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Glutamate metabotropic receptor 4 in breast cancer: a potential and specific target for chimeric antigen receptor

Yien Xu1,2, Ayidana Hayierhan3,4, Zexiao Chen1,4

  • 1The Breast Center, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China.

Frontiers in Oncology
|January 23, 2026
PubMed
Abstract

Insights

Glutamate metabotropic receptor 4 (GRM4) is a novel target for breast cancer immunotherapy. It shows tumor-specific expression and restricted normal tissue distribution, offering potential to overcome toxicity issues in chimeric antigen receptor (CAR) therapy.

Area of Science:

  • Oncology
  • Immunotherapy
  • Molecular Biology

Background:

  • Chimeric antigen receptor (CAR) therapy shows promise in hematologic malignancies but faces challenges in solid tumors due to a lack of validated tumor-specific antigens.
  • Identifying antigens with restricted normal tissue expression is crucial to minimize on-target, off-tumor toxicity.

Purpose of the Study:

  • To identify and validate glutamate metabotropic receptor 4 (GRM4) as a novel, tumor-specific membrane antigen for breast cancer (BC) immunotherapy.
  • To evaluate GRM4 expression patterns in clinical breast cancer specimens and assess its potential as a CAR therapy target.

Main Methods:

  • Integrative multi-database analysis (DESeq2, edgeR, limma, CellMarker, Human Protein Atlas) to prioritize GRM4.
  • Expression validation in BC cell lines (Western blot, qPCR, immunofluorescence) and 158 BC clinical samples (immunohistochemistry).
  • Analysis of subcellular localization, tumor proportion score, subtype distribution, clinical correlations, and survival outcomes.

Main Results:

  • GRM4 was validated as a membrane antigen expressed in 35.44% of BC cases and present in BC cell lines.
  • Tumor-specific membrane/cytoplasmic expression was observed in 80.38% of BC patients across all subtypes.
  • GRM4 expression was absent in normal breast/para-cancerous tissues and restricted to the brain in non-malignant organs, correlating with advanced stage and age but not survival.

Conclusions:

  • GRM4 is a novel CAR-associated target for breast cancer, exhibiting tumor-specific overexpression and restricted normal tissue expression.
  • Its pan-subtype applicability and potential to mitigate on-target, off-tumor effects make it a promising candidate for BC immunotherapy.
  • Further research into GRM4-targeted CAR therapies is warranted for breast cancer treatment.
Keywords:
GRM4breast cancercar-tsolid tumortumor-specific antigen

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