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Regulatory networks of HIFs in tumor‑infiltrating immune cells: From molecular mechanisms to therapeutic implications (Review)

  • Authors:
    • Chaoqun Li
    • Chenge Qin
    • Xingchen Li
    • Jinzhu Wang
    • Yang Li
    • Qin Sun
  • View Affiliations / Copyright

    Affiliations: College of Physical Education and Sport Science, Qufu Normal University, Qufu, Shandong 273165, P.R. China, Respiratory and Critical Care Medicine Department, Yangpu Hospital, Tongji University, Shanghai 200090, P.R. China, College of Life Sciences, Qingdao Agricultural University, Qingdao, Shandong 266109, P.R. China, Center for The Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA, College of Physical Education and Sport Science, Zhejiang Normal University, Jinhua, Zhejiang 321004, P.R. China
    Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 32
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    Published online on: January 12, 2026
       https://doi.org/10.3892/ijo.2026.5845
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Abstract

Hypoxic tumor microenvironment (TME) is a common occurrence in the development of solid tumors, which activates hypoxia‑inducible factors (HIFs) and their downstream signaling pathways in cancer cells to facilitate tumor progression and immune escape. However, among the various immune cells that constitute innate and adaptive immune systems, HIFs have a more intricate function; moreover, different isoforms of HIFs play different functions under spatial and temporal conditions. HIFs are conducive to the adaptation of various immune cells to the hypoxic TME. The stability of HIF‑α can regulate metabolism and directly regulate the expression of immune genes. Additionally, the activation of HIF signaling may also inhibit the development of immune cells in some tumor environments, affecting the antigen recognition and killing processes to assist cancer cells in immune escape. Therefore, understanding the relationship between HIF signaling and immune cells more comprehensively may yield substantial benefits for the immunotherapy of various types of cancer. The present study reviewed the role of HIFs in immunity, including their role in T cells, B cells, macrophages, neutrophils, dendritic cells and natural killer cells. It also discussed the effectiveness of HIF targeted therapy in clinical application, the challenges associated with it and the development of a precise targeting drug delivery system. The present review may help researchers comprehend the tumor immune process in a hypoxic microenvironment. It aimed to offer novel strategies for cancer immunotherapy and prolonging the overall survival of patients.

View Figures

Figure 1

Regulation of HIF Proteins. Under
normoxic conditions, the proline residues of HIF-α are hydroxylated
by the dioxygenase PHD enzymes. Subsequently, VHL protein binds to
the hydroxylated proline sites. The binding of VHL to HIF-α
recruits an E3 ubiquitin ligase complex along with E2
ubiquitin-conjugating enzymes, catalyzing the ubiquitination of
HIF-α and targeting it for proteasomal degradation. However, under
hypoxic conditions, the activity of PHD is inhibited, leading to
the stabilization of HIF-α. Stabilized HIF-α dimerizes with HIF-1β,
translocates into the nucleus and binds to HREs to stimulate the
transcription of target genes. HIF, hypoxia-inducible factor; PHD,
prolyl hydroxylase domain VHL, von Hippel-Lindau; HREs, hypoxia
response elements; PFK, phosphofructokinase; LDHA, lactate
dehydrogenase A; MCT4, monocarboxylate transporter 4; CA-IX,
carbonic anhydrase IX; BNIP3, Bcl2 interacting protein 3.

Figure 2

Regulation of T cell differentiation
and function by HIFs. (A) Effects of HIFs on T cell differentiation
and proliferation. In the TME, HIF-1α-induced glycolysis promotes
the polarization of naïve T cells toward the Th17 phenotype. This
occurs through the direct activation of RORγt, the master
transcription factor of Th17 cells. HIF-1α also forms a complex
with RORγt and p300, which enhances IL-17 transcription, thereby
driving Th17 differentiation. Additionally, HIF-1α inhibits Treg
cell development by suppressing Foxp3 signaling in a
glycolysis-dependent manner. However, overexpression of HIF-2α in
Treg cells antagonizes HIF-1α activity, thereby facilitating Treg
differentiation and function. (B) HIFs Enhance CD8+ T
Cell Function. HIF-1α promotes the expression of CD127 on
CD8+ T cells, enhancing their capacity to secrete
cytokines such as IFN-γ, TNF-α and granzyme B, thereby improving
their tumor-killing efficacy. Furthermore, agents such as ApoA1 and
the immunometabolite S-2-hydroxyglutarate stabilize HIF-1α,
enhancing antitumor immunity. Similarly, HIF-2α strengthens the
immune response of CD8+ T cells by upregulating genes
encoding granzyme B (Gzmb), Cd8a, Cd3g, perforin (Prf1) and IFN-γ
(Ifng). Conversely, overexpression of HIF regulatory proteins such
as PHD domain enzymes or FIH, which suppress HIF-1α activity,
impairs tumor immunity. HIFs, hypoxia-inducible factors; TME, tumor
microenvironment; RORγt, RAR-related orphan receptor γt; IL,
interleukin; GLUT1, glucose transporter 1; Foxp3, forkhead box P3;
IFN-γ, interferon γ; TNF-α, tumor necrosis factor-α; ApoA1,
apolipoprotein A1; PHD, prolyl hydroxylase; FIH, factor-inhibiting
HIF.

