Stepwise progression of bone metastasis in NSCLC. a. NSCLC cells detach from the primary site and invade the circulation. In circulation, CTCs circulate as single cells or in microclusters coated with platelets, neutrophils, and other cells, making them difficult to eliminate. CTCs also express PD-L1 to evade the clearance of immune cells. b. CTCs adhere to the endothelium of bone blood vessels, then extravasate into bone to seed new metastasis. Various chemokines and adhesion molecules participate in CTCs extravasation. For example, NSCLC cells overexpressing CXCR4 are attracted to CXCL12 expressed in the bone matrix. c. NSCLC cells colonize in bone tissue and form macrometastases. Interactions between the NSCLC cells and the bone microenvironment enhance bone remodeling and tumor growth. Furthermore, osteolytic bone resorption and tumor cell proliferation form a "vicious cycle" that promotes bone metastasis.