Effects of yttrium-90 radioembolization on epigenomic immune remodeling in hepatocellular carcinoma: Profiled by blood-based 3D genome conformation assay.

e16273 Background: Yttrium-90 (Y-90) radioembolization for intermediate-stage hepatocellular carcinoma (HCC) has been shown to modulate the tumor immune microenvironment. However, noninvasive biomarkers capable of capturing treatment-induced immune remodeling and informing potential responsiveness to immune checkpoint inhibitors (ICIs) remain limited. We sought to characterize peripheral immune remodeling following Y-90 using Checkpoint Inhibitor Response Test (CiRT) to evaluates three-dimensional (3D) genome conformation signatures in circulating immune cells associated with ICI response. Methods: Peripheral blood samples were collected at baseline and approximately 4 weeks after Y-90 radioembolization in patients with BCLC-B HCC treated in a real-world clinical setting. Paired samples were analyzed using the EpiSwitch CiRT platform, which quantifies epigenomic 3D genome conformations linked to immune checkpoint regulation, interferon signaling, and cytotoxic effector function. A mathematical model classified patients as High or Low probability of response to ICIs. Longitudinal changes in immune-associated loci were assessed using the Wilcoxon signed-rank test. Results: Ten evaluable patients (median age 73.5 years) were included. At baseline, 6 patients were classified as High Probability and 4 as Low Probability for ICI response. Following Y-90, 6 patients were classified as High Probability, including one conversion from Low to High. Epigenomic signal increased across immune checkpoint-associated loci (CTLA4, LAG3, TIGIT), interferon and immune activation markers (STAT1, CXCL9, IRF1), and the cytotoxic effector marker GZMB. LAG3 demonstrated the largest post-treatment increase (P < 0.05). Conclusions: Y-90 radioembolization was associated with detectable epigenomic immune remodeling in peripheral blood, favoring response to ICIs. Circulating 3D genome conformation profiling may provide a complementary, noninvasive approach to assess treatment-induced immune modulation and potential ICI responsiveness following locoregional therapy in HCC. Larger studies are warranted to define clinical implications. Paired pre- and post-Y90 changes in immune-associated epigenomic markers detected in peripheral whole blood. Values reflect three-dimensional (3D) genome conformation signatures rather than transcript or protein abundance. Marker Median Δ (Post–Pre) Wilcoxon p PD-1 +0.75 0.182 CTLA4 +1.25 0.091 LAG3 +3.5 0.018 TIGIT +1.25 0.049 CXCL9 +1.5 0.083 STAT1 +0.75 0.217 IRF1 +0.75 0.156 GZMB +0.75 0.041