## 4 MASLD-HCC Treatment
#### Immunotherapy Outcomes in MASLD-HCC Patients  
According to both basic research and clinical data, non-viral HCC, particularly MASLD-HCC, might show limited efficacy to immunotherapy [24; 77]. A meta-analysis of trials (including IMbrave150 [109], KEYNOTE-240, and CheckMate-459) showed that ICIs improved OS in patients with viral HCC but not in those with non-viral HCC [24]. In the CheckMate-459 trial, which compared nivolumab monotherapy with sorafenib is a first-line therapy, nivolumab showed a lower survival benefit in non-viral HCC patients compared to viral HCC patients [120]. Similarly, in the KEYNOTE-240 study, pembrolizumab extended OS less in non-viral HCC patients than in those with HBV-HCC. In another meta-analysis, [PERSON] et al. [119] found that ICIs were less beneficial in patients with non-viral HCC, while the efficacy of TKIs and anti-VEGF agents remained unaffected by the underlying HCC etiology. Additionally, in the CheckMate-040 trial, which assessed the combination of nivolumab and ipilimumab (an anti-CTLA-4 monoclonal antibody), no significant difference in OS was found among HBV-HCC, HCV-HCC, and non-viral HCC patients [121]. The loss of anti-tumor CD4+ T cells and the accumulation of exhausted, altered CD8+PD-1+ T cells in NASH may impair tumor immune surveillance and reduce the efficacy of immunotherapy [48; 122]. However, in a recent retrospective multicentric study, [PERSON] et al. [123] found that the presence of MASLD did not worsen outcomes in advanced HCC patients treated with atezolizumab and bevacizumab (atezo-beva). Additionally, the post-hoc analysis of the IMbrave150 trial (which tested the combination of atezolizumab and bevacizumab in advanced HCC) did not show significant differences in PFS or OS based on the underlying etiology [124]. Nevertheless, it is important to note that nearly 70% of the population in the IMbrave150 trial had viral HCC [125]. These conflicting results may be due to the lack of clear subgroup distinctions within the non-viral HCC group in some studies or post-hoc analyses, where NASH, alcohol-related HCC, and unknown etiologies are grouped together, complicating data interpretation [126]. Furthermore, none of these key studies distinguished MASLD-HCC as a separate etiology of liver disease at baseline, with cohorts divided mainly by the presence or absence of viral hepatitis. A small study comparing anti-PD-L1 immunotherapy outcomes in MASLD-HCC versus other etiologies demonstrated reduced OS in the MASLD-HCC group [24]. The HIMALYA [127] and CARES-310 [128] trials did not specifically report outcomes for MASLD-HCC patients, and thus, the role of ICIs in MASLD-HCC requires further investigation [2]. Recent studies suggest that combining ICIs with anti-VEGF therapies may improve outcomes in non-viral HCC, including MASLD-HCC. In the GO30140 study, which compared atezolizumab monotherapy with atezolizumab and bevacizumab (atezo-beva combination), PFS was significantly longer in non-viral HCC patients treated with atezo-beva compared to those on monotherapy, indicating that anti-VEGF therapy could complement the limitations of ICIs in monotherapy [129]-VEGF plays a crucial role in the tumor microenvironment by prompting immune cells to recruit regulatory T cells while reducing the infiltration of cytotoxic T cells (CTLs) [130]. Vascular endothelial growth factor A (VEGF-A) plays a central role in tumor angiogenesis. However, VEGF-A also supports tumor progression through a dual mechanism: not only by promoting vessel formation but also by acting as an immunosuppressive factor. As previously discussed, CD4+ and CD8+ T lymphocytes can eliminate tumor cells. However, tumors develop various immune evasion strategies, such as the induction of regulatory T cells (Tregs) and T cell exhaustion. VEGF-A appears to contribute to this T cell-mediated immunosuppression.