Abstract B121: Induction of Immunogenic Cell Death in Pancreatic Ductal Adenocarcinoma by a Sigma-2 Ligand–Conjugated xCT Inhibitor
David Barr, Shubham Mehta, Jack Whelchel, Hesham El-Shewy, William G. HawkinsAbstract
Purpose:
Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal and is largely resistant to current immunotherapy approaches, in part because of a profoundly immunosuppressive tumor microenvironment (TME) that limits antigen presentation and effector immune cell activity. Immunogenic cell death (ICD) is a regulated form of tumor cell death that can enhance antitumor immunity through release or surface exposure of danger-associated molecular patterns (DAMPs), including adenosine triphosphate (ATP), calreticulin, and high-mobility group box 1 (HMGB1). Therapeutic induction of ICD may therefore convert immunologically “cold” PDAC tumors into a more immune-responsive state. We evaluated whether ACXT-3102d, a sigma-2 ligand-conjugated small-molecule inhibitor of xCT (SLC7A11), induces ICD-associated responses in PDAC models.
Methods:
Human and murine PDAC models were treated with ACXT-3102d and compared with gemcitabine, a clinically relevant chemotherapeutic comparator in PDAC. ICD-associated DAMPs were assessed by measuring extracellular ATP release, HMGB1 release, and surface calreticulin exposure. Because sigma-2 ligand-mediated delivery may enable preferential targeting of proliferating tumor cells and xCT inhibition may increase oxidative and endoplasmic reticulum stress, ACXT-3102d was evaluated as a tumor-targeted strategy for inducing immunogenic stress. Exploratory in vivo immune profiling was also performed to assess treatment-associated changes in selected intratumoral immune populations within the PDAC TME.
Results:
ACXT-3102d induced multiple hallmark features of ICD in PDAC models, including extracellular ATP release, HMGB1 release, and surface calreticulin exposure. Across assays, ACXT-3102d produced ICD-associated responses that compared favorably with gemcitabine, supporting its activity as an immunogenic cell death inducer rather than solely a cytotoxic agent. Preliminary in vivo studies further demonstrated modest treatment-associated shifts in selected intratumoral immune populations, suggesting that ACXT-3102d may alter the immune composition of the PDAC TME. Together, these findings indicate that sigma-2 ligand-targeted xCT inhibition can promote DAMP-associated immunogenic stress in PDAC and may provide a mechanistic basis for combination approaches with immunotherapy.
Conclusions:
ACXT-3102d induces key ICD-associated DAMPs in PDAC models and demonstrates preliminary evidence of treatment-associated immune remodeling in vivo. These data support further investigation of ACXT-3102d as a tumor-targeted ICD inducer and as a potential strategy to enhance immune responsiveness in PDAC. Generative artificial intelligence was used to assist with abstract editing and revision; all authors are responsible for the final content.
Citation Format:
David Barr, Shubham Mehta, Jack Whelchel, Hesham El-Shewy, William G. Hawkins. Induction of Immunogenic Cell Death in Pancreatic Ductal Adenocarcinoma by a Sigma-2 Ligand–Conjugated xCT Inhibitor [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr B121.