Fig. 2

Multiple mechanisms of environmental stress regulating CSC transcription A The immune cells in TME activate the STAT, Wnt, AKT and Notch pathway of CSC by mainly releasing cytokines (IL-6) and inducing contact. CAFs secrete various substances (cytokines, POSTN, miRNA) to stimulate distinct pathways of CSC (Wnt/β-Catenin, PI3K/AKT/mTOR, STAT). ECM exerts effect on the PI3K and Hh pathways, as well as transcription of pluripotent TFs through mechanical stress and CSC markers (CD44). B Hypoxia causes the production of HIF and ROS. HIF-1 secretes miRNAs and activates the Wnt, Notch, PI3K/mTOR pathways, as well as acts on histone modifications. HIF-2 tends to directly regulate the gene expression of various TFs. Hypoxia induced ROS may support a transcription promoting role of CSCs. C OXPHOS occurring in the mitochondria of CSC can indirectly affect (through the release of ROS) or directly bear on the expression and effect of TFs. The alterations of mitochondrial function and state (mitochondrial fission and mitophagy) regulate the expression of TFs. The key enzymes in the CSC glycolysis process act on TF through the Hippo pathway and cell marker (CD133). Lactate metabolism plays a role in histone modification (lactylation) of CSC and ubiquitination of TF proteins. Lipid metabolism (LDs and FAO) is associated with the Wnt, Notch, Hippo, Hh and PI3K/AKT pathways and makes a difference in histone modifications (acetylation). Gln deprivation promotes pluripotent gene silencing and increases histone trimethylation