---
title: "AKNA as a Prognostic Biomarker in Endometrial Cancer: STING Activation and Macrophage Reprogramming"
id: "frontiers-in-immunology-19-akna-serves-as-a-prognostic-biomarker-and-restrains-endometrial-cancer"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-19-akna-serves-as-a-prognostic-biomarker-and-restrains-endometrial-cancer"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1905624"
published_at: "2026-10-05T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# AKNA as a Prognostic Biomarker in Endometrial Cancer: STING Activation and Macrophage Reprogramming
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-19-akna-serves-as-a-prognostic-biomarker-and-restrains-endometrial-cancer
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1905624)
- **Published At:** 2026-10-05T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source indicates an original research article in Frontiers in Immunology titled that **AKNA** serves as a prognostic biomarker and restrains **endometrial cancer** progression via **STING activation** and **macrophage reprogramming**. - The available source text contains site navigation, journal sections, and the article title only; methodological details, datasets, experimental results, statistical findings, author list, and specific conclusions were not provided in the source text. - From the title alone, the study likely links AKNA expression or function to cancer prognosis and to modulation of innate immune signaling through the **STING** pathway and changes in macrophage phenotype, but the source does not report the evidence supporting these claims. - No quantitative measures (e.g., hazard ratios, sample sizes, p-values), experimental models (cell lines, animal models, human tissue), or interventions are present in the source text. - The source lists Frontiers in Immunology journal sections relevant to the work, such as Cancer Immunity and Immunotherapy and Dendritic Cells, Macrophages and APC Immunology, indicating the article's thematic placement, but not its content. - Because substantive content is missing, clinical interpretation, recommendations, and translational implications cannot be reliably derived from the provided source and should not be assumed without access to the full article. - Readers are advised to consult the full Frontiers in Immunology article for methods, results, and validated clinical conclusions; those details were not reported in the supplied source text.
## Clinical Analysis & Structured Key Points
Frontiers | AKNA serves as a prognostic biomarker and restrains endometrial cancer progression via STING activation and macrophage reprogramming ORIGINAL RESEARCH article Front. Immunol. , 05 October 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1905624 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Editor & Reviewers Edited by G C Gaia Codolo Reviewed by J P Jingyuan Pei Q Z Qinglin Zhang Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Figure 5 View in article Figure 6 View in article Figure 7 View in article Figure 8 View in article ORIGINAL RESEARCH article Front. Immunol. , 05 October 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1905624 AKNA serves as a prognostic biomarker and restrains endometrial cancer progression via STING activation and macrophage reprogramming Y T Yuan Tu 1 † L X Lingya Xu 2 † C T Chengfan Tian 1 Y S Yuanling Shi 3 J Y Jiaxin Yu 1 C G Chunxia Gong 4 T P Tianyu Peng 1 H Y HangKun Yu 1 R Y Rui Yuan 1 ‡ * P J Peng Jiang 1 ‡ * 1. Chongqing Key Laboratory of Maternal and Fetal Medicine, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China 2. Department of Gynecology, Chongqing University Qianjiang Hospital (Qianjiang Central Hospital of Chongqing), Chongqing, China 3. International Medical College, Chongqing Medical University, Chongqing, China 4. Department of Obstetrics and Gynecology, Women and Children’s Hospital of Chongqing Medical University, Chongqing, China See more Article metrics View details Abstract Background: 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. Methods: 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. Results: 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. Conclusions: 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. 1 Introduction Endometrial cancer (EC) is the most common gynecological malignancy in developed countries, with incidence rising substantially over recent decades. The 2022 Global Cancer Statistics reported approximately 420,242 new cases and 97,704 deaths worldwide annually ( 1 ). Most patients are diagnosed at an early stage and have a favorable prognosis ( 2 ). However, approximately 15% of patients present with advanced disease. Five-year overall survival (OS) rates vary markedly by stage, from 40-65% for International Federation of Gynecology and Obstetrics (FIGO) stage III to only 15-17% for stage IV. Treatment options for advanced or recurrent EC remain limited ( 3 ). Although immunotherapy benefits a subset of patients, objective response rates to checkpoint inhibitors are generally modest ( 4 , 5 ). Therefore, novel biomarkers are urgently needed to improve prognostic stratification and guide therapeutic decisions in EC. AKNA, a member of the AT-hook transcription factor family, has been reported to regulate diverse