Frontiers in immunology · 2026
Targeting the AHR-IDO1-kynurenine pathway in TREM2+ macrophages restores antitumor immunity in thyroid cancer.
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Le Fei, Huang Xianming, Jiang Youfang, Lv Saiping, Chen Yaoyao
Аннотация
INTRODUCTION: Advances in single-cell technologies have provided detailed insight into cellular heterogeneity within tumor microenvironments. However, the regulatory mechanisms driving macrophage-mediated immune suppression in thyroid cancer remain incompletely understood.
METHODS: We applied integrated single-cell multi-omics approaches to tumor samples from patients and murine thyroid cancer models, including single-cell RNA sequencing, single-cell ATAC sequencing, mass cytometry, spatial/histological validation, and in vitro and in vivo functional assays.
RESULTS: We identified a prominent enrichment of TREM2+ tumor-associated macrophages within the thyroid cancer immune microenvironment. These macrophages displayed an immunosuppressive transcriptional and metabolic profile and promoted immune evasion through activation of the AHR-IDO1-kynurenine signaling axis, leading to impaired CD8+ T-cell function. Pharmacological inhibition of AHR and IDO1 reversed immune suppression and reduced tumor burden in experimental models.
DISCUSSION: These findings reveal a TREM2+ macrophage-driven immunometabolic mechanism in thyroid cancer and suggest that targeting the AHR-IDO1-kynurenine pathway may provide a potential strategy for improving antitumor immunity.
METHODS: We applied integrated single-cell multi-omics approaches to tumor samples from patients and murine thyroid cancer models, including single-cell RNA sequencing, single-cell ATAC sequencing, mass cytometry, spatial/histological validation, and in vitro and in vivo functional assays.
RESULTS: We identified a prominent enrichment of TREM2+ tumor-associated macrophages within the thyroid cancer immune microenvironment. These macrophages displayed an immunosuppressive transcriptional and metabolic profile and promoted immune evasion through activation of the AHR-IDO1-kynurenine signaling axis, leading to impaired CD8+ T-cell function. Pharmacological inhibition of AHR and IDO1 reversed immune suppression and reduced tumor burden in experimental models.
DISCUSSION: These findings reveal a TREM2+ macrophage-driven immunometabolic mechanism in thyroid cancer and suggest that targeting the AHR-IDO1-kynurenine pathway may provide a potential strategy for improving antitumor immunity.