To colonize distant organs, tumor cells must extravasate from the vasculature, a process often facilitated by the mechanisms that supported their prior invasion and circulation, as reviewed earlier (Figure 1) (4). Although primary tumors shed cells continuously, only a small fraction successfully seed distant organs, and an even smaller subset progresses to form macroscopic metastatic lesions, underscoring the challenges disseminated tumor cells (DTCs) face when adapting to the unfamiliar conditions in metastatic sites (132).

After entering secondary tissues, DTCs face several possible fates. Most succumb to cell death or immune-mediated clearance. A subset may enter dormancy, persisting in a quiescent, nonproliferative state for variable intervals — a phase thought to confer a survival advantage by allowing cells to adapt to the metabolic and immune constraints of the new environment. Only the rare cells that eventually “awaken” and resume active proliferation progress to clinically overt metastases, driven by an interplay between cell-intrinsic and -extrinsic cues (133). In PDAC, dormancy is less clearly defined, partly because PDAC often presents at advanced stages and rarely exhibits the protracted latency intervals seen in other tumor types (92). Nonetheless, short-lived or context-dependent dormancy likely occurs in PDAC (134–136).

A central mechanism governing dormancy involves the phenotypic plasticity that enables DTCs to remain quiescent yet regain proliferative ability under the right stimuli (Figures 1 and 2) (1). Much like in primary lesions, EMT programs are a key mediator of this plasticity. Mesenchymal cells often cycle slowly and engage cancer stem cell (CSC) pathways to reduce metabolic demand and evade immune clearance (137–140). Transitioning back toward epithelial states (MET) is thought to promote outgrowth (141, 142). Cells in partial EMT states have greater flexibility in their EMT status and can revert to epithelial states more easily, supporting renewed proliferation (37). This flexibility often intersects with rewiring of DTC stress responses, metabolic, and immune programs to adapt to conditions at secondary sites (Figure 2) (143). Metabolically, dormancy is often associated with reduced glycolysis, increased oxidative phosphorylation (OXPHOS), and increased autophagy, which can promote mesenchymal phenotypes (23, 144). These metabolic shifts occur in part to minimize energy expenditure and limit reactive oxygen species (ROS) (143, 145). These adaptations can later be reversed to support growth in response to external cues. DTCs also modulate their immunogenicity through regulation of MHC-I expression (146, 147). For example, heightened ER-stress signaling in DTCs was associated with loss of MHC-I expression to escape T cell–mediated surveillance (147). Autocrine signals from DTCs may also alter metabolic programs or promote immune evasion by recruiting immunosuppressive myeloid cells or Tregs (148). In the context of breast cancer, these immune-mediated and metabolic shifts have been associated with STING activity, WNT pathways, and lactate production (149–151).

Site-specific tumor-stroma interactions regulating metastatic outgrowth. 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.

Local environmental cues can also be pivotal in regulating dormancy and outgrowth (Figure 2). For DTCs to form overt metastases, they must evade or suppress CTLs, NK cells, and other immune elements that constrain tumor expansion (148). Establishing the PMN is instrumental in this regard, as it primes local tissues for diminished immune clearance (10). Once tumor cells arrive, interactions with the resident stroma can perpetuate immunosuppression. For example, minor hepatic damage caused by PDAC cells can trigger efferocytosis by macrophages, reinforcing an immunosuppressive milieu (152). Additionally, metastases in regional lymph nodes may induce peripheral tolerance, and those in the liver can suppress CTL infiltration, collectively weakening antitumor immunity at more distant sites (153, 154).

In concert with local immune factors, metabolic cues such as hypoxia can induce dormancy by triggering cell cycle arrest, promoting EMT, and supporting autophagy to buffer against stress (155, 156). Shifts in nutrient availability likewise induce oxidative stress, prompting tumor cells to upregulate antioxidant pathways such as NRF2, which help promote metastasis (157). Interestingly, treating mice with the antioxidant N-acetylcysteine can increase metastasis in some models, implying that oxidative stress may restrict the expansion of dormant cells (145). However, in PDAC, ROS was found to enhance metastasis (158). These divergent responses to ROS likely reflect context-dependent effects influenced by the tumor’s genetic landscape, tissue of origin, and microenvironment. In PDAC, ROS can promote acquisition of mesenchymal phenotypes important for metastasis, while in melanoma and lung cancer, ROS appears to be detrimental to metastatic ability. Amid the hypoxia and limited nutrients, DTCs adjust their metabolism in concert with stromal cues. In PDAC liver metastases (Figure 2), HSCs can upregulate succinate dehydrogenase subunit B, biasing tumor cells toward an oxidative, quiescent phenotype (144). In contrast, inflammatory myofibroblasts stiffen the ECM and release inflammatory signals that drive proliferation and immune evasion (125). Beyond fibroblasts, the local epithelium also shapes DTC fate. In PDAC, hepatocyte-derived plexin 2 and IL-6/STAT3/SAA1 signaling facilitate liver colonization (124, 159).

The factors driving metastatic outgrowth also differ by organ site (Figure 2), a distinction that is clinically evident in PDAC, where patients with liver metastases have poorer survival than those with lung lesions (160, 161). We previously observed that clonal expansion patterns vary by metastatic location, indicating that tumor-intrinsic and -extrinsic signals differ by tissue context (55). A potential contributor to these differences is the immune and metabolic milieu in each organ. In the liver, NK cells and Kupffer cells can maintain tumor dormancy, but tumor-driven suppression of these defenses can trigger outgrowth (Figure 2) (162–164). In the lung, alveolar macrophages, Tregs, and neutrophils balance protection against airborne pathogens with immune tolerance, which can be coopted by DTCs to promote colonization (Figure 2) (165–167). However, an inflamed lung microenvironment in PDAC correlates with a more indolent course, whereas in other cancers it promotes aggressive spread, suggesting that tumor-intrinsic traits modulate site-specific immune effects (168). Similarly, distinct nutrient compositions also rewire DTC metabolism in a site-specific manner (169). For instance, breast cancer cells adapt to utilize the increased pyruvate and palmitic acid as nutrient source in the lung to proliferate (170, 171). Whether PDAC cells exploit these metabolic niches in a manner analogous to other malignancies and how these differences intersect with local immune regulation remains an open question.