biological processes, including transcriptional regulation, immune response and cancer pathogenesis ( 6 ). Emerging evidence suggests that AKNA plays critical roles in multiple malignancies. In cervical cancer, AKNA single-nucleotide polymorphisms have been linked to cancer susceptibility, and human papillomavirus E6 downregulates AKNA expression to promote tumor progression ( 7 , 8 ). In epithelial ovarian cancer, AKNA genetic variants confer susceptibility ( 9 ). Camargo et al. demonstrated that AKNA regulates epithelial-mesenchymal transition (EMT) during neurogenesis ( 10 ). In gastric cancer, AKNA acts as a tumor suppressor, likely by modulating EMT-associated signaling pathways ( 11 ). Collectively, these findings support a tumor-suppressive role for AKNA, and targeting AKNA may represent a promising strategy. Nevertheless, the prognostic significance and molecular mechanisms of AKNA in EC remain elusive. This study aims to explore the prognostic significance and functional role of AKNA in EC. Our results indicate that AKNA functions as both a prognostic indicator and a tumor suppressor. Through activation of the stimulator of interferon genes (STING) pathway, AKNA promotes macrophage polarization toward an anti-tumor phenotype, thereby suppressing tumor progression. Furthermore, we established a nomogram integrating AKNA expression with clinicopathological features. This model identifies high-risk EC patients and facilitates personalized therapeutic decision-making. 2 Materials and methods 2.1 Data resources and bioinformatics analysis of AKNA Transcriptomic and clinical data were retrieved from The Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA-UCEC) cohort, supplemented with normal controls (35 normal samples from TCGA and 142 normal endometrial samples from GTEx v8). Differential expression of AKNA between tumor and normal tissues was evaluated using the Wilcoxon rank-sum test. The Kruskal-Wallis test was performed to assess AKNA expression stratified across FIGO stages and histological grades. Associations between AKNA expression and molecular subtypes were analyzed using TISIDB ( 12 ). Protein expression data from the Clinical Proteomic Tumor Analysis Consortium were retrieved via the UALCAN database ( 13 ). Bioinformatics resources are summarized in Supplementary Table 1 . 2.2 Analysis of survival outcomes, functional enrichment, and immune infiltration Survival outcomes were analyzed using Kaplan-Meier method for both OS and recurrence-free survival (RFS). Patients were stratified according to an optimal AKNA expression cutoff determined in the TCGA-UCEC cohort, and intergroup differences were assessed using the log-rank test ( 14 ). Protein-protein interaction networks were generated using GeneMANIA and STRING ( 15 , 16 ). Genes co-expressed with AKNA, along with their Pearson correlation coefficients, were retrieved from the cBioPortal co-expression module ( 17 ). Functional annotation was performed using Gene Set Enrichment Analysis (GSEA), with significance thresholds of P 10%, a third pathologist adjudicated. To ensure methodological harmonization across the two cohorts, a fixed H-score cutoff of ≥ 2.5, which corresponds to the natural midpoint of the semiquantitative scale and was established and externally validated in our previous study ( 23 ), was employed to define high expression. Quantification of CD86 + /CD206 + macrophages was performed according to published protocols ( 24 ). 2.6 Western blotting Western blotting was performed as previously described ( 24 ). Primary antibodies were as follows: AKNA (1:1000, 23785-1-AP, Proteintech, China), Ki-67 (1:500, sc-23900, Santa Cruz Biotechnology, USA), N-cadherin (1:10000, 82968-1-RR, Proteintech, China), E-cadherin (1:50000, 20874-1-AP, Proteintech, China), vimentin (1:20000, 80232-1-RR, Proteintech, China), cyclic GMP–AMP synthase (cGAS) (1:1000, PQA3430, Abmart, China), STING (1:50000, 19851-1-AP, Proteintech, China), phospho-STING (p-STING, 1:1000, PA5-105674, Thermo Fisher, USA), TANK-binding kinase 1 (TBK1) (1:1000, 28397-1-AP, Proteintech, China), phospho-TBK1 (p-TBK1, 1:2500, 61294, GenuIN, China), interferon regulatory factor 3 (IRF3) (1:2500, 61219, GenuIN, China), phospho-IRF3 (p-IRF3, 1:2000, 29528-1-AP, Proteintech, China), and GAPDH (1:50000, 60004-1-Ig, Proteintech, China). 2.7 Reverse transcription quantitative PCR (RT-qPCR) Total RNA was extracted using the RNeasy Mini Kit (Qiagen, Hilden, Germany), and RNA concentration and purity were assessed spectrophotometrically. cDNA synthesis was performed using RT Master Mix (MedChemExpress, USA). RT-qPCR was performed on a Bio-Rad CFX96 system using SYBR Green PCR master mix, with GAPDH as the internal reference gene ( 24 ). Primer sequences were provided in Supplementary Table 2 . 