New Insights on Fibrotic Immune Profile Driven Cancer Behavior in MASH, With Bruno Cogliati, PhD, DVM

New research shows the immune composition of fibrotic tissue, whether immune-infiltrated (“hot”) or immune-depleted (“cold”), directly influences hepatocellular carcinoma (HCC) behavior in metabolic dysfunction-associated steatohepatitis (MASH) during and after injury.1

Presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025 by Bruno Cogliati, PhD, DVM, the data highlights that halting metabolic injury through weight loss or diabetes management does not reverse oncogenic risk. Instead, the fibrotic immune phenotype should be considered a therapeutic target to modulate macrophage or hepatic stellate cell (HSC) activity.

In patients with metabolic dysfunction-associated steatotic liver disease (MASLD), 20% also live with MASH. The global burden of MASH, affecting 30-40% percent of adults in the United States, has increased in parallel with rising rates of obesity and other metabolic disorders, such as type 2 diabetes (T2D). Accordingly, MASH treatment has traditionally focused on treating these comorbidities through lifestyle interventions and metabolic control.2,3

“In the hot fibrosis, we have the infiltration of inflammatory cells, especially macrophages. In the cold fibrosis, we have the extracellular matrix, an exclusion of the immune cells,” said Cogliati, an associate professor of veterinary pathology at the University of São Paulo and an associate researcher at Icahn School of Medicine at Mount Sinai, in an interview with HCPLive. “It's quite new in the liver field. The first idea was to try the central hypothesis to see if we could modulate the ‘cold’ and ‘hot’ fibrosis in the liver and better understand how fibrosis is involved in liver cancer and how we can use this in the future for the therapeutic process.”

The classifications of “hot” and “cold” fibrotic tissue play a critical role in the pathogenesis of cardiac fibrosis, but have remained unexplored in liver disease and HCC. Investigators aimed to understand whether these fibrosis immunophenotypes occur in the MASH landscape. Immune type, “hot” or “cold”, determines whether fibrosis stabilizes or drives cancer progression, a concept newly described in liver disease.

“We need to develop new tools to understand what happens when the fibrosis is still there and prove that we can also modulate this hot and cold fibrosis in the liver, and not just in the heart and the kidneys,” said Cogliati. “This can be a potential clinical application in the future. So I think these new concepts, with the new paradigm that the MASH disease is transforming in the liver field, we will be able to develop new tools for the future.”

Investigators explored “hot” and “cold” fibrosis through a 40-week preclinical murine model using the FAT-MASH protocol, a high-fat, high-sucrose, high-cholesterol Western diet plus fructose-glucose water and low-dose carbon tetrachloride, meant to induce advanced fibrosis and HCC. At 40 weeks of injury, all dietary and chemical insults were withdrawn. Post-intervention, mice were monitored at 2, 8, 16, and 24 weeks to assess how the immune environment within the scar tissue impacted liver cancer recurrence. Key endpoints were fibrosis persistence, immune composition, and tumor burden.4

By 40 weeks of FAT-MASH protocol, investigators found mice exhibited marked steatosis, fibrosis, and large HCCs in addition to elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lipid levels.

Early in post-intervention, 2-24 weeks, steatosis and tumor burden significantly declined, whereas fibrosis persisted. From 2-8 weeks, macrophage infiltration decreased, and after an early decline in total leukocytes, macrophages, and T cells, fluorescence-activated cell sorting of fibrotic tissue showed immune reconstitution by 16-24 weeks. At 24 weeks, tumor size began to increase again. The HSC activity peaked during injury and remained elevated during regression.

Following injury, investigators observed a transient “cold” phase, an initial decrease in tumor size, from 2-8 weeks, and a “hot” phase, defined as a rebound in tumor size, from 16-24 weeks. These findings suggest the importance of a new therapeutic paradigm focused on targeting fibrotic immunophenotypes in MASH-related HCC to prevent liver cancer recurrence and progression.

Editor's Note: Cogliati reports no relevant disclosures.

1. Cogliati B, Yashaswini C, Marins-Dos-Santos A, et al. Hot and Cold Liver Fibrosis Reflect Opposing Hepatocellular Carcinoma Trajectories in Experimental Metabolic Dysfunction-Associated Steatohepatitis. Abstract presented at: American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2025; November 7-11, Washington, DC.

2. Metabolic dysfunction-associated steatotic liver disease (MASLD) toolkit. American Gastroenterological Association. Published May 9, 2025. Accessed November 10, 2025. https://gastro.org/clinical-guidance/guideline-toolkits/metabolic-dysfunction-associated-steatotic-liver-disease-masld-toolkit/

3. ‌‌Younossi ZM, Zelber-Sagi S, Lazarus JV, et al. Global Consensus Recommendations for Metabolic Dysfunction-Associated Steatotic Liver Disease and Steatohepatitis. Gastroenterology. Published online November 2025:S0016-5085(25)006328. https://doi.org/10.1053/j.gastro.2025.02.044

4. Tsuchida T, Lee YA, Fujiwara N, et al. A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. Journal of Hepatology. 2018;69(2):385-395. https://doi.org/10.1016/j.jhep.2018.03.011