Loss of optineurin drives cancer immune evasion via palmitoylation-dependent IFNGR1 lysosomal sorting and degradation.

Mutations in IFN- and MHC-signaling genes endow immunotherapy resistance. Colorectal cancer patients infrequently exhibit IFN- and MHC-signaling gene mutations, and are generally resistant to immunotherapy. In exploring the integrity of the IFN- and MHC-signaling in colorectal cancer, we found that optineurin was a shared node between the two pathways, and predicted colorectal cancer patient outcome. Loss of optineurin occurred in early stage human colorectal cancer. Immunologically, optineurin deficiency attenuated IFNGR1 and MHC-I expression, impaired T cell-immunity, and diminished immunotherapy efficacy in murine cancer models and cancer patients. Mechanistically, IFNGR1 was S-palmitoylated on Cys122, and AP3D1 bound with and sorted palmitoylated-IFNGR1 to lysosome for degradation. Unexpectedly, optineurin interacted with AP3D1 to prevent palmitoylated-IFNGR1 lysosomal sorting and degradation - thereby maintaining IFNy- and MHC-I-signaling integrity. Furthermore, pharmacologically targeting IFNGR1-palmitoylation stabilized IFNGR1, augmented tumor immunity, and sensitized checkpoint therapy. Thus, loss of optineurin drives immune evasion and intrinsic immunotherapy resistance in colorectal cancer.