Oncology · Medical Literature
Prognostic significance of tumoral Siglec-15 expression in solid tumors: a systematic review and meta-analysis.
Abstract
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.
Clinical relevance
In patients with solid tumors, is high tumoral Siglec-15 protein expression independently associated with worse survival outcomes, including overall survival (OS) and disease-free/recurrence-free survival (DFS/RFS), compared with low Siglec-15 expression? __SNAPSHOT__ {"studyDesign":"Systematic review and meta-analysis of observational studies","setting":"International; multi-institutional; databases searched: PubMed, Web of Science, EMBASE (inception to March 30, 2026)","sampleSize":"n = 4,075 patients across 27 datasets","population":"Adults with histologically confirmed solid tumors of varied types in whom Siglec-15 protein expression was assessed in tumor cells by immunohistochemistry or analogous protein-level assay; specific cancer types and staging criteria not detailed in the abstract","intervention":"High tumoral Siglec-15 protein expression (exposure; exact cut-off definitions varied by included study)","comparator":"Low tumoral Siglec-15 protein expression","primaryOutcome":"Overall survival (OS); secondary outcomes included disease-free survival / recurrence-free survival (DFS/RFS) and clinicopathological feature associations (not fully reported in available abstract text)","followUp":"Not reported (varies by constituent studies)","fundingSource":"Not reported"}
Key findings
Among 27 datasets encompassing 4,075 patients, high tumoral Siglec-15 expression was significantly associated with poorer overall survival (pooled HR = 1.53, 95% CI: 1.25–1.86, P < 0.001) using random-effects modeling. High expression was also associated with worse disease-free/recurrence-free survival (DFS/RFS); the exact pooled HR, 95% CI, and p-value for DFS/RFS are not fully transcribed in the abstract fragment provided and are therefore not reported here to avoid misrepresentation. An HR of 1.53 for OS represents an approximately 53% higher risk of death in patients with high tumoral Siglec-15 expression relative to those with low expression — a clinically meaningful magnitude if confirmed. No NNT or NNH is calculable from the data available in the abstract. Prespecified subgroup analyses, meta-regression analyses, and publication bias assessments were performed; their specific results are not reported in the available abstract excerpt. Adverse event data are not applicable to this prognostic observational meta-analysis.
Practice implications
This meta-analysis provides the largest pooled prognostic analysis of tumoral Siglec-15 expression to date (27 datasets, n = 4,075), and its primary finding — that high tumoral Siglec-15 protein expression is associated with significantly worse OS (HR 1.53) — strengthens prior smaller meta-analyses and individual cohort studies reporting similar directional associations. However, several important boundaries must be acknowledged. First, only the abstract is available; key methodological details — subgroup findings by cancer type, degree and sources of heterogeneity (I² statistics), publication bias results, and the completeness of DFS/RFS data — cannot be independently verified, per the limitation inherent to abstract-only review. Second, this is a meta-analysis of observational studies; confounding by tumor stage, histologic grade, treatment type, and Siglec-15 assay methodology cannot be excluded and may substantially influence pooled estimates. Third, Siglec-15 expression patterns and prognostic significance have been reported to vary considerably by cancer type (e.g., favorable associations in some pancreatic ductal adenocarcinoma series), and whether the pooled effect applies uniformly across solid tumor subtypes is unclear without subgroup data. Fourth, prior literature demonstrates that Siglec-15 is predominantly expressed in stromal immune cells rather than tumor cells in several cancer types, raising questions about the analytic and biological precision of isolating 'tumoral' expression. Fifth, this evidence base does not establish that Siglec-15 is an independent prognostic biomarker after adjustment for established clinicopathological variables. The findings are hypothesis-generating and support Siglec-15 as a prognostically relevant immune checkpoint target, but they do not constitute sufficient evidence to warrant routine clinical Siglec-15 testing or to guide treatment decisions at this time. Confirmation via prospectively designed biomarker studies with standardized assays, pre-specified cut-offs, and multivariable adjustment is required. __LIMITATIONS__ Abstract-only review: full methodology, heterogeneity statistics (I²), subgroup results, meta-regression outputs, and publication bias data cannot be assessed.,Observational study design with high potential for residual confounding by tumor stage, grade, treatment regimen, and patient performance status.,Variability in Siglec-15 assay methodology, antibody clones, tissue fixation protocols, and expression cut-off thresholds across included studies may introduce substantial clinical and methodological heterogeneity.,Aggregation across biologically heterogeneous cancer types may mask cancer-specific effects; the prognostic direction and magnitude of Siglec-15 expression has been reported to differ by tumor type in prior literature.,Tumoral vs. stromal Siglec-15 expression distinction: Siglec-15 is predominantly expressed by stromal immune cells in several solid tumor types; inclusion criteria limited to 'tumor cell' expression may be inconsistently applied across included studies.,Publication bias is a recognized risk in prognostic biomarker meta-analyses; studies with positive or significant results are more likely to be published.,Multivariable independence of Siglec-15 as a prognostic marker — controlling for established factors — is not confirmed in the abstract.,Follow-up duration not reported, limiting assessment of long-term outcome relevance.,Funding source not reported; potential conflicts of interest cannot be evaluated. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This systematic review and meta-analysis of 27 datasets (n = 4,075) found that high tumoral Siglec-15 protein expression is associated with significantly worse overall survival (pooled HR = 1.53, 95% CI: 1.25–1.86, P < 0.001) across solid tumors, providing the strongest pooled prognostic signal for this immune checkpoint molecule to date. However, the evidence is entirely derived from observational studies with inherent confounding, substantial biologic heterogeneity across cancer types, and unstandardized assay methods, which preclude routine clinical implementation of Siglec-15 testing. These findings support prioritizing prospective, standardized, and multivariable biomarker studies and ongoing anti-Siglec-15 therapeutic trials (e.g., NC318), but should not alter current clinical practice.