SLC4A7 Drives NSCLC Progression and Immune Evasion via pH Dysregulation: Its Targeting Synergizes with Anti-PD-1/L1 Therapy.

Solid tumors create an acidic tumor microenvironment (TME) that drives cancer progression, therapy resistance, and immune evasion. Bicarbonate is crucial for maintaining acid-base balance, however, its role in non-small cell lung cancer (NSCLC) remains unclear. Through the analysis of single-cell RNA sequencing data and the TCGA and CPTAC databases, we identified solute carrier family 4 member 7 (SLC4A7) as the predominantly expressed bicarbonate transporter in NSCLC. Functionally, SLC4A7 knockdown impaired bicarbonate uptake, resulting in intracellular acidification and extracellular alkalinization. This phenomenon led to a decrease in glycolysis and subsequently suppressed the growth and metastasis of NSCLC. Both in vivo and in vitro data demonstrate that the alkalinization of the TME induced by Slc4a7 knockout enhances the infiltration and function of cytotoxic T cells, significantly inhibiting tumor growth. Additionally, Slc4a7 knockout exhibits synergistic antitumor efficacy in combination with PD-1/PD-L1 immune checkpoint inhibitors. Mechanistically, integrative analysis of RNA-seq and ATAC-seq data identified CTCF as a transcription factor regulating SLC4A7 expression. In summary, our study demonstrates that SLC4A7-mediated bicarbonate transport is crucial for maintaining acid-base homeostasis in NSCLC and represents a promising therapeutic target for this disease.