The immunobiology of pancreatic cancer metastasis: premetastatic niche formation, organ-specific immune landscapes, and therapeutic opportunities.

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor overall survival and is largely refractory to standard therapies. Most patients present with locally advanced or metastatic disease, and those with early-stage tumors amenable to surgical resection face high rates of metastatic relapse. Despite the many successes of immunotherapy in other solid tumors, these approaches have shown only marginal activity in PDAC. In PDAC, metastasis occurs through a coordinated, multistep process characterized by a gradient loss of immune surveillance. This process begins with establishment of a receptive premetastatic niche, which occurs via conditioning of distant tissues by tumor-derived exosomes and the recruitment of myeloid cells, leading to extracellular matrix remodeling and local immunosuppression prior to metastatic dissemination. On arrival of metastatic cells, tissues undergo organ-specific immune editing with important implications for therapeutic vulnerability. Importantly, liver metastases maintain a profoundly immunosuppressive environment whereas lung metastases have higher immune activity. These observations challenge the prevailing assumption that insights from primary tumors are broadly applicable to metastatic disease, establishing metastatic PDAC as a distinct immunologic entity. This framework identifies unique therapeutic opportunities across the disease spectrum from early interventions targeting premetastatic niche formation to site-specific strategies for established metastatic disease.