Neoadjuvant therapy for hepatocellular carcinoma: emerging combinations and biomarker challenges

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with high recurrence rates limiting the success of curative treatments. Neoadjuvant therapy has recently arisen as a promising strategy to enhance surgical outcomes and survival. This review focuses specifically on neoadjuvant therapy for resectable HCC.

We summarize current neoadjuvant approaches in this defined setting, focusing on systemic therapies-including targeted agents, immune checkpoint inhibitors, and their combinations-as well as locoregional modalities such as transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), ablation, and radiotherapy. Systemic-locoregional combinations have demonstrated improved pathological response rates and event-free survival, with phase 2/3 trials such as CARES-009 providing the highest level of evidence to date. We further summarize progress in biomarkers for predicting treatment efficacy across molecular, cellular, histopathological, and imaging dimensions. Key advances include baseline immune activation signatures, dynamic serum biomarkers such as alpha-fetoprotein (AFP) kinetics and liquid biopsy indicators, and emerging radiomic signatures and spatial multi-omics approaches. We also highlight ongoing clinical trials that are evaluating novel combination regimens and biomarker-driven patient stratification.

By identifying critical challenges in standardizing pathological response criteria, optimizing treatment duration and sequencing, and validating multimodal biomarkers, this review emphasizes the pivotal role of neoadjuvant therapy in reshaping curative-intent management for HCC and delineates actionable directions for future research.