Time-Dependent Systemic Immune Effects of Y90 Radioembolization

Purpose: To characterize the systemic immune effects of Yttrium-90 (Y90) transarterial radioembolization (TARE) in patients with hepatocellular carcinoma (HCC), identify temporal patterns in immune modulation, and explore whether radiation dose or microsphere type influences immune activation. This information is critical for optimizing timing of combination therapy with immune checkpoint inhibitors (ICIs).

Materials and Methods: This retrospective study reviewed patients treated with Y90 TARE between 2016-2023, excluding those with prior liver radiation or concurrent systemic therapy. Complete blood counts with differential were collected at baseline and at 30- and 60-days post-treatment. Systemic immune-inflammation indices, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte (MLR), and systemic immune-inflammation index (SII), were calculated. Lymphocyte depletion and NLR reduction were defined as >50% decrease from baseline to day 60. Comparisons between Y90 glass and resin microspheres were made using Wilcox rank-sum and Pearson chi-squared tests.

Results: Both microsphere types produced substantial lymphocyte depletion, with >50% declines by day 60 in a large proportion of patients, indicating a delayed systemic cellular immunomodulatory effect. Trends suggested fewer resin-treated patients achieved >50% NLR reduction by day 60, reflecting device-specific immune signature. Eosinophil counts were significantly lower at baseline and day 30 in patients receiving resin microspheres compared with glass (p=0.02 and p=0.004, respectively), but were similar by day 60. Overall, Y90 TARE induces early but transient immune shifts followed by delayed systemic lymphopenia.

Conclusion: Y90 radioembolization elicits time-dependent systemic immune changes in HCC, characterized by delayed lymphocyte depletion, early eosinophil suppression, and device-specific variation in NLR dynamics. These findings support a finite window for synergistic Y90-ICI therapy and highlight the need for prospective trials to refine timing and dosing strategies for optimal immunologic and oncologic outcomes.