Yttrium-90 combination therapies in hepatocellular carcinoma: current evidence and future directions

Yttrium-90 (Y-90) radioembolization, via endovascular delivery of high-dose beta radiation microspheres to tumors, is an invaluable locoregional therapy for hepatocellular carcinoma (HCC). Y-90’s limited off-target radiation exposure enables excellent tumor control with a favorable safety profile. Recent developments suggest that combining targeted radioembolization with systemic treatments, such as molecularly targeted therapies and immune checkpoint inhibitors (ICIs), may offer additive or even synergistic benefits, thereby enhancing both local tumor response and immune activation. This review explores the mechanistic rationale, clinical evidence, and therapeutic strategies involving Y-90 combination therapies in HCC. Data from phase I, II, and III trials suggest improved outcomes with Y-90 plus ICI combination therapy compared with monotherapy. By contrast, trials comparing Y-90 and multi-kinase combination inhibitors with monotherapy have yielded mixed results, highlighting the importance of continued research. Challenges remain in patient selection, optimal sequencing, and toxicity management. To date, no randomized clinical trials have directly compared Y-90 alone with Y-90-based combination therapy, but ongoing trials aim to clarify the role of Y-90 in the evolving systemic treatment landscape. This review highlights the potential of Y-90 combination therapies to enhance the multidisciplinary management of HCC and underscores future research priorities to optimize outcomes.