Neural-Metabolic Crosstalk Governing Cell Death and Therapy Resistance in Tumors

Metabolic reprogramming and resistance to regulated cell death (RCD) are central features of the tumor microenvironment (TME) that drive therapeutic failure. Emerging evidence indicates that neurotransmitter signaling networks-including glutamate, dopamine, 5-hydroxytryptamine (5-HT), and norepinephrine-extend beyond neural communication to function as critical regulators of tumor metabolism, immune modulation, and cell fate. These neurotransmitters influence multiple RCD modalities, such as ferroptosis, cuproptosis, and PANoptosis, through interconnected metabolic and signaling mechanisms. Glutamate is explicitly resolved by compartment and route: high extracellular glutamate inhibits System Xc⁻, restricts cystine uptake and glutathione synthesis, and promotes ferroptosis, whereas intracellular glutamate production, glutaminolysis, SLC7A11-coupled glutamate export, and receptor-mediated signaling have distinct, context-dependent consequences. Dopamine and 5-HT exert context-dependent effects through receptor subtype-specific metabolic rewiring. Sympathetic neurotransmitters, including norepinephrine, enhance glycolysis and lactate-driven immunosuppression through β₂-adrenergic signaling. In parallel, the gut-brain axis modulates tumor susceptibility to RCD by shaping the availability of microbiota-derived neurotransmitter precursors and metabolites. Mechanistically, neurotransmitter signaling converges on RCD programs by regulating redox homeostasis, lipid peroxidation, mitochondrial vulnerability, and inflammatory signaling. Integrating these observations, this review proposes a conceptual framework termed the "Neurotransmitter-Novel Cell Death-Gut-Brain Axis," which links neural signaling, microbial metabolism, and tumor cell death decisions. Building on this framework, we highlight therapeutic strategies combining receptor-subtype-specific neurotransmitter modulation with selective induction of RCD pathways to overcome metabolic plasticity, immune evasion, and therapy resistance. Targeting this integrated neuro-metabolic-death network may offer a clinically actionable avenue to enhance tumor sensitivity to existing and emerging anticancer therapies.