## 2 Immune System, MASLD, and HCC
### MASH and Immune Response
Depending on cellular subtype and environmental cues, DCs can mediate both proinflammatory [34] and anti-inflammatory [35] responses. In healthy livers, DCs predominantly exhibit an immature phenotype, with limited ability to endocytose antigens and stimulate T lymphocytes. However, during hepatic injury or under conditions of increased intracellular lipid accumulation, DCs adopt an immunogenic phenotype with enhanced antigen-presenting capabilities and increased production of proinflammatory cytokines [36]. Hepatic NK cells represent a heterogeneous population that expands in disease states [37; 38; 39]. In individuals with MASH, the number of NK cells in the liver is markedly increased [39], accompanied by elevated expression of the activating receptor NKG2D and its ligands MIC A/B in the liver parenchyma [40]. This suggests that NK cell activation occurs in MASLD and contributes to disease progression. Notably, NK cell proinflammatory activity is hypothesized to drive MASH [41] by exacerbating liver fibrosis [42] and activating NF-kB signaling, which facilitates steatosis and the transition from MASH to HCC [43]. Furthermore, NK cells promote the activation of other immune cells in the liver through increased secretion of IFN-\(\gamma\). As previously mentioned, adaptive immunity also plays a role in MASLD development. Adaptive immunity consists of cell-mediated and humoral immunity, primarily mediated by T and B lymphocytes, respectively. The major T lymphocyte subtypes involved in adaptive immunity include CD4+ T cells (further categorized into T helper cells--Th1, Th2, Th17, regulatory T cells--Tregs, etc. ), CD8+ T cells, and \(\gamma\)\(\delta\) T cells [44]. CD4+ T cells are highly versatile immune cells involved in both pro- and anti-inflammatory processes. These cells are classified based on their cytokine production and transcription factor expression, such as Th1 (IFN\(\gamma\)), Th2 (IL-4, GATA3), Th17 (IL-17), and Treg (IL-10/TGF\(\beta\), FOXP3) cells [45; 46]. Although reports on hepatic CD4+ T cell presence in MASLD are contradictory--some studies document progressive hepatic accumulation in MASLD [47], while others suggest decreased hepatic recruitment during the transition to HCC [48]--evidence indicates that polarization of CD4+ T cells toward Th1 [49] and Th17 [50] subsets correlates with increased IFN\(\gamma\) and IL-17A production [51; 52; 53], contributing to MASLD progression [54]. Furthermore, [PERSON] et al. [55] demonstrated that blocking integrin-mediated hepatic recruitment of CD4+ T cells attenuated liver inflammation and fibrosis in a mouse model of MASLD, providing additional evidence of CD4+ T cells' essential role in MASLD pathogenesis. Th1 and Th2 cells are implicated in MASH pathogenesis, with an imbalance favoring proinflammatory Th1 responses over anti-inflammatory Th2 responses. Increased accumulation of Th1 cells and elevated systemic and hepatic IFN\(\gamma\) levels have been reported in individuals with MASH [56]. IFN\(\gamma\) is considered a key pathogenic driver of MASLD progression, as genetic ablation of IFN\(\gamma\) in mice protects against MASH and hepatic fibrosis [57]. Th17 cells are also major contributors to MASLD pathogenesis, amplifying proinflammatory signals that sustain tissue inflammation, with IL-17A identified as the primary cytokine driving this process [58; 59]. In MASLD, hepatic Th17 cell numbers are increased in mouse models, and IL-17A-producing cells are associated with the transition from steatosis to MASH in humans [50]. Mechanistically, IL-17 promotes the expression of chemokines (e.g., CXCL1 and CCL2) that facilitate neutrophil and macrophage infiltration and activation, further amplifying tissue inflammation and fibrosis [60]. Treg cells, which regulate effector T cell activation, act as immune modulators to prevent excessive pathogenic immune responses. However, their role in MASH progression remains unclear.