Abstract A101: Targeting ATF4 reshapes PDAC’s tumor microenvironment to enhance CAR T-cell anti-tumor efficacy

Abstract Activating Transcription Factor 4 (ATF4) is a key mediator of the Integrated Stress Response (ISR), a conserved cellular pathway that enables survival under stressful conditions. In pancreatic ductal adenocarcinoma (PDAC), the hypoxic and nutrient-deprived tumor microenvironment (TME) promotes ISR activation, supporting tumor cell adaptation and survival. Concurrently, PDAC’s desmoplastic and immunosuppressive TME limits the infiltration and efficacy of mesothelin-directed CAR T cells. Using conditional ATF4 knockout mice, we demonstrate that global ATF4 deletion, in combination with mesothelin-CAR T cell therapy, significantly delays tumor progression in syngeneic PDAC models. Flow cytometry revealed reduced frequencies of immunosuppressive cell populations—including myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs)—in ATF4-deficient tumors. Moreover, both CAR T cells and endogenous CD8+ T cells exhibited enhanced cytotoxicity and reduced exhaustion in the absence of ATF4. Pharmacologic inhibition of ISR with ISRIB recapitulated these effects, leading to slower tumor growth and improved CAR T cell responses. These findings suggest that targeting ATF4 can remodel the PDAC TME and significantly enhance CAR T cell–mediated anti-tumor immunity. Citation Format: Nektarios Kostopoulos, Tej Patel, Rohan Ganesh, Frank Chinga, Costantinos Koumenis. Targeting ATF4 reshapes PDAC’s tumor microenvironment to enhance CAR T-cell anti-tumor efficacy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A101.