Targeting GABA signaling in the tumor microenvironment: implications for immune cell regulation and immunotherapy resistance

Abstract

As an important inhibitory neurotransmitter, γ-aminobutyric acid (GABA) not only plays a key role in the central nervous system, but also has attracted wide attention in the tumor immune microenvironment in recent years. Studies have shown that tumor cells can synthesize GABA and use it to remodel the tumor microenvironment, thereby promoting the occurrence, development and metastasis of tumors. Although previous studies have revealed the important role of GABA in tumor immune escape, there are still many unknown areas of its mechanism, especially the heterogeneous manifestations in different tumor types and tissue environments. This review summarizes the immunomodulatory mechanisms of GABA in tumor-associated macrophages, CD8⁺ T cells and dendritic cells in the tumor immune microenvironment, and discusses its potential role in tumor immune escape and immunotherapy resistance, providing new ideas for the development of immunotherapeutic drugs targeting GABA receptors.

Keywords: GABA signaling; cancers; immune cell reg ulation; tumor immunotherapy; tumor microenvironment.

Figure 1

GABA signaling pathway in tumor microenvironment stimulates the polarization of macrophages to M2 type. Downregulation of GAD expression and downregulation of ABAT expression in tumor cells leads to GABA accumulation. GABA_AR on the surface of TAMs binds GABA from tumor cells to activate JAK1/STAT6 signaling and promote M2 polarization. GABA couples GABA_BR to Gαi, activates ERK1/2 signaling pathway, and promotes M2 polarization.

Figure 2

GABA signaling inhibits CD8+T cell immune infiltration. GABAAR on the membrane of CD8+T cells binds to 4-Ac-GABA from tumor cells, inhibits the phosphorylation of AKT and prevents the production of IFN-γ and Granzyme B, thereby affecting T cell activation and immune infiltration. Activation of GABA_AR results in Cl⁻ efflux, inhibition of Ca²⁺ influx, and ultimately inhibition of T cell activation.