Targeting the STAT5A–LCP2–NF-κB Pathway to Overcome PD-1 Resistance in Esophageal Cancer

Aims: To investigate the tumor-intrinsic lymphocyte cytosolic protein 2 (LCP2) in esophageal squamous cell carcinoma (ESCA) and its molecular mechanisms in mediating resistance to programmed death-1 (PD-1) therapy. Methods: The expression of LCP2 in ESCA was analyzed using bioinformatics databases and further verified in clinical specimens. Functional studies employed patient-derived organoid models, xenograft models, and molecular assays to assess the impact of LCP2 knockout or overexpression on macrophage polarization, CD8 + T cell exhaustion, and PD-1 therapy response. Mechanistic investigations included nuclear factor-κB (NF-κB) inhibition, signal transducer and activator of transcription 5A (STAT5A) knockdown, chromatin immunoprecipitation, and dual-luciferase reporter assays. Results: LCP2 was markedly upregulated in ESCA and correlated with advanced stage, lymph node metastasis, and poor survival. Tumor-intrinsic LCP2 expression positively correlated with M2 macrophage polarization and sorted CD8 + T cell exhaustion. Mechanistically, this association depended on NF-κB pathway activation in EpCAM + tumor fractions, while STAT5A transcriptionally regulates tumor-intrinsic LCP2 expression as an upstream transcription factor. Knockdown of tumor-intrinsic LCP2 or STAT5A in EpCAM + tumor fractions suppressed the secretion of immunosuppressive cytokines and restored effector T cell function of sorted CD8 + T cells. In vivo , LCP2 depletion significantly inhibited tumor growth and synergized with PD-1 blockade. This synergistic effect was characterized by reduced tumor volume and increased CD8 + T cell infiltration. Overexpression of LCP2 reversed these effects, confirming its central role in immune escape. Conclusion: The STAT5A–LCP2–NF-κB axis remodels the immunosuppressive tumor microenvironment to mediate ESCA immune escape and PD-1 resistance. Targeting this regulatory axis provides a novel strategy to overcome immunotherapy resistance in esophageal cancer. Antioxid. Redox Signal. 00, 000–000.