Integrated transcriptomics reveal CTHRC1-associated immune resistance and JAM2– F11R–STAT1 macrophage remodeling in anaplastic thyroid carcinoma

Background Anaplastic thyroid carcinoma (ATC) is a rare but highly lethal thyroid malignancy. Immune checkpoint blockade (ICB) has shown therapeutic activity in ATC, but responses remain limited and heterogeneous. The immune microenvironment underlying ICB resistance in ATC remains incompletely characterized, highlighting the need to identify biologically relevant biomarkers and therapeutic vulnerabilities. Methods We integrated multiple ATC bulk transcriptomic cohorts with single-cell and spatial transcriptomic datasets and two pretreatment ICB cohorts. Candidate genes were prioritized across ATC progression and ICB nonresponse, followed by single-cell and spatial characterization, myeloid state reconstruction, ligand–receptor analysis, and in silico perturbation. Results Integrated analysis prioritized CTHRC1 as a candidate linking ATC progression with ICB nonresponse and confirmed its consistent upregulation in ATC. Single-cell analysis localized CTHRC1 mainly to malignant epithelial, fibroblast/CAF, and endothelial compartments and showed that CTHRC1-positive malignant cells exhibited a broader resistance-associated transcriptional state. Spatial analysis identified focal CTHRC1-high immune resistance niches containing CAF, M2-like macrophage, CD8/cytotoxic, and T-cell exhaustion signals. Myeloid analysis revealed a reproducible S100A12-positive monocyte–SPP1-positive TAM–ADAMDEC1-associated macrophage continuum, with STAT1 as the leading transition-associated regulator. Receiver state-guided communication analysis prioritized JAM2–F11R as the top malignant-to-myeloid interaction, supported by F11R/STAT1 perturbation, independent single-cell replication, and spatial coupling. The integrated CTHRC1-related feature was associated with ICB nonresponse, while virtual CTHRC1 knockout predicted reductions in multiple resistance-related programs. Conclusions The CTHRC1-associated immune resistance niche is linked to ICB nonresponse in ATC, while JAM2–F11R–STAT1 may contribute to ADAMDEC1-associated macrophage state remodeling, suggesting CTHRC1 as a potential therapeutic target to improve immunotherapy responsiveness in ATC.