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Published on: January 7, 2019

FGFR4 suppresses antitumor immunity and cuproptosis by disrupting CYLD-mediated stabilization of STING and FDX1

Hongguang Zhong1, Ruixuan Huang1, Wenyuan Deng2

  • 1Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China.

Cancer Letters
|August 19, 2026
PubMed

Insights

Fibroblast growth factor receptor 4 (FGFR4) suppresses antitumor immunity by degrading STING and FDX1. Inhibiting FGFR4 restores immune responses and enhances cancer treatment efficacy, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Fibroblast growth factor receptor (FGFR) pathway dysregulation is common in cancer, promoting tumor growth and immune evasion.
  • The specific mechanisms by which the FGFR pathway suppresses antitumor immunity are not fully understood.

Purpose of the Study:

  • To identify key FGFR family members involved in immune suppression.
  • To elucidate the molecular mechanisms by which FGFR4 suppresses antitumor immunity.
  • To evaluate FGFR4 inhibition and cuproptosis induction as a combined therapeutic strategy.

Main Methods:

  • Investigated FGFR4's role in regulating antitumor immunity using molecular assays.
  • Examined the impact of FGFR4 on STING and FDX1 stability via GRB2-dependent CYLD inactivation.
  • Assessed the efficacy of combined FGFR4 inhibition (lenvatinib) and cuproptosis induction (elesclomol) in preclinical cancer models.
  • Correlated FGFR4 and STING expression with patient responses to anti-PD-1 therapy.

Main Results:

  • FGFR4 was identified as a suppressor of antitumor immunity.
  • FGFR4 inactivation of CYLD leads to STING and FDX1 degradation, impairing interferon signaling and cuproptosis sensitivity.
  • FGFR4 inhibition restored CYLD activity, stabilized STING and FDX1, and improved responses to STING agonists.
  • Combined lenvatinib and elesclomol synergistically reduced tumor growth in vivo.
  • High FGFR4 and low STING expression correlated with poor responses to anti-PD-1 therapy.

Conclusions:

  • FGFR4 is a critical regulator of antitumor immunity and cuproptosis.
  • Targeting FGFR4 in combination with cuproptosis inducers represents a promising therapeutic approach for cancer.
  • FGFR4-mediated immunosuppression presents a potential mechanism for resistance to immunotherapy.
Keywords:
CYLDCuproptosisFGFR4ImmunotherapySTING

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