Abstract 5625: Epigenetic reprogramming of T cell exhaustion

Abstract During tumor progression, T cells are recruited to the tumor microenvironment (TME), where T cells experience hypoxia, nutrient deprivation, immunosuppressive cytokines, and continuous stimulation by tumor antigens. These harsh conditions drive global epigenetic remodeling of T cells and promote their transition into a state of T cell exhaustion, characterized by impaired capacity in proliferation, reduced production of proinflammatory cytokines, and diminished self-renewal. Immune checkpoint blockade (ICB) treatment has revolutionized cancer therapy; however, it fails to reprogram the exhaustion-associated epigenetic landscape and therefore only partially restores T cell functions. Here, we aim to prevent T cell exhaustion by targeting this epigenetic landscape through ectopic expression of epigenetic reprogramming factors (ERFs). To this end, we first generated a mouse model with inducible ERF expression, isolated CD8+ T cells, and cultured them under hypoxic conditions with continuous stimulation, to mimic the TME. Under these conditions, ectopic expression of ERF factors significantly downregulates expression of exhaustion markers such as Tim3. We next assessed whether ERF-mediated reprogramming can restore the T cell function. In vitro, ERF-reprogrammed T cells exhibit increased durability compared to non-reprogrammed control T cells in response to exhaustion signals. In vivo, ERF-reprogrammed T cells, when transferred into tumor-bearing mice, significantly delays the tumor growth compared with transfer of non-ERF-expressing control T cells. Transcriptomics profiling further reveals that ERF reprogramming upregulates the genes involved in T cell activation, proliferation, and epigenetic remodeling. Collectively, these data support ERF-mediated reprogramming of T cells as a promising strategy to reshape the entrenched exhaustion-associated epigenetic landscape and restore T cell functions, with the potential to improve adoptive cell transfer (ACT)-based therapy such as Tumor-Infiltrating Lymphocytes (TIL) and Chimeric Antigen Receptor (CAR) T therapy. Citation Format: Tsunghan Hsieh, Ruomin Xin, Enchong Zhao, Xiao Tian. Epigenetic reprogramming of T cell exhaustion [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 5625.