Downregulation of SLC44A4 in nasopharyngeal carcinoma is associated with malignant progression, B-cell/TLS-related immune features, and sensitivity to DNA-damaging agents.

Abstract

Nasopharyngeal carcinoma (NPC) is characterized by aggressive progression, frequent metastasis, and heterogeneous therapeutic responses. Through integrated bulk transcriptomic datasets, single-cell analysis, clinical specimens, and NPC cell lines, we identified SLC44A4, a member of the choline transporter-like family, as a significantly downregulated gene in NPC. Transcriptomic analyses revealed that SLC44A4 expression was negatively associated with oxidative phosphorylation-related genes, DNA damage repair pathways, and malignant transcriptional programs related to proliferation, invasion, and metastasis. Moreover, SLC44A4-high tumors exhibited increased B-cell infiltration and enrichment of TLS-related transcriptional signatures. In vitro, SLC44A4 overexpression in NPC cells suppressed proliferation, colony formation, migration, and invasion, induced G0/G1 cell-cycle arrest, reduced expression of oxidative phosphorylation-related proteins, and selectively upregulated CXCL10. SLC44A4 overexpression also increased sensitivity to DNA-damaging agents, including temozolomide, doxorubicin, cisplatin, olaparib, and etoposide, while decreasing sensitivity to 5-fluorouracil. Together, these findings identify SLC44A4 as a potential tumor-suppressive factor in NPC and suggest that SLC44A4 may serve as a biomarker for metabolic state, B-cell/TLS-associated immune features, and vulnerability to DNA damage-based therapies.