Background: Gastric cancer (GC) remains a global health challenge, with high mortality rates often linked to late-stage diagnosis. Novel, non-invasive biomarkers are urgently needed to improve the detection and prognosis of this malignant pathology. This study aimed to evaluate the diagnostic and prognostic utility of serum Cluster of Differentiation 276 (CD276) and Dickkopf Related Protein 3 (DKK3) in patients with GC. Methods: In this case–control study, serum levels of CD276 and DKK3 were quantified in 40 GC patients and 40 age-matched healthy controls. The diagnostic performance of each marker and their combination was assessed using Receiver Operating Characteristic (ROC) curve analysis. Correlations between biomarker levels and clinicopathological features were evaluated using Spearman’s correlation. The Kaplan–Meier method and the Cox Proportional Hazards Regression Model were used to assess survival. Results: Serum CD276 levels were found to be significantly elevated in GC patients compared to healthy controls (median 60.06 vs. 18.71 units, p < 0.001). Conversely, serum DKK3 levels were significantly suppressed in the GC group (median 92.47 vs. 121.02 units, p < 0.001). In ROC analysis, CD276 demonstrated excellent diagnostic accuracy as a standalone biomarker (AUC: 0.836). DKK3 showed independent diagnostic value (AUC: 0.792), but adding DKK3 to CD276 did not provide statistically significant incremental benefit (DeLong’s p = 0.443). Survival analysis was underpowered due to limited events and short follow-up duration. Conclusions: In patients with predominantly locally advanced gastric cancer, CD276 can be a primary diagnostic marker, and the addition of DKK3 does not demonstrate a statistically significant improvement but may provide complementary information. Performance in early-stage disease requires validation in future studies. The opposing dysregulation of these markers, reflecting immune checkpoint activation (CD276) and tumor suppressor loss (DKK3), provides a robust and synergistic noninvasive signature. To assess the prognostic value of these two markers, studies involving a larger number of patients and a longer follow-up period are needed.
Fugărețu et al. (2026) studied this question.