Objective

Elevated indoleamine 2,3 dioxygenase (IDO) activity is a common immune checkpoint in cancer. However, why IDO activity increases in the developing tumour microenvironment (TME) is unclear. Previously, we found that cargo DNA from DNA nanoparticles (DNPs) is sensed to activate the Stimulator of Interferon Genes (STING) adaptor to stimulate type I interferon (IFN-I) production and IDO-dependent tolerogenic responses.  We hypothesized that DNA from dying cells is also sensed to activate STING/IFN-I signalling and induce IDO in the developing TME. Consistent with this paradigm, STING and IDO genes were required for optimal growth of Lewis Lung Carcinoma (LLC) in mice. In contrast, optimal growth of LLC tumours expressing neo-antigens was not STING dependent, indicating that enhanced tumour immunogenicity attenuated tolerogenic responses to DNA. Thus, immune responses to DNA and tumour immunogenicity are key factors influencing the immune balance in the TME that promotes or impedes tumour growth. These findings have important implications for understanding how to manipulate STING/IFN-I signalling and IDO activity to optimize immune and clinical responses to cancer immunotherapy. Moreover, as IDO enhances pain sensitivity due to production of neuroactive tryptophan catabolites, reducing IDO activity may also alleviate pain associated with tumour growth and some chemotherapies.