Abstract C028: Viperin sensitizes melanoma to ICB therapy by enhancing chemokine-mediated immune cell infiltration

Abstract Viperin, an interferon-inducible protein, has been reported to promote cancer progression and enhance cancer stem-like cells (CSCs) properties by increasing cancer metabolic reprogramming in several cancer types. Viperin expression in cancer cells inversely correlated with the survival of most cancer patients, except in melanoma. However, the molecular mechanisms governing viperin expression and its impact in melanoma remain largely unknown. Here, we show the viperin effects on melanoma and its action mechanism. We observed that viperin expression levels in melanoma patients treated with immune checkpoint blockade (ICB) therapy are significantly higher in responders than in non-responders. We also demonstrated that viperin promotes immune cell infiltration into the tumor microenvironment, particularly T cells and macrophages through the upregulation of CXCL9, CXCL10, CXCL11 chemokines. Mechanistically, we found that viperin enhances the expression of these chemokines via activation of the p38 phosphorylation pathway. Functional studies demonstrated that stable expression of viperin in melanoma restored responsiveness to ICB therapy in refractory models, indicating a pivotal role of viperin in reversing immune resistance. Our findings identify viperin as a crucial modulator of anti-tumor immunity in melanoma. By enhancing chemokine-mediated immune cell infiltration through p38 activation, viperin expression sensitizes tumors to ICB therapy. These results suggest that viperin could serve as a promising biomarker and therapeutic target for overcoming resistance to immunotherapy in melanoma. Citation Format: Youngeun Gu, Jun-Young Seo. Viperin sensitizes melanoma to ICB therapy by enhancing chemokine-mediated immune cell infiltration [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr C028.