Figure 1.

Immune mechanisms in the progression of bone metastasis. After being detached from the primary tumor, circulating tumor cells produce CXC-chemokine ligand 12 (CXCL12) to facilitate metastatic homing to the bone. They can also secrete CC-chemokine ligand 2 (CCL2) to recruit CC-chemokine receptor 2 (CCR2)⁺ inflammatory monocytes towards the bone metastatic niche, in which they differentiate into metastasis-associated macrophages (MAMs). Following metastatic seeding into the bone, disseminated tumor cells can remain in a dormant state driven by type I interferon, the receptor of leukemia inhibitory factor (LIFR), transforming growth factor-β (TGF-β). Induced by several immune molecules, dormant tumor cells can be reactivated and initiate metastatic outgrowth. Eosinophils, MAMs, myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) conspire to support the persistent growth of metastatic tumor cells. Furthermore, the tumor-stroma interactions are engaged in the acceleration of bone metastasis. Osteoblasts-derived receptor activator of nuclear factor-κB-ligand (RANKL) induces the differentiation of osteoclasts, which in turn stimulates bone resorption and tumor cell proliferation mediated by growth factors like transforming growth factor-β (TGF-β). In addition, immune cells including neutrophils, nature killer (NK) cells and CD8⁺ T cells act to restrict metastatic tumor cell growth.