Abstract 3121: DWP217, a novel Arginase inhibitor enhancing tumor immunity through tumor microenvironment reprogramming

Abstract Checkpoint inhibitors have transformed cancer immunotherapy, yet their efficacy is often undermined by the immunosuppressive tumor microenvironment (TME). Arginase, a key enzyme secreted by myeloid-derived suppressor cells and tumor-associated macrophages, contributes to this suppression by depleting arginine, a critical nutrient for T-cell and NK cell activation. Elevated Arginase activity is associated with immune resistance and diminished response to immunotherapy, highlighting it as a promising target to reprogram the TME and restore antitumor immunity. Preclinical evaluation of DWP217 revealed its potent ability to inhibit Arginase activity, enabling T-cell proliferation and reversing immune cell dysfunction. Structural analyses uncovered a unique binding mechanism, supporting the rational design of an optimized compound series with enhanced potency. In combination with anti-PD-1 antibodies, DWP217 achieved significantly better tumor control and survival outcomes in syngeneic cancer models compared to anti-PD-1 monotherapy. Notably, DWP217 outperformed competing Arginase inhibitors that had advanced to clinical trials, underscoring its superior efficacy and potential as an immune-oncology therapeutic candidate. Immune profiling revealed that DWP217 enhances tumor-infiltrating lymphocyte activation and reprograms the TME toward a pro-inflammatory state. These findings indicate that DWP217 not only counteracts Arginase-mediated immune suppression but also reshapes the TME to support durable antitumor immunity. With its strong preclinical efficacy and favorable immune modulation profile, DWP217 is a promising therapeutic candidate for overcoming immuno-oncology resistance. Its further development holds the potential to significantly improve therapeutic outcomes in refractory solid tumors. Citation Format: Seung Jae Jeong, Wolyoung Kim, Ji-Hae Kim, Sujin Ha, Youngwoo Choi, Jiyoon Seok, Ye Gi Han, Jong Cheol Shon, Hyoungrok Bak, Eunmi Hong, Jonghyeon Son, Kyung Seok Oh, Ji-Duck Kim, Joon Seok Park. DWP217, a novel Arginase inhibitor enhancing tumor immunity through tumor microenvironment reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3121.