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

Current preclinical and clinical data suggest that selected combinations may improve PFS and OS while
maintaining a manageable safety profile. Nonetheless, the integration of Y-90 with systemic therapies in
routine practice remains limited by the heterogeneity of existing studies and the lack of integration into
standardized treatment algorithms. Prospective randomized trials are needed to define the optimal regimens,
sequencing, and patient selection criteria.

Preliminary data show acceptable safety, with common adverse events, including liver enzyme elevations and
manageable immune-related events. This variability in patient liver function, tumor burden, and immune
status underscores the need for biomarker-driven personalization of treatment. The optimal sequencing and
timing of Y-90 and systemic therapies require a nuanced balance between maximizing antitumor synergy
and managing patient-specific factors and toxicities. A multidisciplinary approach encompassing
interventional radiology, medical oncology, hepatology, radiation oncology, and immunology will be critical
to the successful implementation of these regimens. Future research should aim to incorporate molecular
and immunological profiling to identify patients most likely to benefit from specific combinations.
Integrating clinical, radiologic, and molecular biomarkers into prospective trials will refine treatment
algorithms, generating precise approaches that, when combined with multidisciplinary care, will be pivotal in
optimizing therapeutic outcomes for patients with HCC.

As mechanistic understanding deepens and precision medicine advances, Y-90-based combination therapies
have the potential to transform the therapeutic landscape of HCC, offering improved survival and quality of
life for patients with this complex and historically refractory disease.

DECLARATIONS
Acknowledgments
The graphical abstract was created with BioRender.com (Created in BioRender. Hall, B. (2025) h​t​t​p​s​:​/​/​B​i​o​R​e
n​d​e​r​.​c​o​m​/​u​k​h​r​5​p​o​)

Authors’ contributions
Conducted a literature review and made substantial contributions to the composition of the summary: Hall
B, Ohs Z, Dervishi M, Stevens M
Made contributions to the conception of the review and performed administrative, technical, and material
support: Sutter C, Davidson J

Availability of data and materials
Not applicable.

AI and AI-assisted tools statement
During the preparation of this manuscript, the AI tools OpenEvidence (version 2.0, released 2024-12-16) and
ChatGPT (version 5, released 2025-08-07) were used solely for language editing. The tools did not influence
the study design, data collection, analysis, interpretation, or the scientific content of the work. All authors
take full responsibility for the accuracy, integrity, and final content of the manuscript.

Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.