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Page 4 of 15 Hall et al. Hepatoma Res. 2026;12:20

tomography (SPECT/CT) imaging due to Ho-166’s gamma-emission properties, potentially allowing for
more precise dosimetry and treatment planning.

Once administered, the microspheres become lodged within the tumor microvasculature to deliver localized
radiation doses that induce direct cytotoxic effects, primarily through the induction of double-stranded DNA
breaks [23,24] . This DNA damage triggers apoptosis and mitotic catastrophe in malignant cells, effectively
reducing tumor burden. The localized nature of this therapy allows for high radiation doses to be safely
administered to patients with limited treatment options or who are not candidates for surgery or systemic
therapies.

However, Y-90 microsphere beads exhibit heterogeneous distribution throughout the tumor
microenvironment, likely owing to heterogeneous tumor perfusion . This results in a heterogeneous
[25]
beta-particle distribution, therefore, heterogeneous cytotoxic effects, especially in larger tumors. This effect
may be further confounded with anti-vascular endothelial growth factor (anti-VEGF) agents such as
sorafenib and lenvatinib, potentially leading to even more heterogeneous microsphere distribution. This
mechanism may explain the dose-dependent response observed in the DOSISPHERE-1 study, in which
overall survival (OS) was higher in the group treated with higher doses, overcoming this heterogeneity .
[26]
After combination therapy with Y-90, it is possible that untreated tumoral cells could then be targeted with
other systemic therapies, such as ICIs, through immune-mediated pathways described below.

Beyond direct cytotoxicity, Y-90 radioembolization exerts significant effects on tumor vasculature.
Radiation-induced endothelial injury leads to disruption of the tumor’s abnormal and fragile vasculature,
resulting in ischemia and secondary tumor cell death . This vascular insult not only deprives the tumor of
[27]
oxygen and nutrients but also alters the tumor microenvironment in ways that may modulate therapeutic
response.

Recent studies have demonstrated that Y-90 treatment can provoke immunomodulatory effects within the
tumor microenvironment. Radiation can enhance immune-cell infiltration, including cytotoxic T
lymphocytes (CTLs) and antigen-presenting cells (APCs), potentially transforming an immunologically
“cold” tumor into a more inflamed and “hot” tumor . Additionally, radiation therapy (RT) enhances
[28]
antitumor immunity by releasing damage-associated molecular patterns (DAMPs), which stimulate type I
interferons (IFN-α and IFN-β) and activate immune responses. RT also remodels tumor vasculature and the
tumor microenvironment, improving immune-cell infiltration. By upregulating IFN-γ and major
histocompatibility complex (MHC) expression, RT further activates lymphocytes and increases immune-cell
access to the tumor. The rise in IFN-γ can also reduce tumor resistance to anti-programmed death-1
(anti-PD-1) therapy [Figure 1] [29,30] .

These immune-related changes provide the basis for combining Y-90 radioembolization with
immunotherapies, aiming to amplify durable antitumor immunity. The effects of Y-90 radioembolization are
multifaceted; they encompass direct tumor cell cytotoxicity, vascular disruption, and immune
microenvironment modulation. Collectively, these effects provide a strong mechanistic rationale for
integrating Y-90 with systemic therapies. Understanding these mechanisms is critical for optimizing
combination regimens designed to maximize therapeutic efficacy and overcome resistance in HCC.

Synergy with systemic agents
Targeted agents
Targeted agents, such as sorafenib and lenvatinib, exert their antitumor effects through inhibition of multiple
tyrosine kinase receptors, most notably vascular endothelial growth factor receptors (VEGFRs) and
platelet-derived growth factor receptors (PDGFRs), which play central roles in tumor angiogenesis,