ABSTRACT Type I interferons (IFN1, including IFNα and IFNβ) are critical regulators of intestinal epithelial cells proliferation and of anti-tumor immune responses. Accordingly, pharmacologic IFN1 were used in treatment of colorectal cancer (CRC) alone or combined with the 5-fluorouracil (5FU)- based chemotherapy. However, these approaches yielded underwhelming results indicating that the endogenous pathway mediating IFN1 effects is somehow inactivated in CRC. Importantly, all effects of endogenous or pharmacologic IFN1 require the IFNAR1 receptor chain, which is also essential for the efficacy of the anti-cancer treatment regimens including radio- and chemotherapies. Intriguingly, we recently found that the IFN1-IFNAR1 is indeed inactivated in CRC. Our recently published data demonstrate that (a) IFNAR1 undergoes ubiquitination and rapid degradation in response to tumor microenvironment factors such as tumor-derived vesicles, (b) IFNAR1 is often downregulated in malignant and benign tumor cells in human CRC, and (c) low levels of IFNAR1 correlates with poor survival of CRC patients who received standard chemotherapies. Our additional pilot experiments were then focused on ability to overcome the loss of IFNAR1 to restore the efficacy of chemotherapy. Data from these experiments showed a promise for reactivation of the IFN1-IFNAR1 pathway using several approaches. These include a novel and exciting small molecule sumoylation inhibitor TAK981, as well as reserpine, a hypotensive drug preventing the effects of tumor-derived vesicles. In addition, exciting results are obtained using a novel and unique mutant recombinant IFN1 (sIFN-I) that exhibits an increased affinity to IFNAR1 and can act even at low IFNAR1 density. These recently published and pilot data provide a firm support for an overarching hypothesis that the loss of IFNAR1 in CRC undermines its treatment and, conversely, reactivation of the IFN1 pathway will increase the efficacy of CRC chemotherapy. To test this hypothesis, we propose to (i) determine the importance of IFNAR1 loss in responses of colorectal adenocarcinomas to 5-FU-containing regimen (FOLFOX) with or without novel sIFN-I; (ii) reactivate the IFN1-IFNAR1 pathway using a novel sumoylation inhibitor TAK981 to increase the efficacy of chemotherapy; and (iii) prevent the loss of IFNAR1 by interfering with the effect of tumor-derived vesicles using reserpine to increase the efficacy of FOLFOX. Completion of these studies should reveal a novel role of inactivation of IFNAR1 in the sub-optimal efficacy of CRC therapy and to overcome this problem through using the means to reactivate the IFN1-IFNAR1 pathway.