Targeting SMYD2 improves immunotherapy response in experimental hepatocellular carcinoma

Therapeutic options for hepatocellular carcinoma (HCC) remain scarce and limited by resistance, underscoring the need for novel approaches. The lysine methyltransferase SMYD2 is overexpressed in several cancers and regulates oncogenic signaling through histone and non-histone substrates. However, its role in HCC is incompletely defined. We integrated transcriptomic analyses of patient samples with in vitro assays and orthotopic murine models to evaluate the therapeutic potential of SMYD2 inhibition in HCC. SMYD2 was enriched in intratumoral regions and associated with immunosuppressive and Wnt/β-catenin-driven programs. In vivo , SMYD2 pharmacological inhibition with AZ-505 reduced tumor burden and induced pro-inflammatory transcriptional changes. The antitumor activity of AZ-505 was also evident in Wnt/β-catenin-active tumors, which further displayed reduced expression of proliferative and immunosuppressive signatures. In vitro , SMYD2 inhibition decreased tumor-cell Wnt ligand transcription and shifted macrophage responses toward reduced TGF-β expression, in a pattern consistent with reduced Wnt/β-catenin-associated signaling. Finally, AZ-505 synergized with anti-PD-1 in Wnt/β-catenin-active tumors, expanding cytotoxic T cell and antigen-presenting populations. Transcriptomic analyses of combination-treated tumors showed suppression of Wnt/β-catenin- and TGF-β-pathway-associated signatures alongside activation of immune-stimulatory responses. These results position SMYD2 as a dual regulator of tumor growth and immune suppression, and as a promising target to overcome ICI resistance in HCC.