SLC6A14-mediated carnitine transmembrane uptake from PPARγ + cancer-associated fibroblasts promotes recurrence of pancreatic cancer

Background Postoperative recurrence is a major contributor to the dismal prognosis of patients with pancreatic cancer (PC). Defining the molecular features of PC with recurrence is crucial for the development of effective therapeutic strategies. Objective This study aims to identify metabolic and intrinsic metabolism of PC associated with early recurrence. Designs We analysed resected primary tumours from patients with PC with early (E-Rec) and late (L-Rec) recurrence using an integrated multiomics workflow and spatial metabolomics. Multiplex immunofluorescence quantified carnitine shuttle system (CSS) heterogeneity, and functional in vitro assays alongside in vivo models evaluated pharmacological inhibition of carnitine transport in combination with chemotherapy or immunotherapy. Results Multiomics analysis revealed SLC6A14 was a key CSS-related gene driving early recurrence of PC. Spatial metabolomics showed elevated carnitine levels in cancer-associated fibroblasts (CAFs) from L-Rec and in tumour cells from E-Rec. Mechanistically, cancer cells used carnitine secreted from PPARγ + CAFs via SLC6A14 uptake, activating the AMPK/PPARα/CPT1B signalling cascade to enhance fatty acid β-oxidation. In vivo experiments demonstrated that pharmacological inhibition of carnitine transport by meldonium, tetrahydropalmatine or quinidine suppressed tumour growth and sensitised tumours to chemotherapy and immunotherapy. Conclusions PC cells exploit carnitine secreted by PPARγ + CAFs via SLC6A14-mediated uptake to promote tumour recurrence. Targeting the CSS, particularly in combination with chemotherapy or immunotherapy, represents a promising avenue for mitigating recurrence in PC.