NK Cell Adoptive Transfer Suppresses Metastasis and Prolongs Survival in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest malignancies, with metastatic disease accounting for nearly 90% of these deaths and no therapies that effectively prevent metastatic progression. Here, we identify natural killer (NK) cells as central regulators of metastatic competence in PDAC, actively constraining dissemination and preventing tumor-intrinsic reprogramming toward a metastasis-permissive state. Genetic and antibody-mediated NK cell depletion markedly increased liver and lung metastasis. In vivo tracking of fluorescently labeled PDAC cells revealed that NK cells restrict multiple early steps of the metastatic cascade, limiting intravasation, promoting clearance of circulating tumor cells (CTCs), and suppressing survival and seeding at distant sites. Mechanistically, NK cell loss induced coordinated remodeling of both the tumor microenvironment and tumor cell state. NK depletion reduced myeloid lineage diversity while enhancing phagocytic polarization and drove tumor-intrinsic activation of epithelial-mesenchymal transition (EMT) and metastasis-associated transcriptional programs, indicating that NK surveillance actively restrains metastatic plasticity. Consistent with this model, aggressive human basal-like PDACs exhibited reduced NK cell infiltration and enrichment of EMT-associated gene signatures. Therapeutically, adoptive NK cell transfer reversed these phenotypes across immunocompetent and immunodeficient models, reducing CTC burden, suppressing metastatic outgrowth, and extending survival. In patient-derived xenograft (PDX) models, systemic NK-92 cell administration reduced metastatic recurrence following primary tumor resection. Moreover, NK-92 cells demonstrated robust cytotoxicity against patient-derived PDAC organoids. Concordantly, human tumors enriched for activated or activation-prone NK cell states were associated with improved clinical outcomes. Collectively, these findings redefine NK cells as central regulators of metastatic competence in PDAC and provide a mechanistic and translational framework for NK-based immunotherapy aimed at preventing metastatic progression.