Hematopoietic prostaglandin D2 synthase inhibition to stimulate a pro-inflammatory tumor microenvironment.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death and often shows poor responsiveness to immune checkpoint blockade (ICB) immunotherapies. In a previous study on melanoma, the host laboratory demonstrated that the hematopoietic prostaglandin D₂ synthase (HPGDS)–PGD₂ pathway sustains an immunosuppressive feedback loop in tumor-associated macrophages (TAMs), thereby limiting CD8⁺ T-cell activity and promoting resistance to ICB. Building on these findings, this thesis extends this investigation to HCC, evaluating whether HPGDS contributes to tumor immune evasion in this context and whether the underlying mechanisms are conserved or engage distinct immune pathways. Using a spontaneous HCC mouse model generated by hydrodynamic transfection of c-Myc and h-RasG12V, we assessed the expression and role of HPGDS and its receptor DP1 through molecular, histological, and immunological approaches. Data analysis revealed that Hpgds is selectively expressed in lipid-associated macrophages (LAMs) during hepatocarcinogenesis, while Ptgdr (gene encoding DP1) is mainly expressed by NK⁺ cells. Pharmacological inhibition of HPGDS with HQL-79 reduced tumor nodule size, reprogrammed LAMs toward a pro-inflammatory phenotype, and enhanced NK⁺ cell infiltration along with IFNγ production. Additionally HPGDS inhibition promoted improvements in vascular architecture. Overall, our findings demonstrate that the HPGDS–PGD₂ pathway fosters an immunosuppressive LAM–NK⁺ cell crosstalk in HCC, distinct from the CD8⁺ T cell–TAM interaction described in melanoma. Nevertheless, targeting this pathway may represent a promising strategy to promote a pro-inflammatory TME in tumors unresponsive to existing treatments.