Study maps how liver cancer develops and identifies new paths for treatment

A new review from the Icahn School of Medicine at Mount Sinai and the Hospital Clínic de Barcelona provides one of the clearest roadmaps to date for understanding and treating liver cancer, one of the deadliest cancers worldwide.

Published in Cell, the study, “Hallmarks of Liver Cancer: Therapeutic Implications” (10.1016/j.cell.2026.03.001), applies the widely used “Hallmarks of Cancer” framework to liver tumors, linking the biology of the disease to treatment strategies, including immunotherapy and precision medicine approaches, particularly in the approximately 45 percent of bile duct cancers that harbor targetable mutations.

The study was led by Josep M. Llovet, MD, PhD, Professor of Medicine at the Icahn School of Medicine (Liver Diseases) at Mount Sinai and Director of the Liver Cancer Program at the Mount Sinai Tisch Cancer Center; and Daniela Sia, PhD, Associate Professor of Medicine (Liver Diseases) at the Icahn School of Medicine.

Marking the 25th anniversary of the groundbreaking “Hallmarks of Cancer” framework introduced by Douglas Hanahan, PhD (Swiss Institute for Experimental Cancer Research), and Robert A. Weinberg, PhD (Massachusetts Institute of Technology), the Mount Sinai-led team applies this influential model specifically to primary liver cancer, offering new insights into disease biology and treatment strategies.

Primary liver cancer, which includes hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), is the third-leading cause of cancer-related death globally, with approximately 830,000 deaths each year and nearly 1 million new cases annually. Despite recent advances, many patients are diagnosed at advanced stages and face limited treatment options.

“This work brings together decades of research to better understand what drives liver cancer and how we can treat it more effectively,” said Dr. Llovet. “By applying the Hallmarks of Cancer framework, we connect the biology of these tumors with real therapeutic opportunities, helping guide more precise and personalized care.”

The review highlights key biological processes (known as “hallmarks”) that enable liver tumors to grow and spread. In HCC, the most common form of liver cancer, tumors are driven by processes such as sustained growth signaling, new blood vessel formation, and immune evasion. In contrast, iCCA, a biologically distinct cancer, often shows altered metabolism and is far more likely to harbor targetable genetic alterations.

Over the past two decades, treatment for advanced liver cancer has improved significantly, from limited options and median survival under a year to modern immunotherapy combinations that can extend survival beyond two to three years for some patients.

“This framework helps clinicians better match patients with the therapies most likely to benefit them,” said Dr. Sia. “It also provides a roadmap for developing new treatments by identifying the key vulnerabilities of each tumor.”

Importantly, the researchers note that approximately 45 percent of iCCA tumors contain genetic alterations (such as FGFR2 fusions, IDH1 mutations, ERBB2 alterations, and BRAF mutations) that can be targeted with existing or emerging therapies, highlighting the growing role of precision oncology in liver cancer care.

For clinicians, the study offers a practical framework to guide treatment decisions, including the use of targeted therapies and immunotherapies. For patients, it represents progress toward more personalized approaches that may improve outcomes and quality of life.

“This review is designed to bridge the gap between laboratory discoveries and patient care,” Dr. Llovet added. “Our goal is to accelerate the development of more effective therapies and ultimately improve survival for patients with liver cancer.”

Mount Sinai Liver Cancer Program is one of the nation’s leading centers for the care and study of liver cancer. Established in 2005 as a Center of Excellence within the Mount Sinai Tisch Cancer Center, the program brings together a multidisciplinary team of hepatologists, oncologists, surgeons, radiologists, and scientists to advance care from early detection through state-of-the-art treatment.

Mount Sinai is the leading center in the United States in the number of new hepatocellular carcinoma patients evaluated annually and has played a pivotal role in shaping global standards of care, including landmark clinical trials and advances in precision medicine and immunotherapy. With more than 40 active members, robust National Institutes of Health funding, and leadership in international research collaborations, the program continues to drive innovation aimed at improving outcomes for patients with liver cancer worldwide.

This study was led by the Mount Sinai Liver Cancer Program, with contributions from collaborators at IDIBAPS-Hospital Clínic de Barcelona, The Johns Hopkins University, Mayo Clinic, University of California San Francisco, Memorial Sloan Kettering Cancer Center, Howard Hughes Medical Institute, and NYU Grossman School of Medicine.

Funding for the study was provided by the National Institutes of Health, the Samuel Waxman Cancer Research Foundation, the U.S. Department of Defense, the American Cancer Society, the Cholangiocarcinoma Foundation, and other supporting organizations.

Full study: https://doi.org/10.1016/j.cell.2026.03.001

About the Icahn School of Medicine at Mount Sinai 

The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City’s large and diverse patient population. 

The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master’s degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,600 clinical residents and fellows training throughout the Health System. Its Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 560 postdoctoral research fellows. 

Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges.  More than 4,500 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.

Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai.