A Multi-omics Investigation Identifies TACC3 as a Driver of Immunosuppression in Intrahepatic Cholangiocarcinoma via Activation of the STAT3-PD-L1 Axis
image: A TACC3-STAT3-PD-L1 axis driving immunosuppression in ICC. TACC3 fosters an immunosuppressive TME by upregulating PD-L1 and is associated with a Treg-rich contexture, suggesting that TACC3 may serve as a potential therapeutic target to overcome ICC immunosuppression.
Credit: Rui Liao, Xiaoyong Luo
Background and Aims
The immunosuppressive tumor microenvironment (TME) limits immunotherapy efficacy in intrahepatic cholangiocarcinoma (ICC). Understanding the molecular drivers of this TME is essential for developing new therapies. This study aimed to identify novel oncogenes that modulate the immune landscape of ICC using a multi-omics approach.
Methods
We integrated transcriptomic and proteomic data from our ICC cohorts with public datasets (TCGA-CHOL, GSE107943, OEP002768) to identify genes co-upregulated with PD-L1 (CD274). Single-cell RNA sequencing (scRNA-seq) was used to analyze cell-type-specific expression and intercellular communication. Clinical significance was validated through tissue microarrays and multiplex immunofluorescence in an independent ICC cohort.
Results
Multi-omics screening identified TACC3 as a key candidate in ICC. Elevated TACC3 expression in ICC tissues correlated with poor prognosis and promoted tumor cell proliferation and migration. TACC3 activated the STAT3 pathway, increasing PD-L1 transcription. scRNA-seq showed TACC3/PD-L1 interaction in malignant epithelial cells, with PD-L1 co-expressed with FOXP3 in regulatory T cells (Tregs). Cell–cell communication analysis predicted strong interactions between malignant cells and Tregs. TACC3 knockdown reduced PD-L1 expression and inhibited STAT3 and AKT phosphorylation. Clinical validation confirmed co-expression of TACC3, PD-L1, and FOXP3, with high TACC3 levels linked to worse clinicopathological features and shorter progression-free survival.
Conclusions
Our work unveils a novel oncogenic-immune regulatory pathway in ICC, driven by TACC3. We establish that TACC3 promotes tumor progression not only by enhancing cell proliferation and migration but also by activating STAT3 to upregulate PD-L1, thereby sculpting an immunosuppressive TME characterized by Treg infiltration. These findings provide a crucial mechanistic understanding of immune evasion in ICC and position TACC3 as a promising and previously unexplored therapeutic target. Combinatorial strategies targeting TACC3, along with immune checkpoints, may represent a viable approach to reverse immunosuppression and improve outcomes for patients with this lethal malignancy.
Full text
https://www.xiahepublishing.com/2310-8819/JCTH-2025-00616
The study was recently published in the Journal of Clinical and Translational Hepatology.
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