Fig. 3

Mechanisms of the cancer metastasis cascade. At primary tumor sites, cancer-associated fibroblasts (CAFs) and stromal cells create a metastasis-conducive niche to support cancer cell EMT process, dissemination, and migration. As migrating cancer cells interact with circulating CAFs and myeloid cells to enhance survival and invasiveness while evading immune detection, they eventually reach the metastatic sites where they transition from dormancy and interact with the microenvironment to initiate active proliferation. The metastatic cascade initiated by primary tumor cells invading adjacent tissues via EMT is facilitated by CAFs that promote motility and ECM degradation. Moreover, macrophages and tumor-associated neutrophils (TANs) significantly contribute to ECM breakdown, facilitating cancer cell intravasation and survival in circulation by forming aggregates with platelets and myeloid cells to evade immune surveillance. Key interactions between cancer cells and the endothelium facilitate adhesion and extravasation into bone marrow, supported by the metabolic reprogramming of osteoblasts and osteoclasts. In addition, myeloid cells enhance cancer cell survival and metastasis through immune suppression, metabolic support, and ECM remodeling, including the crucial activities of neutrophils and macrophages in facilitating tumor cell adhesion, invasion, and metastatic proliferation at secondary sites