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Review Open Access

Advancements in research on the role of the key glycolytic enzyme hexokinase 2 in the regulation of tumor immune evasion (Review)

  • Authors:
    • Yiyang Qian
    • Xiaodan Zhu
    • Dong Niu
    • Quan Tang
    • Chunhui Jin
  • View Affiliations / Copyright

    Affiliations: Department of Oncology, Wuxi Affiliated Hospital of Nanjing University of Chinese Medicine, Wuxi, Jiangsu 214071, P.R. China
    Copyright: © Qian et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 593
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    Published online on: October 14, 2025
       https://doi.org/10.3892/ol.2025.15339
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Abstract

Tumor metabolic reprogramming is considered to be a critical driver of immune evasion. Hexokinase 2 (HK2), the initial rate‑limiting enzyme of the glycolytic pathway, serves a central role in the regulatory network governing tumor metabolism and immune interactions. The expression and modification of HK2 are both influenced by various oncogenic factors and signal transduction pathways, enabling HK2 to mediate immune escape through glycolysis‑dependent and independent mechanisms. In this context, HK2 can also interact with the downstream proteins of these oncogenic factors. Furthermore, the high glycolytic activity of tumor cells mediated by HK2 leads to the metabolic reprogramming of immune cells, inhibiting their activation and impairing their function, while releasing high levels of metabolic byproducts that contribute to the formation of immunosuppressive microenvironments. Targeting of metabolic pathways has emerged as a prominent area of research in counteracting immunosuppression. Due to its pivotal role in the glycolysis‑driven metabolism‑immune axis, HK2 has become an important target for reversing immune escape. Innovative strategies, including subcellular targeted inhibitors and combination immunotherapy, have demonstrated potential in mitigating HK2‑driven immunosuppression. The present review provides a comprehensive overview of the intricate immune regulatory mechanisms that involve various signaling pathways, such as phosphatidylinositol 3‑kinase/protein kinase B, mitogen‑activated protein kinase, nuclear factor κ‑light‑chain‑enhancer of activated B cells, transforming growth factor β, Janus kinase/signal transducer and activator of transcription, and HK2. The present review examines how HK2 enhances antitumor immunity by accelerating the Warburg effect and interacting with diverse immune cell subtypes, thereby contributing to the formation of an acidic, hypoxic and hypoglycemic microenvironment. Furthermore, the present review highlights the potential of HK2 as a therapeutic target and predictive biomarker. 
View Figures

Figure 1

HK2-driven lactate metabolism shapes
an immunosuppressive tumor microenvironment. Tumor cells utilize
HK2-driven glycolysis to convert glucose to lactate, resulting in
extracellular acidification (low pH) and the formation of an
immunosuppressive niche. Elevated lactate levels dysregulate immune
cell functions through multiple mechanisms. HK2, hexokinase 2;
2-DG, 2-deoxy-D-glucose; IFN-γ, interferon γ; NFAT, nuclear factor
of activated T-cells; FIP200, FAK family-interacting protein of 200
kDa; MHC-II, major histocompatibility complex class II; NKG2D,
natural killer group 2D; DNAM-1, DNAX accessory molecule-1; iNOS,
inducible nitric oxide synthase; CXCL2, C-X-C motif chemokine
ligand 2; IL-6/10, interleukin 6/10; CTLA-4, cytotoxic
T-lymphocyte-associated protein 4; MCT, monocarboxylate
transporter; DC, dendritic cell; NK cell, natural killer cell;
Treg, regulatory T cell; PD-L1, programmed death-ligand 1; HIF-1α,
hypoxia-inducible factor 1α.

Figure 2

HK2-HIF-1α hypoxic feedforward loop
orchestrates multimodal immunosuppression in the tumor
microenvironment. This schematic depicts the self-reinforcing
hypoxic feedforward loop initiated by HK2-VDAC1 mitochondrial
interaction, which induces localized hypoxia and stabilizes HIF-1α.
The activated HIF-1α axis drives immunosuppression through: i)
Transcriptional upregulation of PD-L1 via HRE binding and
PI3K/AKT/mTOR-mediated post-translational modification; ii)
recruitment of Tregs via CCL28/TGF-β secretion and Foxp3
stabilization; iii) polarization of TAMs to M2 phenotype through
VEGF/IL-10, leading to Arg-1/IL-10 secretion that suppresses
CD8+ T cells; iv) STAT3-dependent expansion of MDSCs; v)
inhibition of MHC-I and DC antigen presentation; vi) IDO-induced
tryptophan depletion promoting Treg differentiation. Concomitant
abnormal angiogenesis (via VEGF) and lactate accumulation further
exacerbate hypoxia, completing the immunosuppressive circuit; vii)
The upregulation of microRNA-224 caused by HIF-1α activation
inhibits the natural cytotoxicity trigger receptor 1/NKp46 pathway
of NK cells. HK2, hexokinase 2; HIF-1α, hypoxia-inducible factor
1α; VDAC1, voltage-dependent anion channel 1; PD-L1, programmed
death-ligand 1; HRE, hypoxia-response element; PI3K,
phosphoinositide 3-kinase; AKT, protein kinase B; Treg, regulatory
T cell; CCL28, C-C motif chemokine ligand 28; TGF-β, transforming
growth factor β; Foxp3, forkhead box P3; TAM, tumor-associated
macrophage; VEGF, vascular endothelial growth factor; IL,
interleukin; Arg-1, arginase 1; STAT3, signal transducer and
activator of transcription 3; MDSC, myeloid-derived suppressor
cell; MHC-I, major histocompatibility complex class I; DC,
dendritic cell; IDO, indoleamine 2,3-dioxygenase; MCT,
monocarboxylate transporter; Trp, tryptophan; PHD, prolyl
hydroxylase domain; IRF, interferon regulatory factors.

