Targeting cancer-intrinsic protein neddylation bypasses the loss of JAK/STAT signaling and overcomes acquired resistance to immunotherapy.

The loss of IFNγ signaling in cancer cells causes primary and acquired resistance to immunotherapy. Using a patient-derived JAK2-deficient melanoma cell line, we have developed a co-culture system to model acquired resistance to immunotherapy. Genome-wide genetic screens uncover that protein neddylation can be targeted to restore sensitivity to PD1 blockade in co-cultures, and in MHC-I and/or JAK/STAT-deficient murine tumors. Analysis of the Jak2-deficient murine tumors with scRNA-seq reveals a heightened cancer-intrinsic inflammatory signature when neddylation is absent, which causes an influx of stimulatory antigen presenting cells. In patients with melanoma, tumors with low cancer-intrinsic neddylation exhibit elevated IFN signatures and are associated with dendritic cell infiltration. Mechanistically, neddylation deletion stabilizes chromatin-bound cGAS in JAK2-deficient cancer cells, which is responsible for the superior response to PD1 blockade, and the recruitment of pro-inflammatory innate immune cells. Altogether, we demonstrate the broad therapeutic potential of protein neddylation in overcoming resistance to immunotherapy.