Comprehensive Analysis of SIGLEC-15 and PD-L1 Expression Identifies Distinct Prognostic Profiles in Gastric Cancer

Gastric cancer remains a major global health burden, with limited response rates to current immunotherapies targeting the programmed death-ligand 1 (PD-1/PD-L1) axis. Recent studies have identified sialic acid-binding immunoglobulin-like lectin 15 (SIGLEC-15) as a novel immune checkpoint molecule that may drive immune evasion through PD-L1-independent pathways. This study aimed to evaluate the expression patterns of SIGLEC-15 and PD-L1 in gastric adenocarcinoma and to investigate their associations with clinicopathological features and patient outcomes. We retrospectively analyzed 133 consecutive cases of gastric adenocarcinoma with complete clinicopathologic and follow-up data. Immunohistochemical staining was performed on formalin-fixed tumor samples; SIGLEC-15 expression on tumor cells was quantified by H-score (high expression defined as ≥110) and PD-L1 status by combined positive score (CPS, positive if ≥1). High SIGLEC-15 expression correlated with multiple adverse pathological features, including lymphatic (p = 0.003), venous (p = 0.030), and perineural invasion (p = 0.010), and was associated with significantly poorer 3-year overall survival (hazard ratio = 3.36, p < 0.001). While SIGLEC-15 and PD-L1 expression were not mutually exclusive, an inverse relationship was generally observed. Patients with dual positivity (SIGLEC-15 high/PD-L1 CPS ≥ 1) showed the lowest 36-month survival (32%), compared to 56% in the dual-negative group (SIGLEC-15 low/PD-L1 CPS < 1). These results highlight the clinical relevance of SIGLEC-15 as an independent marker of tumor aggressiveness and poor prognosis in gastric adenocarcinoma. Moreover, stratification based on combined SIGLEC-15 and PD-L1 CPS expression revealed that patients co-expressing high levels of both markers experienced the poorest survival outcomes. These findings suggest that the dual assessment of SIGLEC-15 and PD-L1 may enhance prognostic accuracy and support immunotherapeutic decision-making in gastric cancer.