Figure 3

Regulation of B Cells by HIFs. (A)
Stage-specific regulation of B cell development by HIF-1α. During
early B cell development, high levels of HIF-1α activation are
required to support glycolysis, facilitating the proliferation of
pro-B and pre-B cells. However, in immature B cells, HIF-1α
expression is downregulated. Persistent HIF-1α activity at this
stage can limit IgHV editing, suppress sIgM expression and reduce
BCR synthesis, ultimately impeding B cell maturation. (B)
Regulation of B Cells by HIFs in the TME. TEBs play a
pro-tumorigenic role by promoting cancer progression. For example,
IL-1β released by TEBs can activate the HIF-2α/Notch1 signaling
pathway in renal carcinoma cells, driving cancer cell migration and
invasion. Additionally, HIF-1α activated by TEBs induces the
transcription of Rab27a mRNA, facilitating the release of
extracellular vesicles containing CD39 and CD73. These vesicles
promote tumor immune evasion and chemoresistance. Moreover,
microRNA miR-92-1, overexpressed in TEBs from CCL patients,
inhibits VHL transcription, stabilizing HIF-1α. The
stabilized HIF-1α forms a complex with p300 and phosphorylated
STAT3, enhancing VEGF expression and thereby promoting angiogenesis
in the TME. (C) Regulation of malignant B Cells by HIF-1α, HIF-1α
promotes CXCR4 transcription, activating the AKT and mTOR
pathways to enhance migration and viability in DLBCL. HIFs,
hypoxia-inducible factors; IgHV, immunoglobulin heavy chain
variable region; sIgM, surface IgM; BCR, B cell receptor; TME,
tumor microenvironment; TEBs, tumor-educated B cells; IL,
interleukin; CCL, chronic lymphocytic leukemia; STAT3, signal
transducer and activator of transcription 3; VEGF, vascular
endothelial growth factor; DLBCL, diffuse large B-cell lymphoma;
RCC, renal cell carcinoma.

Figure 4

HIF Signaling in TAMs and its role in
tumor progression. (A) In the TME, tumor cells release lactate and
succinate, which act on macrophages to stabilize HIF-1α and HIF-2α.
Succinate binds to SUCNR1 and activates the PI3K/mTORC1 pathway and
inhibits PHD activity, both leading to HIF-1α stabilization.
Lactate from tumor cells inhibit mTORC1 in TAMs, which further
suppresses TEEB-mediated transcription of ATP6V0d2 and stabilizes
HIF-2α protein. HIF-1α and HIF-2α promote TAM polarization,
inducing the expression of pro-tumoral factors such as IL-1β, IL-6
and VEGF, which in turn enhance tumor growth and metastasis. (B)
The metabolic and functional polarization of macrophages into M1
and M2 subtypes is depicted. M1 macrophages, driven by HIF-1α
activation, upregulate glycolysis via GLUT1 and glycolytic enzymes,
producing pro-inflammatory cytokines (such as TNF-α, IL-12p40) and
expressing surface markers CD80 and CD86, which are associated with
antitumor immune responses. By contrast, M2 macrophages rely on
HIF-2α, which promotes glutamine metabolism via SLC1A5 and
mitochondrial OXPHOS. HIF-2α also induces MTHFD2 expression,
facilitating metabolic reprogramming and the secretion of VEGF and
TGF-β, contributing to angiogenesis and immunosuppression in the
TME. HIF, hypoxia-inducible factor; TAMs, tumor-associated
macrophages; TME, tumor microenvironment; SUCNR1, succinate
receptor; PHD, prolyl hydroxylase; TEEB, transcription factor
regulating lysosomal proteins; ATP6V0d2, ATPase H+
transporting V0 subunit d2; VEGF, vascular endothelial growth
factor; GLUT1, glucose transporter 1; TNF-α, tumor necrosis
factor-α; IL, interleukin; SLC1A5, solute carrier family 1 member
5; OXPHOS, oxidative phosphorylation; TGF-β, transforming growth
factor-β.

