1358-GABA-Driven Immunotherapy Resistance in Tumors

Recent research by Hernández-Verdin et al. reveals that tumor-derived GABA acts as a metabolic barrier to immunotherapy success in patients whose tumors contain tertiary lymphoid structures (TLSs). Although these structures usually indicate a positive response to treatment, high levels of GABA create a dysfunctional immune environment that leads to therapeutic resistance. The study identifies specific proximal tubule-like tumor cells as the primary source of this neurotransmitter, which suppresses B cell maturation and antibody production. By integrating spatial transcriptomics and metabolic profiling, the authors demonstrate that GABA interferes with the energy cycles and signaling necessary for effective immune activation. Experimental models show that pharmacologically blocking GABA synthesis can reinvigorate the immune response and improve the efficacy of anti-PD1 therapies. These findings suggest that targeting GABA pathways could be a viable strategy to overcome resistance in various cancers, including renal cell carcinoma and soft tissue sarcoma.

References:

• Hernández-Verdin I, Calvez A, Sun C M, et al. GABA promotes resistance to immunotherapy in patients with TLS-positive tumors[J]. Cancer Cell, 2026.