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

interactions within the tumor microenvironment [43-45] .

Despite intense research in the search for specific recurrent mutations that determine tumor progression, it
[44]
has not been possible to determine an exclusive role for them . Instead, changes in gene expression
[44]
associated with tumor progression have been identified . As noted by Feinberg et al. in 2006, genetic
mechanisms were not the only pathway to genetic disruption in cancer ; this led to the proposal of the
[46]
“epigenetic progenitor model of cancer”. According to this model, the epigenetic disruption of progenitor
cells is a critical event not only for the development of cancer, but also for tumor progression and late-stage
heterogeneity observed in tumors derived from these cells . In this way, four additional concepts were
[45]
added to the cancer hallmarks in 2011: genomic instability, tumor-promoting inflammation,
reprogramming of energy metabolism, and evasion of immune destruction . These additions helped to
[44]
shape the conceptual framework of the tumor microenvironment [44-45] .

A better understanding of the influence of the different components of the tumor microenvironment has
highlighted the fundamental role of the immune evasion mechanisms in tumor cells. In 2013, Chen and
Mellman detailed what they termed the “cancer-immunity cycle”, outlining the steps necessary to initiate,
[47]
proceed, and expand the immune response for the effective elimination of tumor cells . The influence of
the tumor microenvironment on the cancer-immunity cycle can be affected by epigenetic changes that, in
the case of HCC, may be determined by the etiological factors of the underlying liver disease [46-48] . The use of
checkpoint inhibitors over the past 10 years has marked a turning point in cancer management strategies .
[48]
Anti CTLA-4 (Cytotoxic T-Lymphocyte-Associated protein 4) and anti PD-1 (programmed cell death
protein 1)/anti PD-L1 (programmed death-ligand 1) therapies play crucial roles, mainly observed in the
steps of priming and activation of T lymphocytes (CTLA-4), as well as in the inhibition of the immunostatic
[47]
blockade (PD-1/PD-L1), respectively . The fundamental strategy of initial systemic treatments against
HCC has been to block tumor neoangiogenesis mechanisms .
[48]

TREATMENT OUTCOMES FOR MASLD-RELATED HCC
The treatment response rate of MASLD-related HCC has been evaluated based on the type of treatment
received and compared with the response rate of non-MASLD-related HCC cases. Response rates have been
analyzed in the contexts of liver resection (LR) [49-51] , liver transplantation (LT) [52-59] , locoregional therapy [60-62] ,
and systemic therapy [63,64] of HCC.

Differences in overall survival (OS) have been observed in patients with MASLD-related HCC undergoing
surgical resection compared to patients with HCC of different etiologies [49-51] . Molinari et al., in a meta-
analysis of 14 studies that included 7,226 patients, described an improvement in disease-free survival (DFS)
and OS after LR in patients with MASLD-related HCC compared to those with HCC of other etiologies .
[49]
Chin et al., in another meta-analysis of 9 studies evaluating 5,579 patients, also reported improvements in
both DFS and OS . It should be noted that in Molinari et al.’s study, the prevalence of cirrhosis in the two
[50]
groups evaluated was similar, although the retrospective nature of the studies limits the assessment of
adequate inclusion of patients with the metabolic comorbidities typical of MASLD . Lin et al. evaluated the
[49]
impact of the new MASLD concept on the OS and recurrence-free survival (RFS) in patients with HCC and
chronic hepatitis B virus infection (HBV) at Barcelona Clinic Liver Cancer classification (BCLC) stage 0/A
[51]
after liver resection . They found no differences in RFS and OS between the MASLD and non-MASLD
[51]
groups . However, within the MASLD group, the lean-MASLD subgroup was identified as a risk factor for
recurrence, suggesting that further analysis of the different MASLD subgroups is required .
[51]