All-trans retinoic acid-driven immune remodeling in esophageal squamous cell carcinoma revealed by single-cell transcriptomics.

Authors

Tianshuo Yang, Ying Huang, Yaxin Liu, Yuqing Wang, Xinyu Zhu, Haoyu Shi, Suli Dai, Lianmei Zhao, Lei Li

Published in

Biochimica et biophysica acta. Molecular basis of disease. Pages 168491. Oct 05, 2026. Epub Oct 05, 2026.

Abstract

Esophageal squamous cell carcinoma (ESCC) remains a highly lethal malignancy with limited durable responses to current therapies. Our previous work showed that all-trans retinoic acid (ATRA) upregulates the deubiquitinase OTUD6B and suppresses ESCC stemness. Here, we integrated in vivo pharmacological treatment, single-cell RNA sequencing, bulk RNA sequencing, immunofluorescence, flow cytometry, and OTUD6B disruption to define how ATRA remodels ESCC tumors. In a syngeneic mEC25 tumor model, ATRA inhibited tumor growth, and the ATRA-plus-anti-PD-1 group showed greater tumor inhibition than the ATRA-alone group. Single-cell profiling of ATRA- and vehicle-treated tumors identified epithelial, stromal, lymphoid, and myeloid compartments and revealed extensive immune remodeling after ATRA treatment. ATRA reduced FOXP3-associated regulatory T-cell features, attenuated M2-like macrophage polarization, and expanded a CD74-high neutrophil state. In epithelial tumor cells, ATRA-regulated genes were enriched in ubiquitination-related protein homeostasis, including protein ubiquitination, ubiquitin-dependent protein catabolism, and proteasome-mediated degradation. These findings prompted transcriptomic analysis of human ESCC cells treated with ATRA or subjected to OTUD6B silencing. ATRA treatment was negatively associated with hallmark epithelial-mesenchymal transition (EMT) enrichment, whereas OTUD6B knockdown was positively associated with EMT enrichment. Importantly, OTUD6B disruption attenuated ATRA-associated tumor suppression and abolished ATRA-induced reductions in CD25⁺FOXP3⁺ regulatory cells and F4/80⁺CD206⁺ macrophages, as well as the induction of CD74⁺ neutrophils. These data support a possible contribution of OTUD6B to ATRA responsiveness and provide a rationale for further evaluation of ATRA-based immunotherapy combinations in ESCC.

PMID:
42833561
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

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