Inhibiting calreticulin palmitoylation enhances the efficacy of elesclomol-CuCl2 on oxaliplatin-triggered immunogenic cell death in pancreatic cancer.

Immunogenic cell death (ICD) is a robust strategy to reprogram immunologically "cold" pancreatic ductal adenocarcinoma (PDAC) into "hot" tumors and augment immunotherapeutic efficacy, yet clinically viable ICD-inducing regimens and their regulatory mechanisms remain elusive. Here, we sought to develop an optimized combinatorial therapy for ICD induction in PDAC and decipher its core molecular pathway. Spatial transcriptomics of human PDAC tissues revealed that elevated ICD activity in cancer lesions correlates strongly with favorable patient prognosis. In vitro and in vivo functional assays demonstrated that co-treatment with elesclomol‑CuCl₂ (ES‑CU, a potent cuproptosis inducer) and oxaliplatin (L‑OHP) synergistically suppresses PDAC cell proliferation, migration and invasion, while triggering robust reactive oxygen species (ROS)-dependent ICD. Mechanistically, this regimen inhibits calreticulin (CALR) palmitoylation at Cys137, abrogating CALR degradation via the autophagy‑lysosome pathway and facilitating its ER-to-membrane translocation to initiate ICD signaling. This potent ICD response promotes dendritic cell maturation and enhances CD8⁺T cell-mediated cytotoxicity through the TLR4/NF‑κB axis, which single-cell RNA sequencing of clinical PDAC samples supported in neoadjuvant therapy responders. Collectively, our findings identify CALR palmitoylation inhibition as a key driver of L‑OHP/ES‑CU-induced ICD, reshaping the tumor immune microenvironment to provide a promising chemo-immunotherapeutic strategy for PDAC.