Abstract Introduction Despite the availability of several approved therapies, continued investigation of novel treatment options is needed to further improve outcomes in advanced hepatocellular carcinoma (HCC). The phase 2 KEYSTEP-004 study evaluated the safety and efficacy of quavonlimab coformulated with pembrolizumab (quavonlimab/pembrolizumab) plus lenvatinib as first-line therapy for advanced HCC. Methods Adults with confirmed advanced HCC and no prior systemic therapy were enrolled. In the safety lead-in phase, participants received intravenous quavonlimab 25 mg coformulated with pembrolizumab 400 mg every 6 weeks plus oral lenvatinib 12 mg (body weight ≥60 kg) or 8 mg (body weight <60 kg) once daily (dose level 0 [DL0]). Allocation to the efficacy expansion phase was permitted if lenvatinib DL0 plus quavonlimab 25 mg coformulated with pembrolizumab 400 mg every 6 weeks was determined to be tolerable. Primary endpoints were objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR) and safety. Secondary endpoints included duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 by BICR, and overall survival (OS). Results As of June 22, 2023, 116 participants were enrolled, and 115 were treated. No dose-limiting toxicities were observed in the safety lead-in phase. Lenvatinib DL0 in combination with quavonlimab 25 mg coformulated with pembrolizumab 400 mg every 6 weeks was determined to be tolerable. Median study follow-up was 18.0 months (range, 12.0–26.6). Confirmed ORR was 37.4% (95% CI: 28.5–46.9). Median DOR was 10.6 months (range, 1.2+ to 23.1+), median PFS was 8.2 months (95% CI: 6.2–10.2), and median OS was 22.1 months (95% CI: 15.5-not reached). Grade 3–5 treatment-related adverse events (AEs) occurred in 66 participants (57.4%); 14 (12.8%) required high-dose steroids for management of a treatment-related AE. Conclusion Quavonlimab coformulated with pembrolizumab plus lenvatinib is an active combination and has a manageable safety profile in advanced HCC.
Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent disease that can progress to hepatocellular carcinoma (HCC). Excess dietary cholesterol is associated with MASLD-HCC, but its role in liver malignancy remains unclear. Here, we aimed to investigate the mechanism of how dietary cholesterol promotes MASLD-HCC. Methods: C57BL/6 mice were fed with high-cholesterol (HC) or low-cholesterol (LC) diet for 14 months. Mouse liver tissues were subjected to transcriptome, whole-exome, and methylation sequencing. Cholesterol-lowering atorvastatin was used for intervention experiment. Mitochondrial function was assessed in mouse liver tissues and human MASLD-HCC cell lines. Plasma samples from 88 hypercholesteremia patients and 88 healthy individuals were collected. Results: Liver tumors were observed in HC-fed mice, and mitochondrial dysfunction was identified as the key pathway in cholesterol-induced MASLD-HCC. In particular, impaired mitochondrial function and reduced mitochondrial membrane potential and integrity were observed in the liver of HC-fed mice. Pten was the central gene associated with mitochondrial dysfunction in cholesterol-induced MASLD-HCC. Cholesterol also dysregulated mitochondrial function and promoted proliferation of human MASLD-HCC cells, whereas the pro-proliferative effect of cholesterol was reversed after pharmacological restoration of mitochondrial function. Similarly, atorvastatin treatment could restore mitochondrial function and increase Pten expression in HC-fed mice, thereby inhibiting MASLD-HCC development. Mechanistically, mitochondrial dysfunction in MASLD-HCC was caused by hypermethylation of mitochondria-associated genes. Hypercholesterolemia patients exhibited features of mitochondrial dysfunction, compared to healthy controls. Conclusion: Dietary cholesterol promotes MASLD-HCC by inducing methylation-mediated mitochondrial dysfunction and PTEN loss. Restoring mitochondrial function and cholesterol-lowering drugs might serve as potential therapeutics for MASLD-HCC.
Background: Portal vein tumor thrombus (PVTT) is the most common form of macrovascular invasion in hepatocellular carcinoma (HCC) and is associated with poor prognosis, rapid intrahepatic dissemination, and limited responsiveness to systemic therapy. Increasing evidence indicates that PVTT is not merely an intravascular extension of the primary tumor, but rather a biologically distinct and highly adaptive immunosuppressive niche that contributes to immune escape and therapeutic resistance. Summary: This review summarizes current genomic, transcriptomic, single-cell, and spatially resolved evidence regarding the immune landscape of PVTT in HCC. We discuss how early clonal divergence, hypoxia-associated metabolic rewiring, and stromal-vascular remodeling cooperatively shape the PVTT microenvironment. PVTT is characterized by enrichment of suppressive myeloid populations, activation of cancer-associated fibroblast programs, extracellular matrix accumulation, endothelial barriers to immune-cell trafficking, and progressive dysfunction or exclusion of effector lymphocytes. Together, these features establish a strongly immune-excluded and immunosuppressive ecosystem, providing a mechanistic basis for the limited efficacy of immune checkpoint blockade in patients with HCC-PVTT. We further highlight the translational implications of this framework for biomarker development, patient stratification, and rational combination strategies targeting suppressive myeloid and stromal programs, vascular barriers, and metabolic-immune crosstalk. Key Messages: PVTT should be regarded as a distinct immunosuppressive niche rather than a passive vascular extension of the primary tumor. Its immune landscape is shaped by coordinated interactions among tumor evolution, metabolic adaptation, stromal remodeling, and immune dysfunction. A better mechanistic understanding of PVTT may support biomarker-guided stratification and the development of more effective precision therapies for HCC with macrovascular invasion.
The combination of transarterial chemoembolization (TACE) with immunotherapy-based systemic therapy is emerging as a promising treatment strategy for unresectable hepatocellular carcinoma (HCC). In addition, emerging data from perioperative immunotherapy-based strategies in resectable, high-risk HCC further support the integration of systemic and TACE across the disease continuum. Recent randomized trials have demonstrated improvements in progression-related outcomes with TACE combined with immunotherapy-based systemic therapies. However, overall survival (OS) benefit has not been consistently demonstrated across randomized studies, with final OS analyses from EMERALD-1 and interim OS analyses from LEAP-012 not showing statistically significant improvement compared with TACE alone. By integrating TACE and immunotherapy-based systemic strategies, this International Society of Multidisciplinary Interventional Oncology (ISMIO) Expert Consensus framework does not advocate routine clinical adoption but aims to provide a structured framework for research design and multidisciplinary decision-making. It summarizes data from pivotal trials and offers guidance on patient selection, treatment sequencing, response evaluation, and safety management. Ten consensus statements through a modified Delphi process, with evidence graded according to the Oxford Centre for Evidence-based Medicine and assessed narratively based on the directness, consistency, maturity, and applicability of available evidence, were developed by ISMIO expert panel. The consensus framework emphasizes multidisciplinary collaboration, individualized therapeutic decision-making based on a comprehensive patient profile, and the need for structured definitions and endpoints to facilitate future research. It aims to provide a flexible, evidence-informed, multidisciplinary framework to facilitate patient stratification, interpretation of emerging evidence, and future research design, while allowing adaptation according to local expertise, treatment availability, and regional practice patterns.
