Cobalt-mediated suppression of IFN-γ-JAK-STAT1 signaling reprograms IDO1-driven immunosuppression for...

Metal ions are increasingly recognized as regulators of immune function, yet their application in cancer immunotherapy remains underexplored. Here, we identified cobalt ions (Co²⁺) as potent suppressors of IFN-γ-induced IDO1 expression through systematic screening of biologically relevant metal ions. Across multiple cancer cell lines, Co²⁺ notably reduced IDO1 expression and kynurenine production. Mechanistically, Co²⁺ 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 Co²⁺, 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 Co²⁺ and establish a promising framework for metalloimmunotherapy through modulation of metal-immune signaling pathways.