Introduction
Immune checkpoint inhibitor (ICI)-based treatments have become the standard first-line therapy for patients with advanced hepatocellular carcinoma (HCC). Despite significant therapeutic improvements, treatment response rates remain low at around 30% [1]. Human metabolic phenotypes can modulate inflammation and tumor immunosurveillance [2].
Aims & Methods
This study aimed to characterize metabolic states of patients with advanced HCC treated with ICI and assess their impact on clinical outcomes, potentially identifying novel prognostic conditions. Data was collected retrospectively from a single center in Germany (LMU University Hospital Munich). Baseline body composition markers, including BMI (<25 vs. ≥ 25), visceral fat (high vs. low, based on median), sarcopenia assessed by skeletal muscle mass index (SMI) (yes vs. no, using Martin’s cut-offs [3]) and psoas muscle density as a correlate of myosteatosis (yes vs. no, using Martin’s cut-offs [3]), were assessed from CT scans at the L3 vertebral level. Markers were correlated with patient survival and analyzed using the log-rank test. In addition, immunophenotyping of peripheral blood mononuclear cells (PBMC) collected at baseline from a cohort subgroup was performed via flow cytometry with subsequent statistical analysis utilizing the Mann-Whitney U test.
Results
A total of 146 patients with unresectable HCC treated with ICI were included. BMI did not significantly impact overall and progression-free survival. Patients with higher levels of visceral fat showed prolonged survival (mOS 1038 days vs. 540 days, p=0.0142). Furthermore, the absence of myosteatosis emerged as a strong prognostic marker for improved clinical outcomes (yes: mOS 240 days vs. no: mOS 709 days, p=0.0038). Sarcopenia did not significantly impact overall and progression-free survival. Flow cytometry analysis of immune cells revealed a relevant impairment of immune cell subsets involved in antitumor immunity in patients with myosteatosis. Dendritic cells showed reduced antigen-presenting capacity and T cells exhibited signs of exhaustion and reduced cytotoxicity in patients with myosteatosis. In contrast, visceral fat did not significantly impact the immunophenotype of PBMCs.
Conclusion
Body composition parameters, such as visceral fat and myosteatosis, are significantly correlated to PFS and OS in patients with advanced HCC treated with ICI. Moreover, in patients with myosteatosis, peripheral immune cell analysis revealed functional impairments in key antitumor immune cell subsets. These findings might help to identify patients who could benefit from nutritional interventions to improve clinical outcomes and underline that future studies are required to broaden our knowledge about the mechanistic links between metabolic states like visceral adiposity and myosteatosis and anticancer immunity in the context of ICI.
References
1. Vogel, A., et al., Hepatocellular carcinoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol, 2025.
2. Alden, S.L., et al., Pan-tumor analysis to investigate the obesity paradox in immune checkpoint blockade. J Immunother Cancer, 2025. 13(1).
3. Martin, L., et al., Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol, 2013. 31(12): p. 1539-47.
Disclosure
OÖ received honorarium from Bayer.
MAF has received third-party funding for research from BZKF, Menarini and Gilead.
MS has received lecture honoraria from Cook Medical, Sirtex Medical, Boston Scientific, Balt, Siemens, Bayer, Falk Foundation, Roche, Astra Zeneca. He has received third-party funding for scientific research from Astra Zeneca, Boston Scientific, Bayer, Sirtex Medical.
AG is advisory board or steering committee member to AbbVie, Alexion, Bayer, BMS, CSL Behring, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Sequana and speaker for Advanz.
EDT has served as a paid consultant for AstraZeneca, Bayer, BMS, EISAI, Eli Lilly & Co, Pfizer, IPSEN, and Roche. He has received reimbursement of meeting attendance fees and travel expenses from Arqule, AstraZeneca, BMS, Bayer, Celsion, and Roche, and lecture honoraria from BMS and Falk. In addition, he has received third-party funding for scientific research from Arqule, AstraZeneca, BMS, Bayer, Eli Lilly, and Roche.
FPR has received honoraria for lectures, consulting activities and travel support from the Falk Foundation, AbbVie, Gilead, Ipsen, Astra Zeneca, Roche and Novartis.
NBK has received reimbursement of meeting attendance fees and travel expenses from EISAI and a lecture honorarium from Falk and Astra Zeneca.
IP reports reimbursement of travel expenses from Roche and received third-party funding for scientific research from Novartis.
All the other authors have no conflicts of interest to declare.