Trogocytosis-orchestrated CLDN18.2-“dressed” CD8 + T cells drive pancreatic cancer progression via glucose metabolic reprogramming-induced cytotoxicity debilitation and systematic immune senescence cascade

Background As it is a tumour-associated antigen in epithelial cells, research on claudin18.2 (CLDN18.2) has focused on its role as a therapeutic target in pancreatic cancers and its part in maintaining tight junctions. Objective We elucidate the role of trogocytosis-related CLDN18.2 in CD8 + T cells and pancreatic ductal adenocarcinoma (PDAC) progression. Design We constructed humanised hCD34 + , Trp53 R172H Kras G12D Pdx1-cre (KPC), Cldn18.2 knockout (KO), and patient-derived xenograft/organoid mouse models. Flow cytometry, immunofluorescence, single-cell RNA-sequencing and immunoprecipitation-mass spectrometry (IP-MS) were performed. Results CLDN18.2 + CD8 + T cells indicated poor pancreatic cancer prognosis and immunotherapeutic resistance. CD8 + T cells acquired CLDN18.2 from tumour cells via trogocytosis, inhibiting their activation and cytotoxicity. “Dressed” CLDN18.2 suppressed glucose uptake, glycolysis and cytotoxicity of tumour-infiltrating CD8 + T cells. Mechanically, trogocytosis-related CLDN18.2 induced GSK3β/CK1α-mediated β-catenin phosphorylation, promoting β-catenin ubiquitination and proteasome degradation in CD8 + T cells. CLDN18.2 interacted with β-catenin’s N-terminal domain via its C-terminal domain, further strengthening the interaction between β-catenin and CK1α. Moreover, CLDN18.2 + CD8 + T cells preferentially ‘homed’ to the bone marrow through the CXCL12/CXCR4 axis, skewed haematopoietic stem cell myeloid differentiation and induced systemic immune senescence via IL1α. Notably, preclinical mouse studies showed PC18.1 peptide sensitised immunotherapy and suppressed PDAC progression by disrupting the CLDN18.2/β-catenin interaction in CD8 + T cells. Conclusions Trogocytosis-related CLDN18.2 inhibited the glucose uptake, glycolysis and cytotoxicity of tumour-infiltrating CD8 + T cells by promoting the ubiquitin-proteasomal degradation of β-catenin in PDAC. Therefore, targeting trogocytosis-related CLDN18.2 + CD8 + T cells may be a promising therapeutic strategy to inhibit PDAC progression.