<i>Calculus bovis</i> hijacks the tumor microenvironment in liver cancer cells in a multifaceted approach: A falling row of dominoes

<i>Calculus bovis</i> (<i>C</i>. <i>bovis</i>) is widely used in traditional Chinese medicine due to its anti-tumor effects. <i>C</i>. <i>bovis</i> shifts liver cancer tumor microenvironment towards regression by hindering tumor-associated macrophages polarization. Huang <i>et al</i> have demonstrated in their study that <i>C</i>. <i>bovis</i> inhibits M2-tumour-associated macrophages (TAM) polarization by halting the Wnt/β-catenin pathway. The mechanism of action by which <i>C</i>. <i>bovis</i> exerts its anti-tumor effects is multifaceted and includes network pharmacology, transcriptomics and molecular docking. <i>In vitro</i> assays demonstrated that <i>C</i>. <i>bovis</i>-containing serum inhibited M2-TAMs polarization in human hepatocellular carcinomas cells. <i>C</i>. <i>bovis</i> was found to have 22 active components of which 11 were detected in the bloodstream. The anti-neoplastic activity of <i>C</i>. <i>bovis</i> lies in suppressing M2-TAM polarization by modulation of the Wnt/B-catenin pathway. <i>In vitro</i> and <i>in vivo</i> experiments have shown that <i>C</i>. <i>bovis</i> suppresses M2-TAM polarization and halts the Wnt signaling pathway. The inhibitory effect of <i>C</i>. <i>bovis</i> on M2-TAM was reversed by SKL2001, a Wnt agonist, which highlights <i>C</i>. <i>bovis</i>'s selectivity and specificity. <i>C</i>. <i>bovis</i> inhibits M2-TAM polarization by modulating the Wnt/ β-catenin pathway, thus impeding liver cancer growth. Owing to the "cross-talk" between transforming growth factor-β (TGF-β) signaling pathways, this paper highlights the potential significance of <i>C</i>. <i>bovis</i> in controlling the tumor microenvironment not only through hindering the polarization of M2-TAMs <i>via</i> the Wnt signaling pathway, but also by downregulating TGF-β. Therefore, <i>C</i>. <i>bovis</i> serves as an igniter to fuel a cascade of signaling events that culminates in the regression of the tumor microenvironment by compromising oncogenesis and angiogenesis. TGF-β is also known for its pro-fibrotic properties. Therefore, <i>C</i>. <i>bovis</i> may play a pivotal role in treating liver fibrosis by downregulating TGF-β, thus hindering oncogenesis, angiogenesis and liver fibrosis. Hence, the "domino effect".