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Page 10 of 18 Llamoza-Torres et al. Metab Target Organ Damage 2024;4:40 https://dx.doi.org/10.20517/mtod.2024.64

there are at least ten positive studies on the management of HCC using checkpoint inhibitors across various
stages of BCLC (stage 0-early, intermediate, or advanced) [Table 2]. However, when reviewing the
stratification by etiology in these trials, it becomes evident that specific subgroups of patients with NAFLD,
MAFLD, or the current term MASLD have not yet been adequately considered. The relevance of this
stratification was highlighted by Pfister et al. in a meta-analysis of three randomized phase III clinical trials
[136]
involving over 1,600 patients with advanced HCC . These trials tested inhibitors of PDL1 (programmed
death-ligand 1) or PD1 and revealed that immune therapy did not improve survival in patients with non-
viral HCC. Likewise, they found a shared gene-expression profile and increased abundance of
unconventionally activated hepatic CD8+PD1+ T cells in human MASH tissue . Subsequently,
[136]
Llovet et al. extended the meta-analysis to five randomized clinical trials, confirming the same suboptimal
outcomes in the MASH-HCC subpopulation .
[48]
Since HCC can develop in the MASH population without requiring progression to cirrhosis, this suggests
distinct carcinogenic mechanisms compared to other etiologies. As previously mentioned, differences at the
molecular level have been identified between MASH-HCC and HCC of other etiologies [86-93] . These findings
indicate differences in key signaling pathways. However, we would like to highlight the role of immune
dysfunction in these tumorigenesis processes. In this regard, Ma et al. demonstrated that MASLD leads to
[137]
selective CD4+ T lymphocyte loss, promoting hepatocarcinogenesis . Subsequently, Heinrich et al.
showed in a murine model that the microenvironment in MASH-induced mice impairs the efficacy of
immunotherapy in the management of liver neoplasms . Dudek et al. detected hepatic accumulation of
[138]
auto-aggressive CXCR6+ CD8 T cells in a mouse model of MASH [139,140] . Leslie et al. provided compelling
[141]
data showing that anti-CXCR2 treatment, which induces the accumulation of immature neutrophils, can
mitigate the presence of auto-aggressive lymphocytes, potentially modifying the natural progression toward
MASH and blocking the associated carcinogenesis process [142-148] . Most of the information regarding this
[148]
immune dysfunction is based on three animal models : (1) Genetically engineered mouse models
(GEMMs) for MASH-HCC, GEMMs; (2) Carcinogen and high-fat diet (HFD)-induced MASH-HCC; and
(3) the sleeping beauty (SB) transposon-induced MASH-HCC model. However, a detailed description of
these models is beyond the scope of this review.

Additionally, a key role has also been proposed for other immune cell populations present in the liver, such
as liver tissue macrophages, in the development of MASH-HCC. During macrophage expansion, there is a
recruitment of Kupffer cells that express proinflammatory characteristics, which impair triglyceride storage
[148]
and promote liver injury . Within this heterogeneous population of monocytes, a subtype known as
LAMs has been described ; these cells are involved in both MASH progression or regression phenomena,
[148]
depending on their phenotype and spatial distribution . TAMs with TREM2+ deficiency enhance the
[149]
infiltration of CD8+ lymphocytes, thereby improving the response to anti-PD-L1 therapies .
[150]
An expanded meta-analysis with new phase III studies, excluding those with a predominant viral
population, concluded that there are no differences in the effectiveness of checkpoint inhibitors between
populations of viral and non-viral etiology. However, the same authors pointed out that the heterogeneity of
the non-viral population may involve an amalgam of risk factors, the impact of which on the efficacy of
HCC treatments cannot be precisely determined . The need for adequate patient stratification in clinical
[151]
trials focused on the HCC population must include a well-characterized MASLD-HCC group, particularly
since it represents one of the main causes of HCC. This emphasizes that non-viral HCC etiology is not
synonymous with MASLD-HCC etiology . Furthermore, subspecialized treatment strategies still do not
[152]
adequately consider the prognostic impact of this population on an individualized basis .
[153]