Fig. 2

The mechanism of the interaction between BM, glia and cytotoxic T cells. Tumor-derived EVs could remotely activate astrocytes and microglia, remolding the premetastatic ecological niche. Gap junctions are the critical pathway for the interaction between astrocytes and BM, forming a cycle in which the two promote activation or survival. TGF-β2 secreted by astrocytes, which are stimulated by inflammatory factors released from the tumor, also promotes BM growth. The upregulation of JAG1-NOTCH1 signaling caused by BM and the high lipid environment originally formed by astrocytes itself both increase malignant proliferation. Moreover, a variety of BM secretion factors upregulate the phosphorylation level of STAT3 in astrocytes, not only upregulating the expression of PD-L1 but also MIF, which combines with CD74 of tumor-supporting microglia to promote BM growth. Signal activation, including STAT3 and PI3K, will cause the anti-inflammatory and tumor-promoting M2 polarization of microglia, while PI3K or microglia-derived ANXA1 (tumor-derived ANXA1 mainly influences migration) will inhibit the anti-M2 signal NF-κB or STAT1. CXCL10 is an important migration guiding marker in the TME. Although it also leads to the recruitment of CD8 + T cells, they will be fettered by multiple immune checkpoints, resulting in immune effectiveness being masked. Created with BioRender.com. CNTF, ciliary neurotropic factor; cGAMP, cyclic GMP-AMP; CX43, connexin 43; PCDH, protocadherin; STING, stimulator of interferon genes; INFα, interferon alpha; TNF, tumor necrosis factor; STAT, signal transducer and activator of transcription; NF-κB, nuclear factor kappa-B; TGF, transforming growth factor; IL, interleukin; JAG1, jagged1; HES, hes family bHLH transcription factor; AA, arachidonic acid; PPARγ, peroxisome proliferator-activated receptor gamma; EGF, epidermal growth factor; JAK2, Janus kinase 2; MIF, macrophage migration inhibitory factor; SIRPα, signal regulatory protein alpha; gp130, glycoprotein 130; PI3K, phosphoinositide 3-kinase; C/EBPβ, C/CAAT enhancer binding protein beta; ANXA1, annexin-A1; FPR, formyl peptide receptor; ERK, extracellular signal-regulated kinase