TGFβ blocks STING-induced IFNα/ β release and tumor rejection in spontaneous mammary tumors

Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA can induce a strong production of IFN and the rejection of transplanted primary tumors. In the present study, we addressed whether targeting STING with DMXAA leads to the regression of spontaneous MMTV-PyMT (Spont-PyMT) mammary tumors. We show that these tumors are refractory to DMXAA-induced regression. This is due to a blockade in the phosphorylation of IRF3 and the ensuing IFNα/β production. Our study identified TGFβ abundant in spontaneous tumors, as a key molecule limiting DMXAA-induced tumor regression: blocking TGFβ promoted infiltration of Spont-PyMT tumors by activated MHCII+ tumor-associated macrophages, restored the production of IFNα following STING activation, and increased the probability of tumor regression. Based on these findings, we propose that type I IFN-dependent cancer therapies may be greatly improved by combinations including the blockade of TGFβ.