Activation of GABBR1 by New Ligand Valerate Transcriptionally Regulates ATF4-NRF2-CXCL13 Axis Mediating CD8+ T Cell Anti-Tumor Immunity.

Lung cancer has the highest mortality rate globally, yet the effective treatment options remain limited. Although short-chain fatty acids (SCFAs) like acetate, propionate, and butyrate are known to modulate immune response and improve the efficacy of cancer therapy, the role of valerate in non-small cell lung cancer (NSCLC) remains unexplored. This study identifies valerate as a biased ligand for GABAB receptor, which specifically binds the GABBR1 subunit, upregulates its expression, and thereby mediates CD8+ T cell anti-tumor immunity in NSCLC. It is demonstrated that GABBR1 overexpression in lung cancer cells suppresses tumor growth both in vitro and in vivo. Single-cell RNA sequencing analysis of public datasets indicates that GABBR1 expression is associated with CXCL13. Mechanically, in vitro and in vivo experiments validate that valerate-induced upregulation of GABBR1 stimulates the secretion of CXCL13, which in turn promotes robust infiltration and activation of CD8+ T cells within the tumor microenvironment. Furthermore, enrichment analysis pinpoints that CXCL13 secretion is negatively transcriptionally regulated by NRF2 and its co-factor ATF4. Analysis of patient samples further confirms that high GABBR1 expression correlates with a longer patient survival rate, underscoring its prognostic value. Overall, these findings identify valerate as a novel immunomodulatory metabolite and propose targeting GABBR1 as a promising strategy to potentiate cancer immunotherapy in lung cancer.