Figure 5

The role of HIFs in modulating innate
immune cells in the TME. In the TME, HIF-1α in neutrophils
regulates the expression of downstream molecules such as TGF-β and
IL-8, while HIF-2α activates TNF-α and IL-1β. Together, these
factors promote the polarization of TANs towards the
pro-tumorigenic N2 phenotype. N2-type neutrophils secrete
pro-inflammatory cytokines (such as IL-6) and angiogenic factors
(such as VEGF), which promote tumor growth and invasion.
Additionally, HIF-1α upregulates CXCR4 expression, enhancing
neutrophil response to tumor-derived CXCL12, thus facilitating the
directed migration of TANs to the tumor site. HIF-1α also activates
PD-L1 expression, which suppresses CD8+ T cell activity,
contributing to immune evasion by the tumor. In DCs, CCR7 signaling
activates HIF-1α, which promotes transcription of chemokine
receptors (CCR3, CCR2, CXCR3) while repressing chemokine ligands
(CCL18, CCL23, CCL26, CCL24). HIF-1α also enhances transcription of
glycolytic enzymes HK2 and PKM2, driving glycolysis and activating
the STING pathway, leading to the production of type I IFNs. In
tumor cells, hypoxia-induced CXCL12 recruits immune cells, while
ADAM10 cleaves MICA/B, reducing NK cell recognition via NKG2D. NK
cells under hypoxia exhibit increased HIF-1α expression, which
impairs cytotoxicity and cytokine secretion by suppressing
activating receptors (NKG2D, NKp30, NKp44), partially through NF-κB
signaling. HIFs, hypoxia-inducible factors; TME TGF-β, transforming
growth factor-β; IL, interleukin; TANs, tumor-associated
neutrophils; VEGF, vascular endothelial growth factor; TME, tumor
microenvironment; PD-L1, programmed cell death ligand 1; DCs,
dendritic cells; CCR7, C-C motif chemokine receptor 7; STING,
stimulator of interferon genes; IFNs, interferons; CXCL, C-X-C
motif chemokine ligand; ADAM10, A disintegrin and metalloproteinase
domain 10; MICA/B, major histocompatibility complex class I
chain-related gene A/B; NK, natural killer; NF-κB, nuclear factor
κ-light-chain-enhancer of activated B cells.
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Copy and paste a formatted citation
Spandidos Publications style
Li C, Qin C, Li X, Wang J, Li Y and Sun Q: <p>Regulatory networks of HIFs in tumor‑infiltrating immune cells: From molecular mechanisms to therapeutic implications (Review)</p>. Int J Oncol 68: 32, 2026.
APA
Li, C., Qin, C., Li, X., Wang, J., Li, Y., & Sun, Q. (2026). <p>Regulatory networks of HIFs in tumor‑infiltrating immune cells: From molecular mechanisms to therapeutic implications (Review)</p>. International Journal of Oncology, 68, 32. https://doi.org/10.3892/ijo.2026.5845
MLA
Li, C., Qin, C., Li, X., Wang, J., Li, Y., Sun, Q."<p>Regulatory networks of HIFs in tumor‑infiltrating immune cells: From molecular mechanisms to therapeutic implications (Review)</p>". International Journal of Oncology 68.3 (2026): 32.
Chicago
Li, C., Qin, C., Li, X., Wang, J., Li, Y., Sun, Q."<p>Regulatory networks of HIFs in tumor‑infiltrating immune cells: From molecular mechanisms to therapeutic implications (Review)</p>". International Journal of Oncology 68, no. 3 (2026): 32. https://doi.org/10.3892/ijo.2026.5845
Copy and paste a formatted citation
x
Spandidos Publications style
Li C, Qin C, Li X, Wang J, Li Y and Sun Q: <p>Regulatory networks of HIFs in tumor‑infiltrating immune cells: From molecular mechanisms to therapeutic implications (Review)</p>. Int J Oncol 68: 32, 2026.
APA
Li, C., Qin, C., Li, X., Wang, J., Li, Y., & Sun, Q. (2026). <p>Regulatory networks of HIFs in tumor‑infiltrating immune cells: From molecular mechanisms to therapeutic implications (Review)</p>. International Journal of Oncology, 68, 32. https://doi.org/10.3892/ijo.2026.5845
MLA
Li, C., Qin, C., Li, X., Wang, J., Li, Y., Sun, Q."<p>Regulatory networks of HIFs in tumor‑infiltrating immune cells: From molecular mechanisms to therapeutic implications (Review)</p>". International Journal of Oncology 68.3 (2026): 32.
Chicago
Li, C., Qin, C., Li, X., Wang, J., Li, Y., Sun, Q."<p>Regulatory networks of HIFs in tumor‑infiltrating immune cells: From molecular mechanisms to therapeutic implications (Review)</p>". International Journal of Oncology 68, no. 3 (2026): 32. https://doi.org/10.3892/ijo.2026.5845
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