N-myc downstream regulated 1 (NDRG1) is a metastasis suppressor that was found to inhibit tumour progression and metastasis in pancreatic ductal adenocarcinoma (PDAC). Our studies investigated the effect of NDRG1 on PDAC metabolism and how this influences key TME elements including tumour-associated macrophages (TAMs) and PSCs. We generated PDAC cells (MIAPaCa-2 and PANC-1) that stably overexpress NDRG1 and performed extensive metabolomic, proteomic and secretome analysis under normoxia and hypoxia. Using conditioned media or direct 3D spheroid co-cultures, we assessed the effect of PDAC cells on THP-1 and U937 monocytes using flow cytometry, Seahorse metabolic analysis, western blot and immunofluorescence analysis. Our findings indicated that NDRG1 expression profoundly altered the metabolism of cancer cells. Further, NDRG1 increased secretion of TNF-α by PDAC cells, which led to re-programming of TAMs from an anti-inflammatory M2 phenotype to a pro-inflammatory M1 phenotype and altered TAM metabolism.