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Single-Cell Reveal GALNT7-Dependent Ferroptosis Suppression as a Mechanism of Immunotherapy Resistance in Non-Small

Jiadi Gan1, Qian Zheng1, Deng Liu2

  • 1Department of Pulmonary and Critical Care Medicine, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|June 19, 2026
PubMed

Insights

Galactosyltransferase 7 (GALNT7) promotes non-small cell lung cancer (NSCLC) resistance to immunotherapy by suppressing ferroptosis. Inhibiting GALNT7 enhances anti-tumor immunity and sensitizes NSCLC to immune checkpoint blockade therapy.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immunotherapy, particularly immune checkpoint blockade (ICB), has revolutionized non-small cell lung cancer (NSCLC) treatment.
  • However, a significant proportion of patients exhibit primary or acquired resistance to ICB, driven by incompletely understood mechanisms.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying ICB resistance in NSCLC using integrative multi-omics analysis.
  • To identify novel therapeutic targets for overcoming ICB resistance in NSCLC.

Main Methods:

  • Integrative multi-omics analysis including single-cell RNA-sequencing, bulk RNA-seq, and spatial transcriptomics on NSCLC tumors from patients receiving ICB.
  • Functional studies involving GALNT7 silencing in NSCLC cells and in vivo tumor models.
  • Assessment of ferroptosis markers, cell death pathways, immune cell infiltration, and cytokine production.

Main Results:

  • Galactosyltransferase 7 (GALNT7) was found to be upregulated in ICB non-responders and linked to suppressed ferroptosis signaling.
  • GALNT7 silencing in NSCLC cells induced ferroptosis, impaired proliferation, and promoted apoptosis.
  • In vivo, GALNT7 knockdown reduced tumor growth, increased CD8+ T cell infiltration, and boosted IFN-γ production.
  • Combined GALNT7 depletion and PD-1 blockade demonstrated synergistic tumor suppression dependent on ferroptosis.

Conclusions:

  • GALNT7 is a key regulator of ferroptosis and anti-tumor immunity in NSCLC.
  • Targeting GALNT7 represents a promising strategy to sensitize NSCLC to ICB therapy.
  • These findings provide a mechanistic basis for ferroptosis-based sensitization strategies in NSCLC immunotherapy.
Keywords:
cancer researchcd8gene knockdowngene silencingimmune checkpointimmunogenic cell deathimmunotherapyinterferon gammat celltumor microenvironment

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