Chronic stress promotes pancreatic ductal adenocarcinoma progression via complement C5a-recruited myeloid-derived...

Chronic stress is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Although the autonomic nervous system (ANS), a key component of the tumor microenvironment (TME), has been closely associated with PDAC pathogenesis and prognosis, the underlying mechanisms remain incompletely understood. This study reveals that chronic stress-induced sympathetic nervous system (SNS) activation upregulates the hepatic complement system, leading to the recruitment of myeloid-derived suppressor cells (MDSCs) that promotes tumor progression. Specifically, chronic stress-triggered neurotransmitter norepinephrine (NE) enters the liver via systemic circulation and binds to upregulated β1 adrenergic receptor (ADRB1) on hepatocytes, enhancing the expression of complement components C3, C5, and CFH. In murine chronic stress-model, elevated systemic and intratumoral complement component 5a (C5a) levels correlated positively with MDSC expansion in both the spleen and tumor tissues. The effect was abrogated by the C5aR1 antagonist PMX-53, identifying C5a as a critical mediator of MDSC accumulation. MDSCs infiltrating the TME exhibited elevated expression of programmed death-ligand 1 (PD-L1) and transforming growth factor-β (TGF-β), contributing to an immunosuppressive niche. Intervention with the ADRB1 antagonist atenolol in PDAC mice significantly reduced serum/tumoral C5a levels, diminished splenic/intratumoral MDSCs proportions, and attenuated tumor growth. Our findings propose that targeting the SNS-driven complement-MDSCs axis represents a promising strategy for PDAC patients.