The spatial landscape of the peritumoral interface: ARG1+ PMN-MDSCs reduction and NETosis as indicators of occult metastasis in tongue squamous cell carcinoma
Frontiers in Immunology, 2026
Zhang S., Xu J., Zhang C., Li X., Wang D., Li X., Guo C., Wang L.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Oncology | Patient Stratification | Serum Tissue Lysate |  Olink Target 96 |
Abstract
Background
Predicting occult lymph node metastasis in early-stage tongue squamous cell carcinoma remains a clinical challenge because traditional markers, such as depth of invasion, exhibit limited accuracy. This study aimed to identify spatial immunological biomarkers to improve risk stratification and clinical decision-making.
Methods
Olink proteomic profiling was conducted to screen for metastasis-associated biomarkers. Subsequently, multiplex immunofluorescence coupled with artificial intelligence-powered spatial analysis was utilized to evaluate the microenvironment in primary lesions and paired cervical lymph nodes. A novel “Spatial Availability Index” was applied to map cellular distribution, and diagnostic performance was evaluated using receiver operating characteristic curve analysis.
Results
Arginase-1 (ARG1) was identified as a top candidate biomarker, exhibiting a unique “tissue-low, serum-high” expression pattern in cases with occult metastasis. Spatial analysis revealed a significant depletion of ARG1 + polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in both primary tumors and paired lymph nodes during metastatic progression. Specifically, the reduction of these intact cells was most pronounced within a 35-μm proximal segment from the tumor boundary. This localized cellular loss inversely correlated with an accumulation of neutrophil extracellular traps (NETs) at the peritumoral interface, indicating that ARG1 + PMN-MDSC-associated spatial alterations coincide with NET-associated remodeling at the peritumoral interface. Integrating the intrastromal density of ARG1 + PMN-MDSCs with depth of invasion significantly enhanced the diagnostic accuracy for occult metastasis (Area Under the Curve = 0.8318) compared to using depth of invasion alone.
Conclusions
Early metastatic risk is driven by localized alterations within the myeloid compartment, characterized by the transition of intact ARG1 + PMN-MDSCs to NETs within a 35-μm peritumoral hotspot. This spatial biomarker provides a high-resolution tool to optimize patient selection for elective neck dissection.