Exosomes (EXOs) are extracellular vesicles (EVs) that are secreted by cells and have diameters of approximately 40–150 nm (Kalluri and LeBleu, 2020). EXOs carry molecules such as nucleic acids, proteins, lipids, and metabolites; thus, EXOs not only serve as diagnostic biomarkers but also play significant roles in tumor progression (Isaac et al., 2021). EXOs transport molecules between cells, and they are crucial for both the growth of primary tumors and the spread and metastasis of tumor cells (Kok and Yu, 2020, van Niel et al., 2018). EXOs can promote the metastasis of tumor cells not only by directly increasing tumor cell adhesion and activating endothelial cells to promote angiogenesis but also by transporting proinflammatory factors to initiate the formation of an immunosuppressive tumor microenvironment (Patel et al., 2023, Wang et al., 2023). Tumor cells can secrete PD-L1 via EXOs (exoPD-L1); when exoPD-L1 binds to PD-1 on CD8+ T cells at distant metastatic sites, it inhibits the proliferation and activation of these CD8+ T cells, resulting in their functional inactivation and ultimately promoting immune suppression (Li et al., 2021, Niu et al., 2022, Xie et al., 2019, Yang et al., 2018). Moreover, exoPD-L1 is a key factor that contributes to the low response and resistance to PD-L1 monotherapy in patients with tumors (Gong et al., 2019). Therefore, immunotherapy that targets the immune checkpoint PD-1/PD-L1 has become a focus of breast cancer research and is a standard therapy (Loibl et al., 2021). Recently, an investigation revealed that the binding of intercellular adhesion molecule 1 (ICAM1) to its ligand lymphocyte function-associated antigen-1 is a prerequisite for the interaction between exoPD-L1 and PD-1 (Zhang et al., 2022). Knockdown or blocking ICAM1 expression by breast cancer cells significantly inhibits the binding of tumor-derived exoPD-L1 to CD8+ T cells, subsequently attenuating the inhibitory effect of tumor-derived EXOs on CD8+ T cells (Zhang et al., 2022). Thus, the immunosuppressive microenvironment that is established by CD8+ T cell inactivation via the exosomal ICAM1 (exoICAM1)-mediated PD-L1/PD-1 interaction may play an important role in TNBC bone metastasis.
ICAM1, which is a cell surface glycoprotein, plays a crucial role not only in immune functions, such as the adhesion between leukocytes and endothelial cells, but also in the occurrence, progression, and metastasis of cancer (Bui et al., 2020, Reina and Espel, 2017, Rosette et al., 2005, Taftaf et al., 2021). Previous studies have shown that the expression of ICAM1 in breast cancer patients is significantly higher than that in healthy individuals, and the level of ICAM1 in patients with triple-negative breast cancer (TNBC) is significantly higher than that in non-TNBC breast cancer patients, such as patients with the hormone receptor (HR)-positive and Her2-positive subtypes of breast cancer (Guo et al., 2014). We previously reported that ICAM1 promotes bone metastasis in mice with breast cancer tumors (Chen et al., 2022). EXOs that are produced by tumor cells can also carry ICAM1 (exoICAM1) and transfer it to other cells, which may help promote tumor growth and metastasis (Linton et al., 2018). The soluble and membrane-bound forms of ICAM1 can also promote the maturation and differentiation of osteoclasts, thereby possibly exacerbating the progression of bone metastasis (Fernandes et al., 2008). However, the role of the exoICAM1-mediated regulatory effect of CD8+ T cell exhaustion in the bone metastasis of TNBC remains unknown.