Obesity contributes to hepatocellular carcinoma development via immunosuppressive microenvironment remodeling

Abstract

It is generally recognized that the initiation of obesity-related hepatocellular carcinoma (HCC) is closely associated with hepatic inflammation. However, the paradoxical role of inflammation in the initiation and progression of HCC is highlighted by the fact that the inflammatory HCC is accompanied by significant immune effector cells infiltration compared to non-inflammatory HCC and HCC with enhanced immune response exhibits better survival. Importantly, the cancer progression has been primarily attributed to the immunosuppression, which can also be induced by obesity. Furthermore, the increased risk of viral infection and thus viral-HCC in obese individuals supports the view that obesity contributes to HCC via immunosuppression. Here, we have reviewed the various mechanisms responsible for obesity-induced tumor immune microenvironment and immunosuppression in obesity-related HCC. We highlight that the obesity-induced immunosuppression originates from lipid disorder as well as metabolic reprogramming and propose potential therapeutic strategy for HCC based on the current success of immunotherapy.

Metabolic Dysfunction-Associated Steatohepatitis and Progression to Hepatocellular Carcinoma: A Literature Review

“…This association was consistent regardless of gender and geographical location. While the incidence appeared to be greater in men than in women, this contrast might be explained by differences in the distribution of adipose tissue, particularly a higher prevalence of visceral obesity in men [ 41 ]. Certain studies have utilized BMI as a criterion for diagnosing obesity, overlooking cirrhosis and disregarding the presence of ascites.…”

From Non-Alcoholic Steatohepatitis (NASH) to Hepatocellular Carcinoma (HCC): Epidemiology, Incidence, Predictions, Risk Factors, and Prevention

“…The exact biological mechanisms linking weight gain and HCC have not yet been fully elucidated; however, it can be assumed that the development of NAFLD and NASH represent milestones. In fact, obesity and the resulting insulin resistance favor the release of pro-inflammatory cytokines such as TNFα and IL-6, responsible for the development of hepatic steatosis, inflammation, and the onset of HCC [41].…”

Obesity-related T cell dysfunction impairs immunosurveillance and increases cancer risk

“…Obesity is also associated with compromised immunity, resulting in increased susceptibility to infections and dampened vaccine efficacy 4 – 6 . Specifically in cancer patients with obesity, tumor-infiltrating T lymphocytes (TIL) show reduced function and metabolic fitness compared to those from non-obese patients 7 – 9 . Because T cells are critical for detection and elimination of malignant cells prior to tumor formation 10 – 14 , lack of vigilant immune surveillance could explain higher rates of cancer in populations with obesity.…”