Timing matters: neoadjuvant and adjuvant immunotherapy in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) carries a high-risk of recurrence following curative-intent therapies such as surgical resection or local ablation, largely due to residual micrometastatic disease and the immunosuppressive hepatic tumour microenvironment. Although immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for advanced HCC, their integration into earlier disease stages remains an evolving area of clinical investigation. This review evaluates current evidence for adjuvant and neoadjuvant immunotherapy in early-stage HCC, examining biological rationale, emerging clinical trial data and future therapeutic strategies. The liver’s tolerogenic immune environment facilitates tumour immune escape via T-cell exhaustion, regulatory T-cell expansion and upregulation of inhibitory checkpoint pathways such as PD-1/PD-L1 and CTLA-4. ICIs aim to reverse these processes and restore antitumour immunity. In the adjuvant setting, immunotherapy is intended to eradicate residual microscopic disease following curative treatment. However, recent phase III trials, including IMbrave050 and KEYNOTE-937, produced mixed or negative outcomes, highlighting limitations of adjuvant-only strategies and the absence of validated predictive biomarkers in HCC. Neoadjuvant immunotherapy may offer distinct biological advantages by exposing the intact tumour to immune priming before resection, potentially generating systemic tumour-specific T-cell responses capable of controlling micrometastatic disease. Early-phase clinical studies demonstrate encouraging pathological response rates without compromising surgical feasibility. Emerging perioperative strategies combining neoadjuvant immune priming with postoperative maintenance therapy, together with biomarker-driven patient selection, may represent a more effective approach to reducing recurrence. Future progress will depend on deeper mechanistic insight into recurrence, validation of predictive biomarkers and pragmatic clinical trials reflecting the evolving global epidemiology of HCC.