Chronic Stress Promotes Pancreatic Ductal Adenocarcinoma Progression via Complement C5a-Recruited Myeloid-Derived Suppressor Cells

Abstract Chronic stress is recognized as one of the risk factors for pancreatic ductal adenocarcinoma (PDAC). The autonomic nervous system (ANS), a critical component of the tumor microenvironment (TME), has been closely associated with PDAC tumorigenesis and prognosis, though the underlying mechanisms remain elusive. Here, we demonstrate that aberrant activation of sympathetic nerves (SNS) upregulates the hepatic complement system, thereby recruiting myeloid-derived suppressor cells (MDSCs) into pancreatic malignancy to promote tumor progression. Chronic stress induces SNS-derived release of the neurotransmitter norepinephrine (NE), which enters the liver via systemic circulation and binds to upregulated β1 adrenergic receptor (ADRB1) on hepatocytes, leading to increased expression of complement components C3, C5, and CFH. In chronic stress-model mice, elevated serum and intratumoral Complement component 5a (C5a) levels showed a positive correlation with MDSCs proportions in both the spleen and tumor tissues. Administration of the C5aR1 antagonist PMX-50 disrupted this association, indicating C5a as a critical mediator of MDSCs expansion and recruitment. Infiltrating MDSCs within the TME exhibit elevated expression of Programmed death-ligand 1 and Transforming growth factor-beta, fostering the establishment of an immunosuppressive microenvironment. Intraperitoneal injection of the ADRB1 antagonist atenolol in PDAC mice resulted in marked reductions in serum/tumoral C5a levels, splenic/intratumoral MDSCs proportions, and tumor burden. Our findings suggest that targeting SNS-driven MDSCs recruitment and TME remodeling may offer novel therapeutic strategies for PDAC patients.