Abstract Tumor hypoxia significantly contributes to cancer development, promoting tumor growth and metastasis. Previous work in our lab has shown that long term hypoxia leads to a marked suppression of type I interferon (IFN) signaling within luminal breast tumor cells. Notably, this suppression was persistent even when hypoxic precultured cells were reoxygenated which is indicative of hypoxic memory. Understanding the basis of IFN pathway suppression is important, as diminished IFN signaling weakens antitumor immune response and can promote tumor cell proliferation and survival. Hypoxia is also known to induce metabolic reprogramming which results in lactate accumulation, acidifying the tumor microenvironment (TME), and function as a signaling metabolite that suppresses antitumor immunity. While lactate’s role in inhibiting immune response within TME is well established, its role within tumor cells in regulating interferon signaling remains poorly understood. In this study, we aim to explore the mechanisms of lactate mediated suppression of type I IFN response in tumor intrinsic manner. We found that long term hypoxia increases lactate accumulation and reduced type I IFN signaling. We also observed that addition of extracellular lactate to cells cultured under normoxia is sufficient to suppress type I IFN signaling, whereas pharmacological inhibition of lactate dehydrogenase A (LDHA) activity restores IFN signaling in hypoxia. Recent discoveries show that lactate can directly alter gene expression through histone lactylation, a novel epigenetic modification. However, its role in breast cancer immune escape remains largely unexplored. We observed that increased lactate levels under hypoxia correlate with elevated histone lactylation. Determining whether histone lactylation alters gene expression that can enhance the activity of suppressors of type I IFN signaling would elucidate the mechanisms of how lactate mediate suppression of IFN signaling. By uncovering this mechanism, our findings may reveal new therapeutic strategies to restore interferon signaling and enhance immunotherapy efficacy in breast cancer. Citation Format: Yaminisree Nagidi, Aidan Moriarty, Min Yu. Lactate mediated suppression of tumor intrinsic type I interferon response in luminal breast cancer cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7304.
Nagidi et al. (2026) studied this question.