Antitumor effects of Leishmania donovani by inducing a pro-inflammatory tumor microenvironment in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), a main subtype of liver cancer, remains a global health threat with limited therapeutic options. Here, we evaluated the immunotherapeutic potential of live-attenuated Leishmania donovani DD8 promastigotes and soluble leishmanial antigen (SLA) in a murine Hepa1-6 HCC model. Both approaches effectively inhibited growth and metastasis in mice. Rather than exerting direct cytotoxic effects, leishmania alters the tumor immune environment with increased infiltration of CD4⁺ and CD8⁺ T cells and activating an immune response with up-regulation of Th1 immune-associated cytokines (IFN-γ, TNF-α) and iNOS, and shifts the CXCL9/MMP balance toward an anti-angiogenic profile at the gene expression level. Additionally, a low dose of live attenuated promastigotes achieved tumor control comparable to that of SLA, underscoring the immunostimulatory potency of the attenuated strain. In short, we report that Leishmania inhibits the progression of liver cancer and exerts antitumor effects by inducing a pro-inflammatory tumor microenvironment, suggesting a potential new therapeutic approach for otherwise incurable cancers.