2.8 Cell culture The human EC cell lines HEC-1A and Ishikawa, and the human monocytic leukemia cell line THP-1, were purchased from the Chinese Academy of Sciences Cell Bank. HEC-1A and Ishikawa cells were cultured in DMEM, high glucose (Gibco, USA) supplemented with 10% fetal bovine serum (FBS, Lonsera, China). THP-1 cells were maintained in RPMI 1640 (Gibco, USA) supplemented with 10% FBS and 50 μM β-mercaptoethanol. All cells were cultured at 37 °C in a humidified 5% CO 2 atmosphere in a Thermo Scientific CO 2 incubator, and the medium was changed every 2–3 days. 2.9 Lentiviral transfection Lentiviral vectors for AKNA knockdown, AKNA overexpression (oeAKNA), and STING overexpression (oeSTING) were purchased from Genechem (China). HEC-1A and Ishikawa cells were plated in six-well plates and incubated for 24 h until they reached ~30% confluency. Transduction was performed at manufacturer-specified multiplicities of infection (20 for Ishikawa and 10 for HEC-1A) using the HitransG™ A enhancer. After replacement of the supernatant with fresh high-glucose DMEM supplemented with 10% FBS, stable pools were selected with 2 μg/mL puromycin for 14 days. Knockdown and overexpression efficiencies were validated by RT-qPCR and western blotting. The shRNA sequences were as follows: shAKNA-1, 5’-GCTCAGAAACAAGCAGAGTTT-3’; shAKNA-2, 5’-CCAATACACAGGCCACGAATA-3’. 2.10 Cell migration, invasion and proliferation assays Cell migration was assessed using Transwell and scratch-wound assays. Transwell migration and invasion assays were performed using 8.0 μm pore-size chambers (Biosharp, China). For invasion assays, chamber membranes were pre-coated with Matrigel (BD Biosciences, USA) and incubated at 37°C for 1 h, whereas uncoated membranes were used for migration assays. HEC-1A and Ishikawa cells (6 × 10 4 ) in serum-free medium were seeded into the upper chambers, and the lower chambers were filled with medium supplemented with 20% FBS. After incubation for 48 h, non-migratory cells on the upper surface were removed. Cells that had migrated to or invaded the lower surface were fixed with 4% paraformaldehyde and stained with 0.5% crystal violet. For the scratch-wound assay, HEC-1A and Ishikawa cells were seeded in six-well plates and cultured in complete medium until they reached confluence. A linear scratch was created using a 200 μL pipette tip. After washing with PBS to remove cellular debris, cells were maintained in serum-free medium. Images of the scratch area were captured at 0, 24, and 48 h. Wound healing area was analyzed using ImageJ to quantify migration. For the proliferation assay, HEC-1A and Ishikawa cells transfected with shNC, shAKNA, or oeAKNA were seeded in 96-well plates at 2 × 10 3 cells per well and cultured for 24 h in a humidified incubator at 37 °C with 5% CO 2 . Cell Counting Kit-8 (CCK-8, Dojindo, Japan) was added at 0, 24, 48, and 72 h after seeding. After incubation for 1 h at 37 °C, absorbance was measured at 450 nm using a spectrophotometer. 2.11 Conditioned medium (CM) collection and macrophage polarization For CM collection, EC cells from each group were cultured to approximately 80% confluency, gently washed with pre-warmed PBS to remove residual serum and metabolic byproducts, and replenished with an equal volume of fresh serum-free medium. Cells were then cultured for an additional 24 h at 37 °C in a humidified 5% CO 2 atmosphere. CM was subsequently collected, centrifuged, and filtered through 0.22 μm membranes to completely remove tumor cells and debris ( 25 , 26 ). For cyclic GMP–AMP (cGAMP)-treated groups, tumor cells were pulsed with 3 μM cGAMP (InvivoGen, France) for 4 h ( 27 ). To ensure that macrophages were not directly exposed to the STING agonist, the cGAMP-containing medium was subsequently removed, and the cells were washed with PBS. After replacement with fresh medium, cells were cultured for an additional 20 h before CM collection. The resulting cell-free CM was used to induce THP-1-derived macrophage polarization. THP-1 monocytes were differentiated into M0 macrophages by treatment with 100 nM phorbol 12-myristate 13-acetate (PMA) (HY-18739, MedChemExpress, USA) for 24 h, followed by a 24 h resting period in fresh PMA-free complete medium ( 28 ). Differentiation was confirmed by adherence morphology under inverted microscopy (characteristic macrophage spreading and flattening). To exclude spontaneous polarization, baseline M1/M2 marker expression was assessed in unconditioned M0 controls using CD86-FITC (374204, BioLegend, USA) and CD206-PE (321106, BioLegend, USA); only batches with < 5% baseline CD86 + or CD206 + cells were utilized. Cells were subsequently washed three times with PBS to remove residual PMA. Macrophages were cultured in a 1:1 mixture of complete RPMI 1640 and CM for 48 h to maintain secretory profile and nutrient balance ( 18 ). Cells were stained with anti-human CD86-FITC (374204, BioLegend, USA) and CD206-PE (321106, BioLegend, USA) for 30 min at 4 °C in the dark. Unstained controls were included to establish baseline fluorescence. Flow cytometry was performed using a Beckman Coulter CytoFLEX S with CytExpert software. For analysis, cell debris was excluded based on FSC-A/SSC-A, followed by singlet gating using FSC-H/FSC-A. Positive/negative boundaries were determined using unstained controls. The detailed gating strategy is provided in Supplementary Figure 1 . 2.12 Colony formation assay HEC-1A and Ishikawa cells were seeded at 3,000 cells per well in six-well plates. All groups, including cGAMP-pretreated (3 μM) and untreated controls, were exposed to paclitaxel (HY-B0015, MedChemExpress, USA) or cisplatin (HY-17394, MedChemExpress, USA) for 14 days ( 29 ). Colonies were fixed (4% paraformaldehyde, 20 min), sta
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