Fig. 4

CSC-immune cell crosstalk involvement in tumor initiation. A Colorectal CSCs suppress the proliferation of T cells via high expression of IL-4. B A high-fat diet reduced the expression of MHC class II molecules in colorectal CSCs by inhibiting the PRR and IFNγ signaling pathways, thereby inhibiting the activity of CD4⁺ T cells and promoting CRC occurrence. C APC mutation, the major oncogenic variant in early colorectal tumorigenesis, activates the Wnt/β-catenin signaling pathway, and the β-catenin-TCF4 complex binds to the promoter of the PD-L1-encoding gene to induce PD-L1 expression, which inhibits CD8⁺ T cell activation. D Colorectal CSCs secrete macrophage migration inhibitory factor (MIF), which binds the CD74 receptor on tumor-associated monocytes and macrophages (TAMMs), inducing immunosuppressive signaling. In addition, TAMMs secrete prostaglandin E2 (PGE2) and promote the proliferation of colorectal CSCs via the action of the PGE2 receptor EP4. E The Wnt/β-catenin signaling pathway activates the expression of RAB27B to mediate the secretion of miR-146a exosomes, which promote the stemness of tumor cells and tumorigenicity and reduces the infiltration of CD8⁺ T cells. (F) Colorectal CSCs secrete exosomal RNAs to increase the number of neutrophils in the bone marrow and induce neutrophils to express IL-1β. In addition, colorectal CSCs secrete CXCL1/2 to recruit neutrophils expressing CXCR2 in bone marrow, and IL-1β secreted by neutrophils can promote tumorigenesis