## 2 Immune System, MASLD, and HCC
### MASH and Immune Response  
Immun cells play a central role in the onset and progression of MASLD (Figure 1). In the MASH phase, immune cell-mediated inflammation is a key driver of disease progression [17]. Numerous studies have highlighted immune dysfunction as a pivotal factor in MASLD pathogenesis [17]. Many innate immune cells are involved in this phenomenon, including Kupffer cells (KCs), monocyte-derived macrophages (Mo-Ms), neutrophils, dendritic cells (DCs), and natural killer (NK) cells. In the liver, macrophages can be categorized into two major subgroups: liver-resident macrophages, or KCs, and Mo-Ms, which are recruited from circulation [18; 19; 20]. In MASLD, KCs undergo heightened activation, leading to increased cytokine and chemokine secretion and the recruitment of circulating monocytes, which subsequently differentiate into macrophages. In MASLD patients, macrophages exhibit enhanced proinflammatory activity but reduced phagocytic function, along with increased expression of chemokines such as TNF-\(\alpha\), IL-1\(\beta\), IL-6, IL-8, and IL-12 [21; 22; 23]. Following KC activation, neutrophils are recruited to the liver via pathogen-associated molecular patterns (PAMPs) [24; 25]. Once in the liver, neutrophils contribute to a proinflammatory environment by intensively secreting IL-6, which promotes tissue inflammation and fibrosis [26; 27], recruiting additional Mo-Ms, and interacting with other antigen-presenting cells (APCs), thereby amplifying the inflammatory cascade [28]. Furthermore, neutrophil granule proteins (e.g., myeloperoxidase, neutrophil elastase, and proteinase 3) enhance reactive oxygen species (ROS) production [29], further exacerbating inflammation, hepatocellular damage, and progression to HCC [30]. Notably, the neutrophil-to-lymphocyte ratio  
Figure 1: Immune cells play a central role in the onset and progression from a healthy liver (**A**) to MASLD (**B**). Various immune cells from both the innate and adaptive immune systems contribute to this process. In healthy livers, dendritic cells (DCs) predominantly exhibit an immature phenotype, with limited ability to endocytose antigens and stimulate T lymphocytes. However, as intracellular lipid concentrations increase, DCs adopt an immunogenic phenotype, gaining enhanced antigen-presenting capacity and producing proinflammatory cytotoxicity. In MASLD, Kupffer cells (KCs) undergo heightened activation, leading to increased secretion of cytokines and chemokines and the recruitment of circulating monocytes that differentiate into macrophages. These macrophages amplify the proinflammatory response by upregulating chemokine expression, including TNF-\(\alpha\), IL-1\(\beta\), IL-6, IL-8, and IL-12. Following KC activation, neutrophils are recruited to the liver, where they induce IL-6 secretion, promoting tissue inflammation and fibrosis. Neutrophils also recruit additional monocyte-derived macrophages (Mo-Ms) and enhance reactive oxygen species (ROS) production, further exacerbating liver damage. In MASLD, hepatic natural killer (NK) cells are significantly increased, contributing to fibrosis and, through NF-\(\kappa\)B signaling activation, facilitating steatosis and the transition from MASH to HCC. Additionally, NK cells stimulate other immune cells in the liver by increasing IFNy secretion. In MASLD, some studies suggest that CD4+ T cell polarization toward Th1 and Th17 subsets correlates with increased IFNy and IL-17A production, further driving MASLD progression. This proinflammatory environment, characterized by increased inflammation, hepatocellular damage, and liver fibrosis, ultimately leads to HCC development (**C**). correlates with MASLD severity and is indicative of a higher risk of advanced cirrhosis [31] and HCC [32], underscoring the pivotal role of neutrophils in MASLD progression. Dendritic cells (DCs) also play a distinctive role in MASLD progression. Hepatic DCs are a heterogeneous population that can be further divided into subgroups, including plasmacytoid and classical DCs [33].