BCG as an Innovative Option for HCC Treatment: Repurposing and Mechanistic Insights

• Published in: Advanced science 2024-04, Vol.11 (14), p.e2308242-n/a
• Main Authors: Vaziri, Farzam, Setayesh, Tahereh, Hu, Ying, Ravindran, Resmi, Wei, Dongguang, Wan, Yu‐Jui Yvonne
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; bacterial immunotherapy; BCG Vaccine - therapeutic use; Bladder cancer; Cancer therapies; Carcinoma, Hepatocellular - drug therapy; Collagen; FDA approval; Female; Females; fibrosis; Histology; Immunotherapy; interferon; Kinases; Ligands; liver; Liver cancer; Liver Neoplasms - drug therapy; Male; Metabolism; Mice; Mycobacterium bovis; Proto-Oncogene Proteins c-akt; trained immunity; Tuberculosis; Tumors; Vaccines
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202308242

This study investigates Bacillus Calmette‐Guérin (BCG) as a potential treatment for hepatocellular carcinoma (HCC), a condition often associated with unfavorable treatment outcomes. Exploiting BCG's recognized immune‐boosting properties, preclinical trials are conducted using HCC mice, with a single subcutaneous dose of BCG administered post‐tumor formation. Results indicate that BCG treatment effectively diminishes tumor burden and extends survival in both male and female HCC mice. Positive influences on hepatic fibrosis and metabolism are observed, leading to a reduction in lipid levels. Spatial analysis underscores BCG's tumor‐specific effects, inducing the enrichment of metabolic pathways and inhibiting various cancer‐related pathways. Furthermore, BCG promotes immune cell infiltration, including CD4+, CD8+ T cells, and M1 macrophages, in both v‐akt murine thymoma viral oncogene homolog 1(AKT)/neutoblastoma RAS viral oncogene homolog (RAS) and β‐catenin positive HCC models. Interestingly, blocking T cells, trained immunity, and Interferon‐γ (IFN‐γ) function reverses BCG's anti‐HCC effects. In conclusion, BCG emerges as a promising treatment option for HCC, characterized by a favorable safety profile and efficacy in inhibiting fibrosis, improving metabolism, and engaging both trained immunity and T cells in therapeutic mechanisms. BCG treat mouse HCC. The mechanisms are several: (1) BCG induce trained immunity and generate IFN‐γ, Chemokine ligand 5 (CCL5), and Interleukin‐12 (IL‐12). (2) The increased cytokines recruit CD4+ and CD8+ T cells. (3) In part, via IFN‐γ releasing, HCC cells are killed. Inhibiting trained immunity by metformin, depleting CD4+ and CD8+ T cells, or blocking IFN‐γ abolishes the anti‐HCC effect of BCG.