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Updated: Jan 9, 2026

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
04:01

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics

Published on: March 15, 2024

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The E2F1-HMGCR axis promotes ferroptosis resistance in immune refractory tumor cells

Sung Wook Son1, Hyo-Jung Lee2,3,4, NaNa Kang1

  • 1Department of Cell biology, Daegu Catholic University School of Medicine, Daegu, South Korea.

Nature Communications
|December 3, 2025
PubMed

Insights

Cancer cells resist immunotherapy by upregulating HMGCR, a process driven by E2F1. Inhibiting HMGCR restores sensitivity to cancer immunotherapy, targeting the E2F1-HMGCR axis for treatment.

Area of Science:

  • Oncology
  • Immunology
  • Cell Death Mechanisms

Background:

  • Cancer cells evade immune responses by altering cell death pathways.
  • Ferroptosis, a form of regulated necrosis, is crucial for anti-tumor immunity.
  • Mechanisms of ferroptosis modulation in immune-refractory tumors are not fully understood.

Purpose of the Study:

  • To investigate how tumor cells develop resistance to ferroptosis during cancer immunoediting.
  • To identify molecular mechanisms underlying ferroptosis resistance in tumors refractory to immunotherapy.
  • To explore the E2F1-HMGCR axis as a therapeutic target.

Main Methods:

  • Utilized preclinical models of immune-refractory tumors after PD-1 blockade and adoptive T cell therapy (ACT).
  • Analyzed the role of E2F1 and HMGCR in mediating ferroptosis resistance.
  • Assessed the efficacy of HMGCR inhibition in restoring immunotherapy sensitivity.

Main Results:

  • T cell-based immunotherapy induces ferroptosis resistance in tumor cells.
  • Immunotherapy upregulates E2F1, which enhances HMGCR expression and promotes ferroptosis resistance.
  • Inhibition of HMGCR resensitizes immune-refractory tumors to PD-1 blockade and ACT.

Conclusions:

  • Cancer cells acquire immunotherapy resistance by modulating ferroptosis via the E2F1-HMGCR pathway.
  • The E2F1-HMGCR axis represents a key molecular target for overcoming ferroptosis resistance in refractory cancers.
  • Targeting HMGCR can re-sensitize tumors to existing immunotherapies.

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