Tumor cell-specific exon 3-deleted FOXP3 isoform promotes growth and metastasis via STAT3 in non-small cell lung cancer.

Forkhead box P3 (FOXP3), the master regulator of regulatory T cells (Tregs), is aberrantly expressed in tumor cells, including lung cancer. Alternative splicing generates multiple isoforms, among which the full-length FOXP3 (FOXP3FL) and exon 3-deleted variant (FOXP3Δ3) are predominant. We identified FOXP3Δ3 as the major isoform in non-small cell lung cancer (NSCLC) tumor cells. FOXP3Δ3 expression was elevated in tumor tissues and correlated with larger tumor size and advanced T stage. Functional assays showed that tumoral FOXP3Δ3 enhanced proliferation, invasion, migration, stemness, and apoptosis resistance in NSCLC cells, exerting stronger effects than FOXP3FL. Knockdown of FOXP3Δ3 in NSCLC cells suppressed tumor growth in nude mice, confirming its oncogenic activity in vivo. Mechanistically, FOXP3Δ3 upregulated phosphorylated STAT3 and mesenchymal markers (N-cadherin, Vimentin, Snail), while reducing epithelial marker E-cadherin compared with FOXP3FL. Coimmunoprecipitation indicated these differences may arise from distinct STAT3 binding affinities. Additionally, FOXP3Δ3 decreased cisplatin-induced apoptosis, suggesting a role in chemoresistance. In summary, FOXP3Δ3 is the predominant oncogenic FOXP3 isoform in NSCLC tumor cells, promoting tumor cell progression and therapy resistance through STAT3 signaling. These findings highlight FOXP3Δ3 as a potential therapeutic target.