Calcitriol suppresses gastric cancer progression and cisplatin resistance by inhibiting glycolysis and M2 macrophage polarization through inhibition of mTOR activation

The tumor microenvironment (TME) plays a critical role in tumor progression, with macrophages and tumor cells interacting within the TME, influencing cancer development. Despite the known anticancer properties of calcitriol, its role in the TME remains uncertain. This study aimed to explore the effects of calcitriol on macrophages and cancer cells in the TME and its impact on gastric cancer cell proliferation and cisplatin resistance. In vitro TME models were established using conditioned medium from gastric cancer cells (CCM) and macrophages (MCM) treated with or without calcitriol. The results revealed that calcitriol treatment suppressed the expression of glycolysis‐related genes and proteins (GLUT1, HKII, LDHA) in MCM‐induced gastric cancer cells, leading to increased cancer cell apoptosis and reduced viability, along with decreased Cyclin D1 gene expression. Moreover, calcitriol treatment inhibited mTOR activation in MCM‐induced gastric cancer cells. Additionally, calcitriol hindered CCM‐induced M2 macrophage polarization by reducing CD206 expression and increasing TNFα gene expression in THP1‐derived macrophages, attenuating cisplatin resistance. These findings suggest that calcitriol may impede gastric cancer progression by targeting glycolysis and M2 macrophage polarization through the regulation of mTOR activation in the TME.