Identification of SPP1+ macrophages in promoting cancer stemness via vitronectin and CCL15 signals crosstalk in liver cancer

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. SPP1 + macrophages promote tumor stemness through a VTN-dependent paracrine mechanism. VTN derived from SPP1 + macrophages could mediate stem transcript factor SOX4 upregulation through integrin αvβ5/AMPK/YAP1signaling, facilitating liver tumor stemness and progression. In tumor, CCL15 derived from liver cancer cells could drive polarization of M0 macrophages toward an SPP1 + macrophage phenotype, thereby establishing a positive feedback loop between SPP1 + macrophages and liver cancer cells. • SPP1+ macrophages regulate tumor stemness in liver cancer. • VTN from SPP1+ macrophages promote integrin αvβ5/AMPK/YAP1/SOX4 signal. • CCL15 by cancer cells drives M0 macrophages polarization toward an SPP1+ macrophage phenotype. • SPP1+ macrophages confer chemoresistance in liver cancer.