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Review Open Access

The multidimensional regulatory network of the PD‑1/PD‑L1 axis in the esophageal squamous cell carcinoma microenvironment: Implications for novel combination therapies and precision immunotherapy (Review)

  • Authors:
    • Haoyue Lai
    • Lu Qi
    • Zhixuan Lin
    • Zhongwen Li
  • View Affiliations / Copyright

    Affiliations: Department of Head and Neck Oncology, Second Clinical College, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China, Zunyi Medical University, Guizhou 563000, P.R. China
    Copyright: © Lai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 16
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    Published online on: November 13, 2025
       https://doi.org/10.3892/or.2025.9021
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Abstract

Esophageal cancer is a highly prevalent malignancy worldwide. Although immunotherapy, particularly programmed cell death‑1/programmed cell death ligand 1 (PD‑1/PD‑L1) inhibitors, has notably improved patient outcomes, the overall response rate remains limited. This limited efficacy is largely attributed to complex immunosuppressive networks within the tumor microenvironment (TME). The present review systematically dissects the multifaceted regulatory mechanisms of the PD‑1/PD‑L1 signaling axis in the TME of esophageal squamous cell carcinoma (ESCC), and its impact on immunotherapeutic efficacy. Emerging evidence indicates that multiple immunosuppressive mechanisms within the TME shape the response to immune checkpoint inhibitors: Regulatory T cells enhance immunosuppression via the TGF‑β‑PD‑1/PD‑L1 axis; IL‑6/STAT3 signaling upregulates PD‑L1 expression and mitochondrial remodeling and amino acid network regulation exacerbate T cell exhaustion. Meanwhile, tertiary lymphoid structure (TLS) maturation is positively associated with clinical prognosis by promoting tissue‑resident memory T cell activation and enhancing antitumor immunity. By contrast, the predictive value of tumor mutational burden (TMB) is constrained by TME heterogeneity. Emerging strategies highlight the predictive potential of TLS maturity and TMB, although the predictive relevance of TMB in ESCC remains inconsistent. Combination approaches show promise in reversing T/natural killer cell exhaustion and remodeling immunosuppressive TMEs. Future research should combine multi‑omics data with clinical information to develop personalized immunotherapy models for ESCC.
View Figures

Figure 1

Mechanisms of PD-1/PD-L1-mediated
immunosuppression in TMEs. Binding PD-1 on activated T cells to
PD-L1 in the TME triggers immunoreceptor tyrosine-based switch
motif phosphorylation and recruitment of SHP-1/2 phosphatases,
leading to inhibition of PI3K and subsequent suppression of
PI3K/Akt signaling and impairs proliferation and effector function.
PD-1 also inhibits the RAS-ERK1/2 and PKCδ pathways and activates
PTEN, further dampening TCR signaling. IFN-γ and TNF-α upregulate
PD-L1 expression, establishing a positive feedback loop that
enhances immune evasion. PD-L1, programmed death ligand 1; SHP-2,
Src Homology 2 domain-containing phosphatase-2; ZAP70,
zeta-chain-associated protein of 70 kDa; LCK, lymphocyte-cellular
kinase; PKCδ, protein kinase C delta δ; MHC, major
histocompatibility complex; TCR, T-cell receptor; Ras, rat sarcoma
virus oncogene; Raf, rapidly accelerated fibrosarcoma kinase; TME,
tumor microenvironment.

Figure 2

IL-2-driven CD8+ T cell
depletion in the ESCC TME. IL-2 levels are elevated in ESCC TMEs
compared with normal tissues. In early tumor stages, IL-2 promotes
CD8+ T cell differentiation through autocrine signaling.
During tumor progression, sustained IL-2 secretion by
CD4+ T cells chronically activates STAT5 in
CD8+ T cells, inducing TPH1 expression and converting
tryptophan to 5-HTP. 5-HTP triggers AhR nuclear translocation,
upregulating inhibitory receptors such as PD-1 and tim-3 while
suppressing cytokine and effector molecule production, ultimately
driving T cell exhaustion. Trp, tryptophan; Tph1, tryptophan
hydroxylase 1; AhR, aryl hydrocarbon receptor; 5-HTP,
5-hydroxytryptophan; IRs, immunoreceptor signaling; PD1, programmed
death 1; TME, tumor microenvironment; tim-3, T cell immunoglobulin
and mucin-domain containing-3.

