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Research Article: AKNA serves as a prognostic biomarker and restrains endometrial cancer progression via STING activation and macrophage reprogramming

Date Published: 2026-10-05

Abstract:
AKNA, an AT-hook transcription factor, plays a critical role in cancer development. However, its prognostic value and biological function in endometrial cancer (EC) remain unclear. To systematically investigate AKNA in EC, we integrated multi-omics data (The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and single-cell transcriptomics), dual independent clinical cohorts (TCGA-UCEC dataset and two institutional cohorts), and in vitro / in vivo experimental models. Immunohistochemistry, RT-qPCR and Western blotting were used for expression validation. Functional assays, including lentiviral-mediated AKNA knockdown/overexpression, CCK-8, scratch-wound, Transwell, flow cytometry, and colony formation assays were conducted to assess the effects of AKNA modulation on proliferation, migration, invasion, epithelial-mesenchymal transition, chemosensitivity and macrophage polarization. Mechanistically, chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), ChIP-qPCR, and dual-luciferase reporter assays were employed to define the transcriptional regulation of stimulator of interferon genes (STING) by AKNA. A prognostic nomogram integrating AKNA expression with clinicopathological features was developed and externally validated in independent cohorts. AKNA was significantly downregulated in EC tissues compared with normal endometrium, which was associated with advanced International Federation of Gynecology and Obstetrics stage, aggressive histological subtypes, and poor prognosis. AKNA knockdown promoted EC cell proliferation, migration, invasion, and epithelial-mesenchymal transition, while enhancing M2 macrophage polarization and reducing sensitivity to paclitaxel and potentially compromising anti-tumor innate immunity. Conversely, AKNA overexpression or STING activation by cyclic GMP–AMP reversed these malignant phenotypes. Mechanistically, AKNA directly bound to the STING promoter and transcriptionally activated STING, thereby inducing TANK-binding kinase 1 and interferon regulatory factor 3 phosphorylation. The nomogram combining AKNA with clinicopathological features demonstrated high accuracy in predicting EC recurrence and outperformed single-variable models in both training and validation cohorts. AKNA deficiency promotes EC progression by transcriptionally suppressing STING and driving M2 macrophage polarization. AKNA serves as a robust prognostic biomarker and predictive indicator for chemotherapy and innate immune modulation, offering a promising therapeutic target for precision treatment of EC.

Introduction:
AKNA, an AT-hook transcription factor, plays a critical role in cancer development. However, its prognostic value and biological function in endometrial cancer (EC) remain unclear.

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