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limitation of this approach is that it is based on post-surgical HCC samples, which are typically from more
advanced disease stages and primarily represent prevalent etiologies at the time (HBV, HCV, and alcohol).
In a subsequent study published in 2017, Sia et al. analyzed samples from 956 patients with HCC and found
that approximately 25% presented markers of inflammatory expression, which they termed the “Immune
Class” . Within this class, they identified two subtypes: one with active immune responses and another
[115]
with exhausted immune responses. The immune-exhausted subtype showed marked activation of
transforming growth factor-beta (TGF-β), which stimulates the polarization of macrophages toward the M2
type, and a significant methylation profile of immune-related genes, suggesting an important epigenetic
effect in this group. It is worth noting that viral etiologies (HBV and HCV) predominated in this cohort,
comprising around 80% of cases, while non-viral cases represented less than 18%.

In 2019, Jaitin et al., using single-cell RNA-sequencing, evaluated the complete immune cell behavior in
adipose tissue from obese mice and humans, identifying the lipid receptor triggering receptor expressed on
[116]
myeloid cells 2 (TREM2) as a key regulator of immune responses at the tissue level . Lipid-associated
macrophages (LAMs), which develop in conditions of obesity from circulating monocytes and are located
around adipocytes, are characterized by TREM2 receptor activation. In this regard, recent findings by
Fredrickson et al. demonstrate that TREM2+ macrophages can facilitate MASH resolution independently of
weight loss following bariatric surgery . These findings highlight TREM2 as a key regulatory checkpoint
[117]
in the regulation of macrophage activation in MASH and potentially in HCC.

Other relevant aspects of the role of macrophages in HCC were pointed out by Ding et al., who analyzed
137 resected HCC samples (mostly from patients with HBV infection and in the cirrhosis stage), finding
that high intratumoral macrophage density [tumor-associated macrophages (TAMs)] was associated with a
[118]
poor prognosis . In another study, Kuang et al., analyzed the expression of PD-L1 in the peritumoral
stromal tissue of 28 patients with HCC, demonstrating that these activated monocytes suppressed the
activity of T lymphocytes, favoring tumor progression and linking proinflammatory states to tumor
immunotolerance . Furthermore, Wang et al., using single-cell RNA-sequencing, identified nine cell types
[119]
in HCC samples, with macrophages showing the highest rates of intercellular communication, and
characterized macrophage subtypes associated with differing OS, TME infiltration, and response to
immunotherapy . These findings underscore the importance of molecular mechanisms that maintain
[120]
hepatic immune homeostasis and influence macrophage polarization in the progression of both MASH and
HCC.

On the other hand, the impact of the microbiome on the mechanisms associated with the development of
MASLD and carcinogenesis is increasingly evident. Obesity due to overnutrition is very common, often
driven by an excess intake of foods rich in fructose, which induces fructose-associated lipogenesis via
microbiome-derived acetate, as demonstrated by Zhao et al. . This suggests that different microbiome-
[121]
derived substrates can influence hepatic lipid metabolism. Hu et al., using murine models of HCC,
demonstrated that modifying the intestinal microbiota using strains of Lactobacillus reuteri or the presence
of short-chain fatty acids (SCFA) inhibits the production of IL-17A by innate lymphoid cells subtype 3
(ILC3), potentially modulating the antitumor efficacy of immune checkpoint therapies (e.g., anti-PD-1) .
[122]
However, it remains possible that additional intermediaries contribute to these immune response
modifications.

INFLUENCE OF MASLD ON THE RESPONSE TO SYSTEMIC THERAPY FOR HCC
The use of immunotherapy in the last decade has revolutionized oncological treatments, significantly
improving response rates compared to previous systemic treatment strategies [8,48] . As of the first half of 2024,