Background and PurposeInvestigating the assessment of innovative serum indicators with elevated sensitivity and specificity is crucial for enhancing the early diagnosis and prognosis of HCC (Hepatocellular carcinoma). This study aimed to evaluate the efficacy of COPA (Coatomer Subunit Alpha) in diagnosing hepatocellular carcinoma and assessing the effectiveness of immunotherapy.MethodsThis study included two cohorts: a diagnostic cohort comprising 81 healthy controls, 118 patients with benign liver diseases, and 81 patients with pathologically confirmed HCC, and an immunotherapy cohort comprising 131 HCC patients treated with PD-1/PD-L1 inhibitors. Serum COPA was measured by ELISA, while AFP and PIVKA-II were measured by electrochemiluminescence. Diagnostic performance and immunotherapy monitoring efficacy were then evaluated.ResultsCOPA is upregulated in serum and HCC tumor samples. The ROC analysis indicated that the diagnostic efficacy of COPA (AUC = 0.911) surpassed that of traditional biomarkers. Importantly, COPA retained favorable diagnostic performance in both AFP-negative and PIVKA-II-negative HCC patients. Dynamic monitoring revealed that when comparing PIVKAII and AFP with imaging-based efficacy assessments, serum COPA changes demonstrated superior consistency pre- and post-immunotherapy (Kappa of COPA = 0.73, P < 0.01). COPA expression was significantly elevated in HCC tissues compared with adjacent non-tumor tissues.ConclusionThis study established that COPA outperforms AFP and PIVKAII in diagnostic and immunotherapeutic monitoring reliability, offering a novel technique for the precise diagnosis and treatment of hepatocellular carcinoma.