Integration of Circulating Immune Checkpoint Proteins and Osteopontin Refined Risk Stratification in Osteosarcoma.
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BACKGROUND: Osteosarcoma remains the most common primary malignant bone tumor in children and adolescents, with largely unchanged survival outcomes in recent decades. Non-invasive biomarkers for preoperative risk stratification are urgently needed. Circulating immune checkpoint proteins (ICPs) and bone remodeling factors (BRFs) represent promising candidates; however, their combined prognostic value in osteosarcoma remains unclear. METHODS: We prospectively analyzed plasma samples from 47 patients with osteosarcoma, selecting the earliest available sample before disease progression or the last follow-up. A panel of ICPs and BRFs was quantified using multiplex immunoassays. sHVEM and sCD27 were used to construct a two-marker ICP signature (ICP2); subtypes were defined by unsupervised consensus clustering (k = 2) applied to log2-transformed sHVEM and sCD27 concentrations, and sOPN was included for integrative analysis. Survival associations were assessed using Kaplan-Meier analysis and Firth's penalized Cox regression. The model performance was evaluated using Harrell's C-index. RESULTS: Two ICP2 subtypes were identified (type1, n = 26; type2, n = 21). ICP2-type2 was associated with significantly worse progression free survival (PFS) (p = 0.0045) and overall survival (OS) (p = 0.0024) and remained an independent predictor after adjusting clinicopathological factors. The ICP2 model demonstrated high discriminative performance (C-index 0.924 for PFS and 0.903 for OS). Internal validation by leave-one-out cross-validation (LOOCV), in which consensus clustering was re-derived at each fold, yielded corrected C-indices of 0.612 for PFS and 0.806 for OS (versus apparent estimates of 0.687 and 0.689, respectively), confirming acceptable-to-good discrimination after accounting for overfitting. Elevated sOPN was associated with poorer survival in the exploratory analyses, although its prognostic value was less consistent under a pre-specified cutoff. In the combined models, sOPN provided modest additional value for OS stratification, with the grdgfdgICP2-type2/OPN-high subgroup exhibiting the poorest outcome. CONCLUSIONS: The circulating sHVEM/sCD27 signature defines prognostically distinct osteosarcoma subtypes with a strong discriminative performance. This minimally invasive model may support preoperative risk stratification. Integration with sOPN suggests a potential biological link between immune regulation and bone remodeling, warranting validation in larger cohorts.