Sepsis as a pre-metastatic niche mimic: post-sepsis microenvironmental priming through an Immuno–Vascular–Matrix Triad

Metastasis is a systemic biological process in which distant tissues undergo molecular, vascular, immune, and extracellular matrix remodeling before the arrival of circulating malignant cells. The classical pre-metastatic niche paradigm attributes this process mainly to tumor-derived soluble mediators and extracellular vesicles; however, it does not explain whether severe systemic inflammation alone can generate tissue states permissive to future metastatic colonization. This review examines whether sepsis may function as a clinical model of post-inflammatory pre-metastatic niche-like priming through persistent immune dysfunction, endothelial activation, and extracellular matrix remodeling. Sepsis triggers a coordinated host-response program characterized by thromboinflammation, endothelial injury, and sustained immunodisruption. Early release of alarmins, including high-mobility group box 1, mitochondrial DNA, and adenosine triphosphate, activates Toll-like receptor signaling pathways and promotes platelet activation, diffuse microthrombosis, dysregulated neutrophil extracellular trap formation, focal hypoxia, and hypoxia-inducible factor-1α activation. Concurrently, prolonged lymphopenia, checkpoint-mediated T-cell exhaustion, regulatory T-cell expansion, and reduced monocytic human leukocyte antigen-DR expression impair immune surveillance beyond apparent clinical recovery. In parallel, mesenchymal stromal cells and inflammatory extracellular vesicles induce matrix metalloproteinase-mediated degradation and reorganization of collagen, laminin, and fibronectin, generating a mechanically unstable, permeable, and pro-adhesive extracellular matrix. These immune, vascular, and matrix alterations converge in an Immuno–Vascular–Matrix triad that may generate transient states of systemic permissiveness characterized by endothelial hyperadhesiveness, reduced immune selectivity, persistent myeloid recruitment, and increased tissue susceptibility to aberrant cellular persistence. Sepsis may represent a biologically plausible host-conditioned model of pre-metastatic niche-like priming rather than a direct oncogenic event. This framework generates testable mechanistic hypotheses linking persistent post-sepsis immune, endothelial, and extracellular matrix alterations with future oncologic vulnerability and supports longitudinal strategies for biological risk stratification and post-sepsis recovery monitoring.