Figure 3

HK2-mediated glycolysis drives
glucose starvation in the tumor immune microenvironment,
suppressing antitumor immunity. This schematic depicts how
HK2-driven glycolytic flux creates a hypoglycemic TME that
selectively impairs immunocompetent cells while favoring
immunosuppressive populations. Cancer cells exacerbate glucose
scarcity through GLUT1-mediated glucose uptake and HK2-dependent
pyruvate production, triggering AMPK activation. Phosphorylated
AMPK induces nuclear-to-cytoplasmic translocation of HuR via Ser318
phosphorylation, enhancing HuR binding to PD-L1 mRNA to stabilize
PD-L1 transcripts. Concurrently, hypoglycemia forces effector T
cells toward inefficient fatty acid oxidation due to suppressed
CPT1A translation, culminating in T cell exhaustion and diminished
IFN-γ/TNF-α secretion. DCs adopt a tolerogenic phenotype with
elevated PD-L1/IL-10 expression, impairing T cell priming.
Conversely, Tregs thrive through Foxp3-mediated metabolic
reprogramming, utilizing lactate and fatty acids to enhance OXPHOS
and maintain immunosuppressive function, thereby outcompeting
effector cells for nutrients. This metabolic imbalance establishes
a self-perpetuating immunosuppressive circuit. HK2, hexokinase 2;
GLUT1, glucose transporter type 1; AMPK, AMP-activated protein
kinase; HuR, Hu antigen R; PD-L1, programmed death-ligand 1; CPT1A,
carnitine palmitoyltransferase 1A; IFN-γ, interferon γ; TNF-α,
tumor necrosis factor α; DC, dendritic cell; IL, interleukin; Treg,
regulatory T cell; Foxp3, forkhead box P3; OXPHOS, oxidative
phosphorylation; TME, tumor microenvironment.
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Copy and paste a formatted citation
Spandidos Publications style
Qian Y, Zhu X, Niu D, Tang Q and Jin C: Advancements in research on the role of the key glycolytic enzyme hexokinase 2 in the regulation of tumor immune evasion (Review). Oncol Lett 30: 593, 2025.
APA
Qian, Y., Zhu, X., Niu, D., Tang, Q., & Jin, C. (2025). Advancements in research on the role of the key glycolytic enzyme hexokinase 2 in the regulation of tumor immune evasion (Review). Oncology Letters, 30, 593. https://doi.org/10.3892/ol.2025.15339
MLA
Qian, Y., Zhu, X., Niu, D., Tang, Q., Jin, C."Advancements in research on the role of the key glycolytic enzyme hexokinase 2 in the regulation of tumor immune evasion (Review)". Oncology Letters 30.6 (2025): 593.
Chicago
Qian, Y., Zhu, X., Niu, D., Tang, Q., Jin, C."Advancements in research on the role of the key glycolytic enzyme hexokinase 2 in the regulation of tumor immune evasion (Review)". Oncology Letters 30, no. 6 (2025): 593. https://doi.org/10.3892/ol.2025.15339
Copy and paste a formatted citation
x
Spandidos Publications style
Qian Y, Zhu X, Niu D, Tang Q and Jin C: Advancements in research on the role of the key glycolytic enzyme hexokinase 2 in the regulation of tumor immune evasion (Review). Oncol Lett 30: 593, 2025.
APA
Qian, Y., Zhu, X., Niu, D., Tang, Q., & Jin, C. (2025). Advancements in research on the role of the key glycolytic enzyme hexokinase 2 in the regulation of tumor immune evasion (Review). Oncology Letters, 30, 593. https://doi.org/10.3892/ol.2025.15339
MLA
Qian, Y., Zhu, X., Niu, D., Tang, Q., Jin, C."Advancements in research on the role of the key glycolytic enzyme hexokinase 2 in the regulation of tumor immune evasion (Review)". Oncology Letters 30.6 (2025): 593.
Chicago
Qian, Y., Zhu, X., Niu, D., Tang, Q., Jin, C."Advancements in research on the role of the key glycolytic enzyme hexokinase 2 in the regulation of tumor immune evasion (Review)". Oncology Letters 30, no. 6 (2025): 593. https://doi.org/10.3892/ol.2025.15339
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