Circulating sPD-L1 as a tumor microenvironment-derived biomarker: enhancing diagnostic discrimination accuracy in breast cancer

Programmed cell death ligand 1 (PD-L1) plays a pivotal role in breast cancer immune evasion, yet tissue-based detection suffers from invasiveness and spatial heterogeneity. This study investigated circulating soluble PD-L1 (sPD-L1) as a non-invasive alternative for tumor microenvironment (TME) assessment and breast cancer diagnosis. Serum sPD-L1 levels were evaluated in healthy and breast-affected populations, with correlations assessed against inflammatory markers and clinicopathological parameters. Diagnostic performance of sPD-L1 was compared to conventional biomarkers using receiver operating characteristic (ROC) curve analysis. Cellular-level interactions were investigated by quantifying sPD-L1 and interleukin-6 (IL-6) in culture supernatants. Circulating sPD-L1 expression was significantly elevated in breast cancer versus healthy controls and benign cases, with notably higher levels observed in advanced stages and distant-metastatic cases. Moderate correlations were observed between serum sPD-L1 and various inflammatory indicators. Specifically, ROC curve analysis identified an optimal diagnostic cut-off value of 1.144 ng/mL for sPD-L1, with its discriminative power outperforming conventional biomarkers such as CEA and CA15-3. In vitro, peripheral blood mononuclear cells (PBMCs) co-cultured with breast cancer cells showed enhanced sPD-L1 and IL-6 secretion versus normal epithelial cell co-cultures, with parallel sPD-L1/IL-6 elevation. This coordinated induction was clinically validated by a positive serum sPD-L1/IL-6 correlation. In conclusion, circulating sPD-L1 represents a promising non-invasive biomarker reflecting TME and disease progression, supporting its potential utility for breast cancer diagnostic discrimination.