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Page 6 of 15 Hall et al. Hepatoma Res. 2026;12:20

Combining Y-90 radioembolization with anti-angiogenic targeted agents may offer a biologically rational
strategy to counteract this process. While Y-90 induces direct cytotoxicity and vascular destruction,
concurrent or sequential inhibition of VEGFR and PDGFR would theoretically blunt the hypoxia-driven
surge in angiogenic signaling, effectively suppressing rebound neovascularization. By preventing
reconstitution of the tumor vasculature, targeted agents may prolong the ischemic and cytotoxic effects of
radiation, thereby enhancing local tumor control. Systemic inhibition of angiogenic and proliferative
pathways may also limit the growth of microscopic residual disease and distant metastases, further extending
the therapeutic benefit beyond the treated hepatic territory.

This complementary interaction positions anti-angiogenic therapy as a critical modulator of
radiation-induced tumor adaptation and may produce more durable disease control and improved clinical
outcomes in patients with HCC.

Immune checkpoint inhibitors
ICIs targeting programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4) have revolutionized cancer therapy by restoring
T-cell-mediated tumor killing . These agents essentially release the brakes on the immune system, allowing
[12]
cytotoxic T-cells to recognize and eliminate tumor cells more effectively. Importantly, radiation delivered by
Y-90 induces immunogenic cell death, characterized by the release of tumor-associated neoantigens. These
neoantigens activate dendritic cells, which then prime and expand cytotoxic T-cell populations, effectively
“vaccinating” the immune system against the tumor . This process can convert immunologically “cold”
[14]
tumors, which are typically resistant to immunotherapy due to a lack of immune infiltration, into “hot”
tumors that are more responsive to ICIs.

The integration of Y-90 radioembolization with ICIs has the potential to produce synergistic antitumor
immunity. Radiation-induced immunogenic cell death enhances tumor antigen presentation and T-cell
activation, while ICIs sustain and amplify the immune response by preventing T-cell exhaustion and
inhibition. This combined approach may yield more durable clinical responses and improve long-term
survival outcomes compared to either modality alone.

CLINICAL EVIDENCE OF Y-90 COMBINATION THERAPIES
Y-90 plus targeted therapy
The combination of Y-90 radioembolization with systemic targeted therapies has been investigated in
patients with HCC and demonstrated promising, yet nuanced clinical outcomes.

Phase II/III trials comparing therapies
The Sorafenib in Advanced Hepatocellular Carcinoma (SORAMIC) trial is a multicenter randomized,
open-label phase II trial that compared survival in patients with advanced HCC treated with sorafenib alone
to those treated with Y-90 in addition to sorafenib. According to the most recent BCLC staging and
treatment strategy guidelines, sorafenib is a first-line systemic treatment alternative for advanced-stage HCC
when atezolizumab-bevacizumab or durvalumab-tremelimumab are not feasible . The study found no
[10]
significant improvement in OS with the addition of Y-90 to sorafenib therapy. Specific subgroup analyses
within this trial, however, did demonstrate statistically significant survival benefits with the addition of Y-90
to sorafenib therapy. For example, survival benefits were observed in patients without cirrhosis [Hazard ratio
(HR), 0.46; 0.25-0.86; P = 0.02], in patients with cirrhosis of non-alcoholic etiology (HR 0.63; P = 0.012), and
in patients aged 65 years or younger (HR 0.65; P = 0.05) .
[31]