Macrophages are highly abundant in the microenvironment of pancreatic ductal adenocarcinoma (PDAC), with reported roles of tumour-associated macrophages (TAMs) in chemotherapy resistance. New research now provides clues to the influence of TAMs in pancreatic cancer therapy, demonstrating that pyrimidine nucleoside release (notably deoxycytidine) from macrophages inhibits the effectiveness of gemcitabine treatment of pancreatic cancer. Macrophages programmed by PDAC cells released a spectrum of pyrimidine species, including deoxycytidine, in vitro. Crucially, deoxycytidine inhibited gemcitabine, directly competing with drug uptake and metabolism. In mouse models of PDAC, genetic or pharmacological depletion of TAMs sensitized these tumours to gemcitabine treatment.
Halbrook, C. J. et al. Macrophage-released pyrimidines inhibit gemcitabine therapy in pancreatic cancer. Cell Metab. https://doi.org/10.1016/j.cmet.2019.02.001 (2019)
About this article
Cite this article
Ray, K. Metabolite crosstalk could modulate chemotherapy response in pancreatic cancer. Nat Rev Gastroenterol Hepatol 16, 262 (2019). https://doi.org/10.1038/s41575-019-0143-9