Abstract LB320: Broad and synergistic anti-tumor effects of small-molecule dual HIF-1/2 inhibitors in combination with immune checkpoint inhibitors

Abstract Motivation: Hypoxia inducible factors (HIFs) are critical transcriptional regulators that play fundamental roles in adaptive responses to low oxygen, both in normal and disease conditions. Dysregulated activation of HIFs has been implicated in a variety of cancers due to their role in mediating a broad range of key processes including angiogenesis, glycolysis, immune evasion, cancer stem cell specification, and metastasis. Methods: In this study, we utilized virtual and cell-based screening approaches to identify compounds that directly bind to HIF-1α and HIF-2α to HIF-1β, leading to their degradation and suppression of HIF target gene expression. Results: In syngeneic mouse models of melanoma, breast, colorectal, and prostate cancer, we observed significant tumor regression when dual HIF-1/2 inhibitors were combined with anti-CTLA4 immunotherapy. The combined treatment enhanced the infiltration of T cells and natural killer (NK) cells into the tumor microenvironment. An orally-administered dual HIF-1/2 inhibitor showed superior anti-tumor efficacy to the HIF-2-selective inhibitor PT2385 in a colorectal cancer model. Conclusion: This study demonstrates the anti-tumor effects of dual HIF-1/2 inhibitors and their ability to modulate the tumor immune cell microenvironment, resulting in sustained tumor regression when added to immunotherapy. The promising outcomes of this study warrant further exploration of these inhibitors as potential cancer treatment modalities. Citation Format: Shaima Salman, Tina Y. Huang, Yousang Hwang, Anmol Kumar, Alexander D. MacKerell Jr., Gregg L. Semenza. Broad and synergistic anti-tumor effects of small-molecule dual HIF-1/2 inhibitors in combination with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB320.