Tumors arise despite anti-tumorigenic activities of endogenous type I interferons (IFN1) directed at malignant cells and tumor stroma to suppress proliferation/viability, inhibit angiogenesis and stimulate anti-tumor immunity. Furthermore, therapies using pharmaceutical IFN1 are largely inefficient. These phenomena points to a reduced responsiveness of cancer cells or non-malignant tumor cells to IFN1. Here we describe that diverse stress stimuli characteristic of tumor microenvironment (i.e. hypoxia and amino acid deficit), trigger activation of the stress-activated p38 kinase leading to ubiquitin-dependent down-regulation of IFNAR1 chain of IFN1 receptor and desensitization of tumor cells to the anti-tumorigenic effects of IFNs in vitro. Given that IFNAR1 levels are decreased in some clinical cancers, we hypothesize that IFNAR1 downregulation in different tumor compartments (malignant cells, endothelial cells, tumor-associated fibroblasts or infiltrating immune cells) may promote tumor progression. We sought to test this hypothesis in malignant cells by preventing IFNAR1 downregulation via expressing an ubiquitination-deficient IFNAR1S526A mutant. Colon adenocarcinoma MC38 cells that stably express red fluorescent protein were transduced with lentiviruses encoding EGFP with or without IFNAR1S526A and subcutaneously injected into syngeneic C57Bl6 mice. While all tumors of the same size exhibited a gradual loss of double positive RFP+/GFP+ cells, we found that the loss of GFP expression in RFP-positive cancer cells was much more pronounced in cells that received IFNAR1S526A (80±4% loss) than in those that received GFP only (60±1% loss). This result indicates that inability to downregulate IFNAR1 confers a survival and selective disadvantage in cancer cells and is suggestive of a role for IFNAR1 downregulation in cancer cells in tumor growth and progression. While the role of IFNAR1 downregulation in the tumor stromal components is yet to be investigated, we propose that prevention of IFNAR1 downregulation in tumors may increase the effectiveness of the IFN1-based therapies.