ADAMDEC1-driven CCL2-CCR2-PD-1 axis in esophageal squamous cell carcinoma: a dual threat of O-GlcNAcylation and m6A methylation in neoadjuvant therapy resistance and immune evasion

Esophageal squamous cell carcinoma (ESCA) constitutes a major global health burden, with immune evasion and therapeutic resistance posing significant challenges. This study aims to elucidate the molecular mechanisms underlying ESCA immune escape and resistance to neoadjuvant therapy, focusing on the role of ADAMDEC1 in regulating the tumor microenvironment (TME) and immune evasion. We performed transcriptome sequencing on 14 ESCA tumor tissues and adjacent non-tumor tissues from patients with or without neoadjuvant paclitaxel plus camrelizumab (PC) treatment. Bioinformatics analysis, functional validation, and in vitro and in vivo experiments were conducted to explore the regulatory mechanisms of ADAMDEC1 in ESCA. Patient-derived organoids (PDOs) and xenograft mouse models were utilized to assess the therapeutic effects of ADAMDEC1 knockout. ADAMDEC1 was found to be overexpressed in ESCA tumor tissues and positively correlated with M2 macrophage infiltration. ADAMDEC1 promotes M2 polarization of tumor-associated macrophages (TAMs) through the CCL2-CCR2-PD-1 signaling axis, facilitating immune evasion. Mechanistically, ADAMDEC1 stabilizes O-GlcNAc transferase (OGT) via protein-protein interaction, enhancing O-GlcNAc glycosylation of YTHDF1. This post-translational modification increases YTHDF1’s stability and translational efficiency of GLI2 mRNA, thereby activating the CCL2-CCR2-PD-1 axis. Additionally, FTO was identified as a key regulator of GLI2 expression by modulating m6A methylation levels on GLI2 mRNA in a YTHDF1-dependent manner. Our study reveals a novel ADAMDEC1-OGT-YTHDF1-GLI2 regulatory axis governing ESCA immune evasion and therapeutic resistance. Targeting this axis may provide a theoretical foundation for developing personalized immunotherapies and improving clinical outcomes in ESCA patients.