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. 2023 Dec 16;16:121. doi: 10.1186/s13045-023-01518-1

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© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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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