated expression of SPP1, which correlates with poor prognosis in liver cancer patients. These SPP1+ macrophages induce upregulation of tumor stemness through a vitronectin (VTN)-dependent paracrine mechanism. Mechanistically, VTN derived from SPP1+ macrophages promote integrin αvβ5/adenosine 5'-monophosphate-activated protein kinase (AMPK)/Yes-associated protein 1 (YAP1)/SYR-box transcription factor 4 (SOX4) signaling, mediating liver tumor stemness and progression. Conversely, CCL15 produced by liver cancer cells drives polarization of M0 macrophages toward an SPP1+ macrophage phenotype, establishing a positive feedback loop of macrophage-tumor stemness. Furthermore, the presence of SPP1+ macrophages confers chemoresistance in liver cancer, and inhibition of the macrophage-tumor feedback loop through targeting integrin αvβ5/YAP1 signaling sensitizes liver cancer cells to chemotherapy. Our study highlights the crucial role of SPP1+ macrophages in liver cancer progression, providing novel insights for clinical liver cancer therapy.Copyright © 2024. Published by Elsevier B.V.