Association of HAMP Expression and CD8 + T‐Cell Infiltration With Atezolizumab–Bevacizumab Response in Hepatocellular Carcinoma

ABSTRACT Aim Atezolizumab combined with bevacizumab is the standard first‐line therapy for unresectable hepatocellular carcinoma; however, predictive biomarkers of therapeutic response remain undefined. We aimed to identify molecular features associated with therapeutic efficacy to develop personalized treatment strategies. Methods Transcriptomic analyses were performed using public RNA‐sequencing datasets of patients with hepatocellular carcinoma receiving anti‐PD‐L1‐based therapy, comparing responders (complete response/partial response) with non‐responders (stable disease/progressive disease). Differentially expressed genes and enriched pathways were identified using integrated differential expression and pathway analysis. For validation, RNA‐sequencing was performed on institutional tumor samples ( n = 6) underwent. Immunohistochemistry was performed on resected specimens ( n = 9) to evaluate CD8+ tumor‐infiltrating lymphocytes and hepcidin protein expression encoded by the HAMP gene. Group comparisons for the pre‐specified immunohistochemistry endpoints were analyzed using exact Wilcoxon rank‐sum tests with multiplicity control (Holm adjustment). Results Analysis of public datasets revealed distinct expression profiles in responders, enriched in immune‐related and chemokine signaling pathways. Candidate genes, including HAMP, TAT, and HRG, were upregulated in responders. In institutional samples, HAMP expression was significantly higher in preoperatively treated tumors ( p = 0.001). Immunohistochemistry demonstrated greater CD8+ tumor‐infiltrating lymphocyte density (median 36.6 vs. 5.0 cells/high‐power field; exact Wilcoxon p = 0.032) and higher HAMP immunoreactive scores (median 4 vs. 0.5; p = 0.032) in responders than in non‐responders. Conclusions Upregulation of HAMP and hepcidin protein expression, together with increased CD8+ T‐cell infiltration, was associated with a favorable response to atezolizumab–bevacizumab in patients with hepatocellular carcinoma. HAMP may serve as a component of a composite biomarker predictive of therapeutic sensitivity, warranting validation in larger, multi‐institutional cohorts.