Targeting SMYD2 improves immunotherapy response in experimental hepatocellular carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Hepatocellular carcinoma (HCC) treatments are limited by resistance, necessitating new therapeutic strategies.
• SMYD2 (lysine methyltransferase SMYD2) is overexpressed in cancers, regulating oncogenic signaling, but its role in HCC is unclear.
• Understanding SMYD2's function is crucial for developing novel HCC therapies.

Purpose of the Study:

• To investigate the therapeutic potential of SMYD2 inhibition in hepatocellular carcinoma (HCC).
• To evaluate SMYD2's role in HCC progression and immune suppression.
• To assess the efficacy of SMYD2 inhibition alone and in combination with immunotherapy.

Main Methods:

• Integrated transcriptomic analysis of patient samples.
• In vitro assays and orthotopic murine models for evaluating SMYD2 inhibition.
• Pharmacological inhibition of SMYD2 using AZ-505.
• Combination therapy with AZ-505 and anti-PD-1 immunotherapy.

Main Results:

• SMYD2 expression was enriched in HCC intratumoral regions, associated with immunosuppressive and Wnt/β-catenin pathways.
• SMYD2 inhibition with AZ-505 reduced tumor burden and induced pro-inflammatory changes.
• AZ-505 demonstrated antitumor activity in Wnt/β-catenin-active tumors, decreasing proliferation and immunosuppression.
• SMYD2 inhibition modulated macrophage responses and synergized with anti-PD-1, enhancing anti-tumor immunity.

Conclusions:

• SMYD2 is a key regulator of tumor growth and immune suppression in HCC.
• SMYD2 inhibition represents a promising therapeutic strategy for HCC, potentially overcoming resistance to immune checkpoint inhibitors (ICIs).
• Targeting SMYD2 can re-sensitize Wnt/β-catenin-driven HCC to immunotherapy.