At distant sites, tumor cells encounter tissue microenvironments distinct from the primary tumor. Colonization depends partly on how they adapt to and reprogram local immune and metabolic niches. Here, we outline key tumor-intrinsic and -extrinsic interactions enabling liver and lung metastases, drawing on evidence from diverse cancer types, including PDAC. (A) Liver: Often considered tolerogenic, the liver epithelial and immune environments can be coopted by tumor cells to stimulate outgrowth. For instance, hepatocyte-derived plexin B2 activates epithelial programs in tumor cells, while induction of STAT3/SAA1 signaling in hepatocytes suppresses T cell responses. Tumor cell–induced damage of hepatocytes can trigger efferocytosis, which activates tumor-promoting myeloid cells. Antitumor Kupffer cells and NK cell responses are limited by tumor cells and local immunosuppression. Additional quiescent stellate cells that help maintain dormancy may be reprogrammed by monocyte-derived granulin or ECM stiffening into activated myofibroblasts that promote metastatic growth. (B) Lung: The lung harbors a distinct immune and metabolic niche compared with the liver. It contains type I and lipid-rich type II pneumocytes, alveolar macrophages, and immune defenses adapted to airborne pathogens and particulates. In PDAC, elevated immune infiltration in the lung may slow metastatic progression; however, multiple protumorigenic factors can facilitate growth, as described in other cancer types. Increased oxygen availability stimulates Tregs, while surfactant-derived lipids (e.g., palmitic acid) can fuel tumor growth. Both pneumocyte subtypes can suppress T cell activity and drive neutrophil recruitment, leading to NET formation or diminished NK cell function. Tumor cells further adapt by shifting to oxidative phosphorylation or downregulating STING to limit immune activation. Changes in pyruvate metabolism can influence collagen remodeling and Coco expression can counteract BMP signaling, both enabling metastatic expansion.