Locoregional therapies plus immunotherapy reshape care for unresectable liver cancer

Unresectable hepatocellular carcinoma has seen its systemic treatment landscape transformed by immune-checkpoint inhibitor (ICI)-based regimens, and a new review in Nature Reviews Clinical Oncology examines how these immunotherapies might be combined with locoregional therapies (LRTs) to improve tumour control and extend the benefits of immunotherapy to patients with intermediate-stage disease. The review, published on 28 October 2026, focuses on three main locoregional partners: transarterial chemoembolization, transarterial radioembolization and external beam radiotherapy.

The biological rationale for pairing these approaches rests on what the locoregional treatments do to the tumour beyond destroying tissue. According to the authors, LRTs can induce immunogenic cell death and the release of tumour antigens, and they can reprogramme the immunosuppressive tumour microenvironment. This provides a mechanistic route to enhance immune cell capabilities or convert immunologically inactive, so-called ‘cold’ tumours — estimated at roughly 70% of hepatocellular carcinoma tumours — into immunologically active ones, thereby sensitizing them to immune-checkpoint inhibitors.

The strongest clinical evidence to date involves transarterial chemoembolization. The review reports that five phase III trials have shown improvements in progression-free survival and objective response rates with regimens combining ICIs with transarterial chemoembolization. The authors state that these phase III trials consistently demonstrate such gains, establishing chemoembolization-based combinations as the most practice-relevant strategy. However, they emphasize that an overall survival benefit remains unproven.

For the other two locoregional modalities, the evidence base is less mature. Early-phase clinical studies and real-world data support combining ICIs with transarterial radioembolization or external beam radiotherapy, particularly in selected patients with focal disease unsuitable for embolization and in patients with portal vein tumour thrombosis. The review characterizes the current evidence for these combinations as promising but immature, meaning that firmer conclusions about their clinical value await further study.

A central challenge highlighted by the authors is the difficulty of translating progression-free survival gains into overall survival benefit. They attribute this to confounding factors including subsequent post-progression therapies, crossover between treatment arms, and informative censoring, and they describe this as a major gap in clinical validation. The growing difficulty of demonstrating survival advantages is compounded, they note, by widespread post-progression crossover and the availability of effective subsequent therapies.

The review also raises questions about how treatment response should be measured when locoregional therapies and immunotherapies are combined. Conventional imaging criteria — modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST 1.1 — might need to be revisited to capture the effects of combined LRT–ICI approaches, whereas the use of immunotherapy-adapted criteria (iRECIST) in this setting remains marginal, according to the authors.

Looking ahead, the authors argue that future trials should either assess progression-free survival alongside meaningful improvements in overall survival or focus on overall survival as the primary end point. They also identify patient selection and therapy sequencing as unresolved challenges, and they call for advances in imaging and biomarker-driven patient selection to guide the integration of locoregional therapies with immune-based regimens.

As a review article rather than a new clinical trial, the publication synthesizes existing evidence rather than reporting new experimental results, and its conclusions reflect the state of the field as summarized by its authors. The overall picture it presents is one of substantial progress — particularly for chemoembolization–immunotherapy combinations validated in phase III testing — tempered by unproven survival benefits, immature data for radioembolization and radiotherapy combinations, and unresolved questions about response assessment and trial design that will shape how these combined strategies move into routine practice.

Subject of Research: Combining locoregional therapies with immune-checkpoint inhibitors for unresectable hepatocellular carcinoma

Article Title: Combining locoregional treatments and immunotherapies in patients with unresectable hepatocellular carcinoma

Article References: Cioni, D., Mauro, E., Feng, D., Cano-Segarra, G., Kim, E., Dekervel, J., Ronot, M., Fanni, S. C., Lencioni, R., & Llovet, J. M. (2026). Combining locoregional treatments and immunotherapies in patients with unresectable hepatocellular carcinoma. Nature Reviews Clinical Oncology. https://doi.org/10.1038/s41571-026-01210-6

Image Credits: AI Generated

DOI: 10.1038/s41571-026-01210-6

Keywords: hepatocellular carcinoma, immune-checkpoint inhibitors, transarterial chemoembolization, transarterial radioembolization, radiotherapy, progression-free survival, overall survival, tumour microenvironment, immunogenic cell death, clinical trials, response assessment, review article