Abstract
Metal ions are increasingly recognized as regulators of immune function, yet their application in cancer immunotherapy remains underexplored. Here, we identified cobalt ions (Co
2+
) as potent suppressors of IFN-γ–induced IDO1 expression through systematic screening of biologically relevant metal ions. Across multiple cancer cell lines, Co
2+
notably reduced IDO1 expression and kynurenine production. Mechanistically, Co
2+
destabilized IFNGR1 and inhibited IFN-γ–JAK–STAT1 signaling, thereby restoring kynurenine/tryptophan metabolic balance and alleviating immunosuppression of CD8
+
T cell. These effects reprogrammed the immunosuppressive tumor microenvironment toward enhanced cytotoxic T cell activity. To minimize the toxicity associated with free Co
2+
, we developed ConaHA, a hyaluronic acid–based nanoparticle platform enabling sustained and tumor-targeted cobalt delivery. ConaHA enhanced cobalt-mediated immune checkpoint blockade in vivo, resulting in notably improved antitumor efficacy in subcutaneous Panc02, MC38, and B16F10 tumor models and KPC (
LSL-Kras
G12D/+
;
LSL-Trp53
R172H/+
;
Pdx-1-Cre
) models. Collectively, these findings reveal a previously unrecognized immunoregulatory role of Co
2+
and establish a promising framework for metalloimmunotherapy through modulation of metal-immune signaling pathways.