Exploring Sex-Associated Systemic Inflammatory Profiles Linked to Macrophage Responses and Survival in Pancreatic Ductal Adenocarcinoma

Abstract Sex differences influence clinical outcome and therapeutic response in pancreatic ductal adenocarcinoma (PDAC), yet the contribution of systemic immune-inflammatory programs remains insufficiently defined. In this study, we characterized sex-associated circulating proteomic signatures, evaluated their prognostic relevance, and assessed their association with macrophage polarization. Olink Explore quantified 1536 proteins in a cohort of 50 PDAC patients (27 women and 23 men). Proteomic differences were explored alongside TCGA-PAAD survival associations and macrophage responses to conditioned supernatants from male- and female-origin PDAC cell lines. Exploratory analysis identified 51 proteins with nominal sex-associated differences (p < 0.05), of which 37 were higher in women and 14 in men. Female-associated proteins were enriched in immune-regulatory and macrophage-associated pathways. Among the PDAC cell lines examined, male-origin supernatants induced M2-like macrophage polarization, whereas female-origin supernatants promoted M1-associated programs. Survival analysis revealed 29 prognostic factors, including 18 sex-specific associations. A female-specific lipid–inflammation module comprising PCSK9, OLR1, IL1RN, and MMP8 was associated with overall survival. Collectively, these findings suggest sex-associated systemic immune-inflammatory profiles link to macrophage responses and prognosis in PDAC, supporting consideration of sex in biomarker development and therapeutic stratification.