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GABA promotes resistance to immunotherapy in patients with TLS-positive tumors

Isaias Hernández-Verdin1, Anne Calvez2, Cheng-Ming Sun2

  • 1Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, 75006 Paris, France; Equipe labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France; Institut du Cerveau-Paris Brain Institute-ICM, Inserm, Sorbonne Université, CNRS, 75013 Paris, France.

Cancer Cell
|July 9, 2026
PubMed

Insights

Gamma-aminobutyric acid (GABA) is linked to resistance against immune checkpoint inhibitors (ICIs) in tumors with tertiary lymphoid structures (TLSs). Targeting GABA metabolism may improve ICI efficacy in these patients.

Area of Science:

  • Immunology
  • Metabolomics
  • Oncology

Background:

  • Tertiary lymphoid structures (TLSs) are associated with favorable responses to immune checkpoint inhibitors (ICIs).
  • However, many patients with TLS-positive tumors exhibit resistance to ICIs.
  • The mechanisms underlying this resistance remain incompletely understood.

Purpose of the Study:

  • To investigate the role of gamma-aminobutyric acid (GABA) in ICI resistance in clear cell renal cell carcinoma (ccRCC) and soft tissue sarcoma (STS).
  • To explore the impact of GABA on B cell function within TLSs.
  • To evaluate the therapeutic potential of targeting GABA metabolism to overcome ICI resistance.

Main Methods:

  • Multi-omic profiling of ccRCC and STS tumors from patients with varying responses to ICIs.
  • Analysis of TLS characteristics, including B cell maturation and immunoglobulin production, in relation to GABA-producing tumor cells.
  • In vitro experiments exposing human B cells to GABA.
  • Pharmacological inhibition of GABA synthesis in a TLS-positive STS mouse model.

Main Results:

  • Upregulation of GABA-related signatures was observed in non-responders to ICIs.
  • TLSs in non-responders showed impaired B cell maturation, reduced IgG production, and increased GABA receptor expression.
  • GABA exposure reduced HLA-DR expression, proliferation, and immunoglobulin secretion in human B cells.
  • Inhibition of GABA synthesis enhanced ICI response and immune infiltration in a mouse model.

Conclusions:

  • GABA acts as an immunoregulatory metabolite contributing to ICI resistance.
  • GABA negatively impacts B cell function within TLSs.
  • Targeting GABA synthesis presents a potential strategy to improve ICI therapy outcomes in patients with TLS-positive tumors.
Keywords:
clear cell renal cell carcinomagamma-aminobutyric acidimmune checkpoint inhibitorsmulti-omicsresistancesoft tissue sarcomatertiary lymphoid structures

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