Figure 3

VEGF/VEGFR-2-mediated
immunosuppression and immune evasion in ESCC. VEGF promotes
CD8+ T cell exhaustion by upregulating PD-1, CTLA-4,
TIM-3 and LAG-3 via the VEGFR-2-PLC-γ-calmodulin-NFAT pathway. In
M2-type TAMs, VEGFR-2 activation enhances VEGF secretion through
PI3K/Akt/mTOR and induces PD-L1 expression through Nrf2 activation.
VEGF/VEGFR2 binding also inhibits monocyte-to-DC differentiation
and reduces DC maturation and antigen presentation, driving immune
escape. PLC-γ, phospholipase C-γ; P, phosphate group; DAG,
diacylglycerol; Cam, calmodulin; NFAT, nuclear factor of activated
T-cells; Irs, immunoreceptor signaling; Tim-3, T cell
immunoglobulin and mucin-domain containing-3; PD1, programmed cell
death protein 1; CTLA-4, cytotoxic T-lymphocyte associated
protein-4; LAG-3, lymphocyte-activation gene 3; VEGF, vascular
endothelial growth factor; DC, dendritic cell; TAM,
tumor-associated macrophage; PDL1, programmed cell death ligand
1.
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Copy and paste a formatted citation
Spandidos Publications style
Lai H, Qi L, Lin Z and Li Z: The multidimensional regulatory network of the PD‑1/PD‑L1 axis in the esophageal squamous cell carcinoma microenvironment: Implications for novel combination therapies and precision immunotherapy (Review). Oncol Rep 55: 16, 2026.
APA
Lai, H., Qi, L., Lin, Z., & Li, Z. (2026). The multidimensional regulatory network of the PD‑1/PD‑L1 axis in the esophageal squamous cell carcinoma microenvironment: Implications for novel combination therapies and precision immunotherapy (Review). Oncology Reports, 55, 16. https://doi.org/10.3892/or.2025.9021
MLA
Lai, H., Qi, L., Lin, Z., Li, Z."The multidimensional regulatory network of the PD‑1/PD‑L1 axis in the esophageal squamous cell carcinoma microenvironment: Implications for novel combination therapies and precision immunotherapy (Review)". Oncology Reports 55.1 (2026): 16.
Chicago
Lai, H., Qi, L., Lin, Z., Li, Z."The multidimensional regulatory network of the PD‑1/PD‑L1 axis in the esophageal squamous cell carcinoma microenvironment: Implications for novel combination therapies and precision immunotherapy (Review)". Oncology Reports 55, no. 1 (2026): 16. https://doi.org/10.3892/or.2025.9021
Copy and paste a formatted citation
x
Spandidos Publications style
Lai H, Qi L, Lin Z and Li Z: The multidimensional regulatory network of the PD‑1/PD‑L1 axis in the esophageal squamous cell carcinoma microenvironment: Implications for novel combination therapies and precision immunotherapy (Review). Oncol Rep 55: 16, 2026.
APA
Lai, H., Qi, L., Lin, Z., & Li, Z. (2026). The multidimensional regulatory network of the PD‑1/PD‑L1 axis in the esophageal squamous cell carcinoma microenvironment: Implications for novel combination therapies and precision immunotherapy (Review). Oncology Reports, 55, 16. https://doi.org/10.3892/or.2025.9021
MLA
Lai, H., Qi, L., Lin, Z., Li, Z."The multidimensional regulatory network of the PD‑1/PD‑L1 axis in the esophageal squamous cell carcinoma microenvironment: Implications for novel combination therapies and precision immunotherapy (Review)". Oncology Reports 55.1 (2026): 16.
Chicago
Lai, H., Qi, L., Lin, Z., Li, Z."The multidimensional regulatory network of the PD‑1/PD‑L1 axis in the esophageal squamous cell carcinoma microenvironment: Implications for novel combination therapies and precision immunotherapy (Review)". Oncology Reports 55, no. 1 (2026): 16. https://doi.org/10.3892/or.2025.9021
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