Abstract 1566: Genetic and pharmacologic targeting of host ATF4 sensitizes pancreatic ductal adenocarcinoma to CAR T and immune checkpoint blockade

Abstract Activating Transcription Factor 4 (ATF4) is a central mediator of the Integrated Stress Response (ISR), a conserved adaptive pathway activated under conditions of nutrient deprivation, hypoxia, and oxidative stress. In pancreatic ductal adenocarcinoma (PDAC), this pathway supports tumor survival and contributes to the establishment of an immunosuppressive tumor microenvironment (TME). Here, we demonstrate that global ATF4 deletion in the host - affecting the non-tumor, non-CAR T compartments - in combination with mesothelin-CAR T cell therapy, significantly delays tumor progression in syngeneic PDAC models. ATF4 loss in the host was associated with reduced numbers of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), alongside enhanced cytotoxicity and reduced exhaustion in both meso-CAR T and endogenous CD8+ T cells. Spatial metabolomic profiling revealed that ATF4-deficient tumors exhibit focal oxidative stress and depletion of key amino acids, including leucine, suggesting impaired metabolic adaptability that may hinder Treg and MDSC maintenance. Preliminary in vitro differentiation assays further showed that ATF4 loss or pharmacologic ISR inhibition with ISRIB impaired Treg polarization under amino acid-limiting conditions, indicating a metabolic link between ATF4 activity and Treg stability. Importantly, in vivo ISRIB treatment recapitulated the host ATF4-knock out effects, leading to slower tumor growth and improved CAR T cell responses. Finally, combinatorial experiments with anti-PD-1 and anti-CTLA-4 therapy revealed enhanced tumor control in ATF4-KO mice, suggesting that targeting the ISR can sensitize PDAC to immune checkpoint blockade. Collectively, these findings identify ATF4 as a key regulator of PDAC immune evasion and establish ISR inhibition as a promising strategy to enhance both CAR T-cell and checkpoint immunotherapy efficacy in pancreatic cancer. Citation Format: Nektarios Kostopoulos, Rohan Ganesh, Tej Patel, Frank Chinga, Dan Boehmler, Arjun Sengupta, Aalim Weljie, Costa Koumeis, . Genetic and pharmacologic targeting of host ATF4 sensitizes pancreatic ductal adenocarcinoma to CAR T and immune checkpoint blockade [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 1566.