Pancreatic ductal adenocarcinoma (PDAC) is characterized by immune cell dysfunction and poor prognosis. CD44, a cell surface glycoprotein with multiple splice variants, has been implicated in tumor progression, but its compartment-specific roles in PDAC remain unclear. CD44 standard and variant isoform expression was analyzed in patient-derived lymph nodes (LNs) by quantitative PCR. Immune cell-specific CD44 expression was assessed by flow cytometry in LNs and peripheral blood. Soluble and exosome-associated CD44 (exo-CD44) were measured in plasma. Clinical associations and survival analyses were performed. Transcriptomic, immune infiltration, immune checkpoint, and drug sensitivity analyses were conducted using TCGA-PAAD and pharmacogenomic datasets. CD44 standard isoform expression was unchanged in PDAC LNs, whereas multiple CD44 variant isoforms (v4–v10) were significantly reduced and associated with metastatic disease and poor survival, particularly CD44v5, v6, v7, and v10. CD44 expression was enriched in CD45⁺ immune cells, with highest levels in CD4⁺ T cells in both LNs and blood. Soluble CD44 levels showed no clinical associations. In contrast, exo-CD44 levels were reduced overall in PDAC but increased in patients with distant metastasis, positive resection margins, systemic inflammation, and reduced survival. High CD44 expression was associated with advanced disease, immune cell infiltration, immune checkpoint gene expression, reduced sensitivity to gemcitabine, paclitaxel, rapamycin, and FMK, and distinct CTLA4/PD-L1 checkpoint profiles. CD44 exhibits compartment-specific regulation in PDAC, linking immune remodeling, exosome signaling, and therapeutic resistance to adverse clinical outcome.

Circulating myeloid cells are critical regulators of pancreatic ductal adenocarcinoma (PDAC) progression. However, their postoperative dynamics and clinical relevance remain poorly defined. In a prospective longitudinal study, blood was collected from PDAC patients prior to surgery and on postoperative day 7. Flow cytometry was used to characterize monocytes, including classical (CM), intermediate (IMM), and non-classical (NCM) subsets, along with regulatory and co-stimulatory molecules (CD71, CD40, CD141, CD80, CD86, PD-L1). Cytokine levels (IL-6, IL-10, TNF-α, IL-1β) were quantified by ELISA and correlated with clinical parameters and survival. Total monocytes and CM increased significantly at day 7, whereas IMM and NCM decreased. CD71, CD141, CD80, and CD86 expression were significantly altered across subsets, with the most pronounced reduction observed in CD86 expressing NCM. CD86 expressing NCM correlated inversely with systemic bilirubin but not CEA, lymphocytes, thrombocytes, or hospital stay. IL-6 and IL-10 increased postoperatively; IL-10 showed a tendency toward inverse correlation with CD86⁺ NCM. Low CD86 expression on NCM at day 7 was associated with reduced survival and higher relapse probability. CD86 expression on NCMs is profoundly reduced after PDAC surgery and serves as a prognostic biomarker linked to inflammation, bilirubin metabolism, survival, and recurrence. Postoperative monocyte profiling may improve risk stratification and inform early clinical decision-making.