Intratumoral Proton Density Fat Fraction Predicts the Outcome of <scp>HAIC</scp> Combined With <scp>PD</scp> ‐1 Inhibitors in Advanced Hepatocellular Carcinoma

BACKGROUND AND AIMS: This study aimed to explore the predictive value of intratumoral proton density fat fraction (PDFF) and the clinical efficacy of hepatic arterial infusion chemotherapy (HAIC) combined with anti-programmed cell death protein 1 (anti-PD-1) therapy in advanced hepatocellular carcinoma (HCC). METHODS: In this retrospective cohort study, patients with advanced HCC received FOLFOX-HAIC or HAIC combined with anti-PD-1 (camrelizumab). Progression-free survival (PFS) was evaluated as the time-to-event outcome, while therapeutic efficacy was assessed using tumor response rates. The Kaplan-Meier method and log-rank test were used to compare PFS. In the MRI-PDFF subset, receiver operating characteristic (ROC) analysis was used to determine the optimal PDFF cutoff for predicting nonresponse (SD or PD). RESULTS: Between September 2020 and August 2025, 103 patients were included, of whom 47 received HAIC monotherapy and 56 received HAIC combined with anti-PD-1 therapy. The HAIC-PD1 group demonstrated significantly longer PFS compared with the HAIC group (HR 0.423; 95% CI 0.218-0.818; p = 0.0085), and a higher objective response rate (ORR: 46.4% vs. 21.3%; p = 0.012). In the MRI-PDFF subset, baseline intratumoral PDFF was associated with treatment response. ROC analysis identified an optimal PDFF cutoff of 2.64% for predicting nonresponse (AUC 0.784; 95% CI 0.664-0.903). Patients with PDFF < 2.64% achieved a higher ORR and longer PFS compared with those with PDFF ≥ 2.64%. Longitudinal analyses showed treatment-dependent changes in PDFF after HAIC-PD1 therapy; however, ΔPDFF did not differ significantly between responders and nonresponders. CONCLUSION: HAIC combined with anti-PD-1 therapy demonstrated superior efficacy compared with HAIC monotherapy in advanced HCC. Baseline intratumoral PDFF may serve as a promising imaging biomarker associated with treatment response in patients receiving HAIC-PD1 therapy. Its potential prognostic relevance for time-to-event outcomes requires further validation in prospective cohorts.