Neoadjuvant Nivolumab–Ipilimumab in Resectable HCC- J Hepatol Feb.26

Immune checkpoint inhibitors have transformed the treatment of advanced hepatocellular carcinoma (HCC), but their role in potentially resectable disease remains under active investigation. This single-arm study evaluated nivolumab plus ipilimumab as neoadjuvant therapy, followed by surgery when feasible, and explored biological markers associated with treatment response.

Patients with potentially resectable HCC received combination immunotherapy before reassessment for curative surgery. Nearly half of the treated patients ultimately underwent resection, demonstrating the feasibility of integrating dual immune checkpoint blockade into a perioperative strategy. Importantly, a meaningful proportion of resected tumours showed major pathological response, indicating deep antitumor activity prior to surgery. Long-term follow-up revealed encouraging progression-free and overall survival, suggesting that this approach may translate into durable clinical benefit.

Beyond clinical outcomes, the study provides important mechanistic insights. Tumours responding to immunotherapy showed increased interferon-γ signalling and formation of tertiary lymphoid structures (TLS), specialised immune aggregates that support sustained antitumor immunity. Preclinical experiments confirmed that B cells are critical for the efficacy of combined PD-1 and CTLA-4 blockade, reinforcing the functional relevance of TLS. Additionally, profiling of peripheral blood demonstrated that patterns of T-cell activation and exhaustion, assessed with advanced flow cytometry and computational analysis, correlated with response and survival.

In summary, neoadjuvant nivolumab plus ipilimumab followed by surgery is feasible and may offer long-term benefit in selected patients with resectable HCC. The identification of TLS and peripheral immune signatures highlights promising biomarkers to guide patient selection and future perioperative immunotherapy strategies.