BACKGROUND & AIMS: Most patients with hepatocellular carcinoma (HCC) have underlying chronic liver disease, which may influence survival outcomes. Mac-2 binding protein glycosylation isomer (M2BPGi) is a biomarker reflecting liver fibrosis status, which in turn may be associated with survival in patients with HCC treated with immune checkpoint inhibitors (ICIs), particularly in regions where viral hepatitis is endemic.

METHODS

From September 2017 to September 2022, 158 patients receiving ICIs for unresectable HCC were prospectively enrolled, and baseline serum samples were collected for M2BPGi measurement. Variables associated with overall survival (OS) were analyzed. An additional 60 consecutive patients with unresectable HCC were recruited after October 2022 for validation.

RESULTS

In the training cohort, serum M2BPGi level correlated strongly with Fibrosis-4 score, Child-Pugh class and ALBI (albumin-bilirubin) grade. An M2BPGi ≥1.68 COI (cut-off index) was associated with significantly reduced OS (hazard ratio 1.992, 95% CI 1.369-2.900; <0.001). By incorporating baseline alpha-fetoprotein (≥100 ng/ml), M2BPGi (≥1.68 COI), portal vein invasion, and non-HBV infection, a new Mac-2 score was developed that effectively stratified patients by OS (28.8, 13.6 and 8.3 months for scores of 0-1, 2 and 3-4, respectively, <0.001). The Mac-2 score demonstrated superior discrimination and calibration abilities (the highest AUROC, greatest homogeneity, and the lowest corrected Akaike information criterion value), and net reclassification improvement compared with the CRAFITY score, ALBI grade, and Child-Pugh class.

CONCLUSION

Serum fibrosis marker M2BPGi correlates with liver reserves and survival in patients with HCC undergoing ICI-based immunotherapy. The newly developed Mac-2 score may offer improved clinical utility in this population.

IMPACT AND IMPLICATIONS

Most cases of hepatocellular carcinoma occur in patients with underlying liver fibrosis or cirrhosis, and the fibrotic microenvironment may influence the anti-tumor effects of immune checkpoint inhibitors. Serum M2BPGi reflects liver fibrosis status and liver reserve in hepatocellular carcinoma and is associated with survival outcomes in patients receiving ICI-based immunotherapy. The novel Mac-2 score, based on baseline M2BPGi levels, has the potential to enhance patient selection and guide therapeutic strategies.