Changing Course: Semaphorins and Plexins as Novel Therapeutic Opportunities and Key Regulators of Pancreatic Cancer Microenvironment

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors, and despite recent advances in surgical and systemic therapies, outcomes remain poor, rooted as much in the genetic mutations that initiate the disease as in a fibrotic, poorly vascularized microenvironment marked by scarce immune infiltration and a dense network of nerve fibers. Semaphorins, together with their receptors plexins and co-receptors neuropilins, have emerged as pivotal orchestrators of this microenvironment, shaping crosstalk between malignant cells, fibroblasts, macrophages, the endothelium, and peripheral neurons. This review examines how individual semaphorin family members drive, or in select contexts restrain, stromal activation, immune exclusion, pathological angiogenesis and neural remodeling. Building on this mechanistic framework, we explore the clinical relevance that semaphorin-mediated signaling holds for PDAC, from its potential as a prognostic and predictive biomarker to its growing promise as a therapeutic target, positioning this axis as a compelling frontier for improving outcomes in a disease that has long resisted meaningful therapeutic advances.