GABAergic signaling in colorectal cancer: Mechanistic insights, tumor microenvironment crosstalk, and therapeutic opportunities

γ-Aminobutyric acid (GABA) and its receptors have emerged as critical modulators of colorectal cancer (CRC) progression and the tumor microenvironment (TME). Although GABA is traditionally recognized as an inhibitory neurotransmitter in the central nervous system, recent studies have uncovered its complex and sometimes paradoxical roles in cancer biology. In vivo, elevated GABA levels in CRC tissues have been associated with enhanced tumor growth, immune evasion, and metabolic adaptation. In contrast, in vitro studies suggest that exogenous GABA and GABA receptor agonists can inhibit CRC cell proliferation, highlighting a context-dependent role for GABAergic signaling. This duality may stem from variations in GABA receptor subtype expression, tumor-intrinsic metabolic reprogramming, and immune modulation within the TME. A better understanding of these mechanisms may offer new therapeutic opportunities. In this review, we summarize recent advances in the field, focusing on the molecular mechanisms, immune and metabolic interactions, and therapeutic potential of targeting GABAergic signaling in colorectal cancer.