ArticleResearch square2026
Targeting cancer-intrinsic protein neddylation bypasses the loss of JAK/STAT signaling and overcomes acquired resistance to immunotherapy.
Article in Research square, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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.
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