Neoadjuvant Hepatic Arterial Infusion Chemotherapy with FOLFOX Plus Tislelizumab for Resectable Hepatocellular Carcinoma Beyond the Milan Criteria: Efficacy, Safety and Biomarker Exploration.

This study aimed to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy of oxaliplatin, fluorouracil, and leucovorin (FOLFOX-HAIC) combined with tislelizumab as a neoadjuvant regimen in patients with resectable hepatocellular carcinoma (HCC) beyond the Milan criteria, and to explore predictive biomarkers of treatment response. 26 patients completed neoadjuvant therapy, with a median tumor size of 6.35cm. The objective response rate according to mRECIST criteria reached 57.7%, and the disease control rate was 96.2%. 22 patients underwent radical surgery, and 10 patients (10/22, 45.5%) achieved major pathological response (residual viable tumor ≤10%). Six patients (27.3%) achieved complete pathological response, and 25 patients (96.2%) experienced at least one treatment-related adverse events (TRAEs) The most common TRAEs were elevated transaminases (76.9%), HAIC-related pain (34.6%). Transcriptomic analysis revealed that differential genes between responding and non-responding tumors primarily involved pathways related to bile acid secretion and fatty acid metabolism. Metabolomic analysis showed elevated serum chenodeoxycholic acid (CDCA) in non-responders and elevated tumor glycocholic acid (GCA). Microbiome analysis further confirmed increased abundance of bile acid metabolism-related bacteria such as bacteroides in non-responders. Serum interleukin-6 (IL-6) levels after neoadjuvant therapy were correlated with treatment response. FOLFOX-HAIC combined with tislelizumab as neoadjuvant therapy for HCC beyond the Milan criteria demonstrates favorable anti-tumor efficacy and controllable toxicity. The level of GCA in tumor, peripheral blood CDCA, IL-6, and fecal bacteroides may hold the potential to serve as a composite biomarker panel to predict pathological response and treatment sensitivity.