Figure 3.

Establishment of the metastatic immune microenvironment: The primary tumor can actively prime organs by forming a metastasis-permissive microenvironment before the arrival of disseminated tumor cells (DTCs) (1). This premetastatic niche includes recruited monocytes, macrophages, and neutrophils, as well as tumor-secreted factors such as cytokines, chemokines, growth factors, and proteases. Enhanced vascular leakiness, reorganization of the stroma and extracellular matrix, and the establishment of an immunosuppressive environment are hallmarks of the metastatic microenvironment (2). These allow DTCs to evade natural killer (NK) cell immunity and colonize the ectopic organ as single cells or micrometastatic lesions. Micrometastatic lesions often enter a period of dormancy, as they are ill-adapted to the new microenvironment, encounter growth suppressive factors such as TGF-β, and are subjected to NK cell-mediated immune surveillance. Outgrowth involves tumor-intrinsic changes alongside the induction of angiogenesis and the creation of a mature immunosuppressive microenvironment to evade recognition by cytotoxic lymphocytes (3).