Microenvironmental regulation of metastasis. Joyce, J.A., Pollard, J.W. Nat Rev Cancer 9, 239–252 (2009).doi:10.1038/nrc2618. Metastasis is a multistage process involving cancer cells escaping the primary tumor, surviving in circulation, seeding at distant sites, and growing. These processes are influenced by non-malignant cells in the tumor microenvironment, many of which are derived from the bone marrow, particularly the myeloid lineage. These cells are recruited by cancer cells to enhance their survival, growth, invasion, and dissemination. The microenvironment plays a critical role in metastasis, with evidence showing that it can inhibit aggressive malignant cells. However, tumors circumvent these inhibitory signals and exploit surrounding cells to promote inappropriate growth, invasion, and metastasis. Tumor-stroma interactions at the primary site involve various stromal cells that enhance primary tumor growth and facilitate metastatic dissemination. Normal tissue homeostasis requires a balance of cell proliferation and death, maintained through intercellular communication. The extracellular matrix (ECM) plays a key role in maintaining organ homeostasis and preventing neoplastic transformation. Studies have shown that the microenvironment can reprogram cancer cells to a less aggressive phenotype, and that chronic inflammation can override protective constraints, shifting the microenvironment to a growth-promoting state. Stromal cells, including endothelial cells, pericytes, fibroblasts, and various bone marrow-derived cells (BMDCs), contribute to tumor angiogenesis and progression. BMDCs, such as macrophages, neutrophils, and myeloid cell-derived suppressor cells (MDSCs), have been shown to promote tumor angiogenesis, invasion, and metastasis. The recruitment of stromal cells to developing tumors is a crucial aspect of tumor progression, with BMDCs playing a central role in malignant progression. Chronic inflammation can lead to the recruitment of bone marrow-derived inflammatory cells to the tumor mass, promoting a cascade of events that amplify tumor-promoting effects of immune cells. The classification of immune cells into different states or subtypes has provided insights into their disparate functions. For example, type 1 CD4+ T cells (TH1) aid CD8+ T cells in tumor rejection, whereas type 2 CD4+ T cells (TH2) and CD4+ T regulatory cells block the activation of CD8+ T cells. The induction of angiogenesis is a crucial early stage in the development and growth of most solid tumors, and is necessary for hematogenous dissemination of cancer cells. Bone marrow-derived myeloid cells, including macrophages, TIE2-expressing monocytes, neutrophils, and mast cells, contribute to tumor angiogenesis through the production of growth factors, cytokines, and proteases. These cells also play aMicroenvironmental regulation of metastasis. Joyce, J.A., Pollard, J.W. Nat Rev Cancer 9, 239–252 (2009).doi:10.1038/nrc2618. Metastasis is a multistage process involving cancer cells escaping the primary tumor, surviving in circulation, seeding at distant sites, and growing. These processes are influenced by non-malignant cells in the tumor microenvironment, many of which are derived from the bone marrow, particularly the myeloid lineage. These cells are recruited by cancer cells to enhance their survival, growth, invasion, and dissemination. The microenvironment plays a critical role in metastasis, with evidence showing that it can inhibit aggressive malignant cells. However, tumors circumvent these inhibitory signals and exploit surrounding cells to promote inappropriate growth, invasion, and metastasis. Tumor-stroma interactions at the primary site involve various stromal cells that enhance primary tumor growth and facilitate metastatic dissemination. Normal tissue homeostasis requires a balance of cell proliferation and death, maintained through intercellular communication. The extracellular matrix (ECM) plays a key role in maintaining organ homeostasis and preventing neoplastic transformation. Studies have shown that the microenvironment can reprogram cancer cells to a less aggressive phenotype, and that chronic inflammation can override protective constraints, shifting the microenvironment to a growth-promoting state. Stromal cells, including endothelial cells, pericytes, fibroblasts, and various bone marrow-derived cells (BMDCs), contribute to tumor angiogenesis and progression. BMDCs, such as macrophages, neutrophils, and myeloid cell-derived suppressor cells (MDSCs), have been shown to promote tumor angiogenesis, invasion, and metastasis. The recruitment of stromal cells to developing tumors is a crucial aspect of tumor progression, with BMDCs playing a central role in malignant progression. Chronic inflammation can lead to the recruitment of bone marrow-derived inflammatory cells to the tumor mass, promoting a cascade of events that amplify tumor-promoting effects of immune cells. The classification of immune cells into different states or subtypes has provided insights into their disparate functions. For example, type 1 CD4+ T cells (TH1) aid CD8+ T cells in tumor rejection, whereas type 2 CD4+ T cells (TH2) and CD4+ T regulatory cells block the activation of CD8+ T cells. The induction of angiogenesis is a crucial early stage in the development and growth of most solid tumors, and is necessary for hematogenous dissemination of cancer cells. Bone marrow-derived myeloid cells, including macrophages, TIE2-expressing monocytes, neutrophils, and mast cells, contribute to tumor angiogenesis through the production of growth factors, cytokines, and proteases. These cells also play a