Letter: Comparing the Efficacy of Adjuvant PD–1 Inhibitor After Curative Resection for Metabolic Dysfunction-Associated Steatotic Liver Disease Related HCC Versus Other Aetiologies—Authors' Reply

We thank Su et al. for their interest in our study [1], which interrogated the role of hepatocellular carcinoma (HCC) aetiology on long-term outcomes following liver resection. In our work, we found that European patients with metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC had significantly shorter overall survival (OS) after liver resection compared to patients with HCC of other etiologies. Su et al. have raised a pertinent issue by discussing their recent findings in Asian patients receiving adjuvant anti-PD-1 immunotherapy, where no significant survival differences were observed between MASLD-related HCC and other aetiologies [2].

As highlighted by Su et al. [2], several studies have reported better disease-free (DFS) and OS in patients with MASLD-related HCC after liver resection, which contrasts with the results of our study [3]. Discrepancies in outcomes may be attributable to variations in patient populations (Asian vs. European cohorts), tumour characteristics, severity of underlying liver disease, retrospective application of diagnostic criteria (e.g., alcohol intake) and adjuvant therapy. These variations emphasise the need for standardised prospective settings to address these questions.

The investigation of MASLD-related HCC is especially crucial, as the underlying pathophysiology suggests distinct immune dynamics that may affect prognosis and response to therapy. Specifically, an autoreactive conventional dendritic cell (cDC1)-CD8 T-cell axis drives disease progression and cancerogenesis and can be stimulated through checkpoint inhibition in MASLD [4, 5]. A meta-analysis of published trials found that checkpoint inhibitor therapy (anti-PD-1 and anti-PD-L1, monotherapy or combination therapy) did not significantly improve survival in patients with advanced non-viral HCC. Interestingly, in patients with advanced HCC fulfilling metabolic dysfunction-associated steatohepatitis (MASH) criteria, survival outcomes were significantly worse with checkpoint inhibitor therapy compared to non-MASH-related HCC [6], suggesting that the immune microenvironment in MASLD-related HCC may differ from that in other HCC subtypes [7].

Current European guidelines do not recommend adjuvant therapy after curative-intent HCC resection, due to insufficient evidence to support their long-term efficacy in Western cohorts [8]. The Imbrave050 trial recruited Western and Asian patients to receive Atezolizumab (anti-PD-L1) plus Bevacizumab (anti-VEGF) in an adjuvant setting. Despite encouraging initial results, long-term oncological outcomes were not significantly improved through combination immunotherapy [9]. However, emerging data from Asia are more promising. For instance, a recent phase II trial of sintilimab (anti-PD-1) as adjuvant treatment after resection of high-risk HCC demonstrated significantly prolonged recurrence-free survival compared to post-operative active surveillance alone [10]. The prolonged DFS reported by Su et al. [2] corroborates these findings and sheds additional light on potential regional differences in HCC outcomes.

In conclusion, our study provides insights into the prognostic implications of MASLD-related HCC in European patients, but the global survival differences highlight the need for further research into how HCC aetiology affects treatment outcomes, particularly in the context of immunotherapy. Prospective studies with standardised treatment regimens are essential to tailor therapeutic strategies based on aetiology and region. The interplay between metabolic liver diseases and immune responses remains a critical area of research, with the potential to optimise treatment outcomes for patients with HCC globally.