Cobalt-mediated suppression of IFNγ-JAK-STAT1 signaling reprograms IDO1-driven immunosuppression for metalloimmunotherapy

Indoleamine 2,3-dioxygenase 1 (IDO1), an interferon-γ (IFNγ)-inducible immune checkpoint frequently upregulated in solid malignancies, catalyzes tryptophan degradation to kynurenine and establishes a metabolically immunosuppressive tumor microenvironment. Although IDO1 represents an attractive therapeutic target, strategies to modulate its activity with precision are limited.

Here we identify cobalt ions (Co2+) as potent suppressors of IFNγ-induced IDO1 expression through a systematic screen of biologically relevant metal ions. Across multiple cancer cell lines, Co2+ markedly attenuated IDO1 expression and reduced kynurenine production. Mechanistically, Co2+ disrupted IFNγ-JAK-STAT1 signaling by engaging main receptor of IFNγ, IFNGR1, promoting its destabilization and degradation, thereby constraining tumor cell-intrinsic IDO1 induction, re-established kynurenine/tryptophan metabolic homeostasis and alleviating CD8+T cell exhaustion.