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

ABSTRACT: Metal ions are increasingly recognized as dynamic regulators of immune function, yet their systematic exploitation for cancer immunotherapy remains underexplored. 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. These effects reprogrammed the immunosuppressive niche towards enhanced cytotoxic T cell function. To mitigate the off-target toxicity and immune cell damaging associated with free Co2+, we engineered ConaHA, a hyaluronic acid-based nanoparticle platform that enables sustained cobalt release and tumor-directed delivery. ConaHA potentiated cobalt-mediated immune checkpoint blockade while improving therapeutic tolerability in vivo, which dramatically improved the antitumor efficacy in subcutaneous Panc02, MC38 and B16F10 tumor models. Collectively, these findings uncover a previously unappreciated immunoregulatory function of Co2+ and establish a conceptual framework for metalloimmunotherapy through targeted modulation of metal-immune signaling axes.

ORGANISM(S): Mus musculus

PROVIDER: GSE332993 | GEO | 2026/09/23

REPOSITORIES: GEO

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Project description:Many tumors escape by activating multiple cellular pathways that induce immunosuppression. One pivotal immune-suppressive mechanism is the production of tryptophan metabolites along the kynurenine pathway by IFNγ-induced IDO1 enzyme production 4-8. Phase III clinical trials using chemical inhibition of IDO1 in combination with PD1 pathway blockade, however, failed to improve melanoma treatment 9-12. This points at an incomplete understanding of the role of IDO1 and the consequent tryptophan degradation on mRNA translation and cancer progression. Here, we investigated the effects of prolonged IFNγ treatment on mRNA translation in melanoma cells by ribosome profiling. Surprisingly, we observed a massive accumulation of ribosomes ~20 amino acids downstream of tryptophan codons (termed here as W-Bumps) along with their expected stalling at the tryptophan codon itself. This indicated ribosomal bypass of the tryptophan codons in the absence of tryptophan. Detailed examination of W-Bumps position and its corresponding peptide sequences pinpointed towards ribosomal frameshifting events and their effects in the ribosome exit tunnel. In particular, W-Bumps strength was associated with the disorderedness level of potential out-of-frame peptides predicted downstream of tryptophan codons. Indeed, reporter assays demonstrated the induction of ribosomal frameshifting, and the generation of trans-frame proteins and their presentation at the cell surface after IFNγ treatment. Proteomics and immunopeptidomics analyses verified the production of IFNγ-induced trans-frame and out-of-frame aberrant peptides and their presentation on HLA class I molecules. Priming of naïve T cells from healthy donors with aberrant peptides resulted in identification of reactive, peptide-specific T cells. Altogether, our results suggest that IFNγ-induced IDO1-mediated tryptophan depletion plays a role in the immune recognition of melanoma cells by contributing to the diversity of the peptidome landscape, and by inducing the presentation of aberrant peptides.

Project description:Understanding the mechanisms of host macrophage responses to M. tuberculosis (M.tb.) is essential for uncovering potential avenues of intervention to boost host resistance to infection. Macrophage transcriptome profiling revealed M.tb. infection strongly induced expression of several enzymes controlling tryptophan (Trp) catabolism. This included indole 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2), which catalyze the rate-limiting step in the kynurenine pathway, producing ligands for the aryl hydrocarbon receptor (AHR). The AHR and heterodimeric partners AHR nuclear translocator (ARNT) and RELB are robustly expressed, and AHR and RELB levels further increased during infection. Infection enhanced AHR/ARNT and AHR/RELB DNA binding, and stimulated expression of AHR target genes, including that encoding the inflammatory cytokine IL1beta. AHR target gene expression was further enhanced by exogenous kynurenine, and exogenous Trp, kynurenine or synthetic agonist indirubin reduced mycobacterial viability. Comparative expression profiling revealed that AHR ablation diminished expression of numerous genes implicated in innate immune responses, including several cytokines. Notably, AHR depletion reduced expression of IL23A and IL12B transcripts, which encode subunits of interleukin 23 (IL23), a macrophage cytokine that stimulates production of IL22 by innate lymphoid cells. The AHR directly induced IL23A transcription in human and mouse macrophages through near-upstream enhancer regions. Taken together, these findings show that AHR signaling is strongly engaged in Mtb-infected macrophages, and has widespread effects on innate immune responses. Moreover, they reveal a cascade of AHR-driven innate immune signaling, as IL1B (IL-1β) and IL23 stimulate T cell subsets producing IL22, another direct target of AHR transactivation. Gene expression profiling of Mtb-infected THP-1 monocytic cells following siRNA-mediated Aryl hydrocarbon receptor (AHR) knockdown.

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

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