Type I interferons are evolutionally conserved cytokines, with broad antimicrobial and immunoregulatory functions. Despite well‐characterised role in spontaneous cancer immunosurveillance, the function of type I IFNs in cancer immunotherapy remains incompletely understood.

We utilised genetic mouse models to explore the role of the type I IFN system in CD8⁺ T‐cell immunotherapy targeting the melanocytic lineage antigen gp100.

The therapeutic efficacy of adoptively transferred T cells was found to depend on a functional type I IFN system in myeloid immune cells. Compromised type I IFN signalling in myeloid immune cells did not prevent expansion, tumor infiltration or effector function of melanoma‐specific Pmel‐1 CD8⁺ T cells. However, melanomas growing in globally (Ifnar1^−/−) or conditionally (Ifnar1^ΔLysM) type I IFN system‐deficient mice displayed increased myeloid infiltration, hypoxia and melanoma cell dedifferentiation. Mechanistically, hypoxia was found to induce dedifferentiation and loss of the gp100 target antigen in melanoma cells and type I IFN could directly inhibit the inflammatory activation of myeloid cells. Unexpectedly, the immunotherapy induced significant reduction in tumor blood vessel density and whereas host type I IFN system was not required for the vasculosculpting, it promoted vessel permeability.

Our results substantiate a complex and plastic phenotypic interconnection between melanoma and myeloid cells in the context of T‐cell immunotherapy. Type I IFN signalling in myeloid cells was identified as a key regulator of the balance between antitumor immunity and disease‐promoting inflammation, thus supporting the development of novel combinatorial immunotherapies targeting this immune cell compartment.