## 2 Immune System, MASLD, and HCC
### MASH and Immune Response
In experimental models of high-fat diet (HFD)-induced MASLD, hepatic Treg cells are reduced [61], yet paradoxically, Treg depletion appears to mitigate progression to HCC [62], while adoptive Treg transfer in MASH models exacerbates steatosis and liver damage [63]. Similarly, human studies on Treg cells in MASLD report conflicting findings, with both increased [64] and reduced [50] intrahepatic Treg cell frequencies and numbers. The contribution of CD8+ T cells to MASLD pathogenesis is context-dependent. CD8+ T cell numbers are elevated in the liver of individuals with MASH [43], and inhibition of CD8+ T cell function in animal models reduces hepatic steatosis and inflammation [65]. Hepatic accumulation of activated CD8+ T cells [66] amplifies the proinflammatory environment by increasing IFNy and TNF production and inducing cytotoxic activity-driven hepatocellular damage. Notably, MASH impairs CD8+ T cell mobility through metabolic and mitochondrial dysfunction [66], weakening tumor antigen-specific CD8+ T cell responses [67] and ultimately promoting HCC progression. A preclinical study by [PERSON] et al. [68] demonstrated that NASH-related liver damage is associated with elevated levels of activated CD8+ T cells expressing CD69, CD44, and PD-1. The abundance of hepatic CD8+PD-1+ T cells correlates with body mass index, liver damage, and fibrosis severity (F0-F4). Additionally, immunohistochemical analysis revealed that increased PD-L1 expression in hepatocytes and non-parenchymal cells corresponds with NASH severity. Although limited, existing evidence supports a pathogenic role for B cells in MASLD [69]. Hepatic B cell accumulation has been observed in both humans [70] and mice [71] with MASLD, accompanied by increased expression of inflammatory mediators such as IL-6 and TNF. However, whether B cell-derived mediators directly drive MASLD pathogenesis or indirectly exacerbate hepatic inflammation by inducing CD4+ T cell differentiation toward Th1/Th17 subsets remains unclear [72]. Given the immune system's central role in MASLD pathogenesis, immunotherapy has emerged as a promising treatment strategy. Abnormal gene expression related to immune regulation and response is observed in MASLD progression. For example, the mitochondrial antiviral signaling (MAVS) protein regulates interferon expression and inflammatory factor production while also inhibiting lipid accumulation in hepatocytes. MAVS deficiency accelerates hepatic steatosis, and its expression is significantly reduced in MASLD-affected livers [73]. On the contrary, high levels of mac-2 binding protein (M2 BP), a glycoprotein involved in immune regulation, is a predictive biomarker of liver fibrosis progression in MASLD patients [74]. Another key player, secreted phosphoprotein 1 (SPP1), is implicated in autophagy, inflammation, and hepatocyte fibrosis. Elevated SPP1 levels are associated with increased hepatic lipid synthesis and steatosis [75]. Immun signaling alterations and receptor hyperactivation are also hallmarks of MASLD. For instance, the macrophage scavenger receptor 1 (MSR1), predominantly expressed in Kupffer cells, triggers proinflammatory activation via JNK signaling when stimulated by lipids. MSR1 deficiency mitigates MASLD-related metabolic dysregulation, liver injury, and proinflammatory macrophage activity, underscoring its role in lipid-induced inflammation [21; 76]. Additionally, the innate immune signaling pathway STING, which promotes intrahepatic inflammation, may also inhibit lipid degradation, contributing to MASH progression [22]. To sum up, chronic steatosis induces auto-aggressive CD8+PD-1+ T cells that, by responding to metabolic stimuli in an antigen-independent way, kill hepatocytes and promote a proinflammatory environment and a pro-tumorigenic environment resulting in chronic liver damage. Therefore, CD8+PD-1+ T cells in a fatty liver are hyperactivated and even exhausted due to chronic dysregulation [77]. As is well established, advanced NASH stages are associated with a higher risk of developing HCC [78].