Prognostic significance of tumoral Siglec-15 expression in solid tumors: a systematic review and meta-analysis

Siglec-15 has emerged as a novel immune checkpoint molecule and a potential therapeutic target in solid tumors. Previous studies reported inconsistent prognostic significance of tumoral Siglec-15 expression across cancer types. We therefore conducted a systematic review and meta-analysis to comprehensively evaluate the association of tumoral Siglec-15 expression with survival outcomes in patients with solid tumors.

PubMed, Web of Science, and EMBASE were systematically searched from database inception to March 30, 2026. Observational studies investigating Siglec-15 protein expression in tumor cells and prognosis were included. Study quality was assessed using the Newcastle-Ottawa Scale. Random-effects models were applied to calculate pooled hazard ratios (HRs) and odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Prespecified subgroup analyses, meta-regression analyses, and publication bias assessment were performed.

Twenty-seven datasets involving 4075 patients were included. High tumoral Siglec-15 expression was significantly associated with poorer overall survival (OS, HR = 1.53, 95% CI: 1.25-1.86, P < 0.001) and worse disease-free/recurrence-free survival (DFS/RFS, HR = 1.30, 95% CI: 1.09-1.55, P = 0.004). No significant association was observed for progression-free survival (HR = 1.03, 95% CI: 0.67-1.56, P = 0.903). High Siglec-15 expression showed a marginal association with improved disease-specific survival (DSS, HR = 0.66, 95% CI: 0.43-1.00, P = 0.050). Tumor-specific analyses demonstrated significantly worse OS in colorectal cancer, gastric cancer, and osteosarcoma, whereas breast cancer showed a non-significant association in the opposite direction (HR = 0.72, 95% CI: 0.33-1.56). Tumoral Siglec-15 expression was inversely associated with PD-L1 positivity (OR = 0.40, 95% CI: 0.23-0.72, P = 0.002), supporting a mutually exclusive immune checkpoint pattern. No significant associations were observed between Siglec-15 expression and most clinicopathological features.

Elevated tumoral Siglec-15 expression was associated with unfavorable OS and DFS/RFS, whereas the borderline association with improved DSS should be interpreted cautiously because it was based on only three studies. These findings support a highly cancer-type dependent role of Siglec-15 as a clinically relevant prognostic biomarker and a promising immunotherapeutic target. Further prospective studies are needed to validate these findings and develop standardized assessment strategies, preferably using fixed cutoff values and simplified scoring methods.