Abstract Background: While immune checkpoint blockade (ICB) has transformed cancer treatment, only a minority of hepatocellular carcinoma (HCC) patients achieve durable responses. Studies have demonstrated the gut microbiome as an important modulator of anti-tumor immunity, yet its influence on tumorigenesis and ICB response in HCC remains incompletely characterized. Methods: We analyzed fecal microbiome composition via 16S rRNA sequencing from 17 patients with resectable HCC (stage Ib, II, and IIIb) receiving anti-PD-1 (NCT03916627). Treatment response was radiographically assessed (RECIST 1.1). Gut microbiota samples were collected pre-treatment and during therapy. To investigate the microbiome’s causal link with HCC tumorigenesis, we employed an immunogenic murine HCC model generated via hydrodynamic tail-vein delivery of MYC-lucOS and CTNNB1 plasmids. Ex-germ-free mice received fecal microbiota transplantation (FMT) from either (i) a clinical non-responder with high Bacteroidetes abundance (44.7%), or (ii) a responder with low Bacteroidetes abundance (0.89%). Results: Overall response rate was 26.3% (5 responders, 14 non-responders). Microbiome profiling revealed no significant difference in alpha diversity between responders and non-responders. Longitudinal analysis between pre- and during-treatment stools showed minimal change in alpha diversity. Taxonomic comparisons between responders and non-responders revealed significant Bacteroidetes phylum enrichment in non-responders (p0.05). In the murine model, FMT from the non-responder donor markedly accelerated tumor progression and reduced median survival compared with responder-derived FMT (p0.05). Conclusions: Integrating clinical microbiome profiling with a humanized HCC mouse model, we identify Bacteroidetes enrichment as a contributor to HCC tumor progression. FMT from a non-responder stool with high Bacteroidetes accelerated tumorigenesis and reduced survival relative to responder-derived microbiota with low Bacteroidetes. Because mechanistic microbiome studies in liver cancer have long been limited by the absence of models that faithfully reflect patient tumor biology and immune evasion, we developed a genetically engineered, immunogenic HCC model that enabled us to also investigate the microbiome signatures observed in patients. Together, these findings support Bacteroidetes-targeted microbial modulation as a potential therapeutic strategy to abrogate tumor progression and enhance ICB efficacy in HCC. Citation Format: Joan Shang, Marina Barcena-Varela, Illaria Mogno, Anthony Lozano, Ian Liebling, Kai Mead, Zhihua Li, Lauren Grinspan, Katherine Lindblad, Marina Ruiz de Galarreta, Romain Donne, Sacha Gnjatic, Miriam Merad, Tomi Jun, Celina Ang, Thomas Marron, Jeremiah Faith, Amaia Lujambio. Bacteroidetes Enrichment Associated with Immune Checkpoint Blockade Resistance and Promotes Tumorigenesis in Hepatocellular Carcinoma abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C063.
Shang et al. (2026) studied this question.