Tams Metabolic Dysfunction Disrupts Cd74-Dependent Antigen Presentation In Oscc

This research aims to elucidate the key mechanism by which lactate accumulation in the tumor microenvironment of OSCC reprograms the energy metabolism of tumor-associated macrophages (TAMs), leading to acetylation-mediated suppression of the transcription factor C/EBPα. This epigenetic modification disrupts CD74-dependent antigen presentation in TAMs, ultimately driving immune evasion and promoting tumor invasion and metastasis. We employed single-cell RNA sequencing combined with clinical samples to analyze the relationship between CD74hi TAMs and the prognosis of OSCC.In vivo and in vitro experiments and multi-omics approaches were utilized to screen and validate the interplay among lactate accumulation, energy metabolism reprogramming, and impaired antigen presentation in TAMs, specifically investigating the role of TAMs antigen presentation in tumor progression. Finally, in vitro functional assays were conducted to dissect the mechanistic link between lactate-induced metabolic dysregulation and transcriptional suppression of CD74 via C/EBPα acetylation. CD74hi TAMs, identified as an antigen-presenting functional subset, exhibit reduced infiltration in OSCC, which is strongly correlated with poor patient prognosis. CD74 expression in TAMs is essential for antigen presentation, and its downregulation leads to impaired antigen-presenting capacity, thereby suppressing subsequent T cell activation and promoting tumor immune evasion. In the tumor microenvironment of OSCC, lactate accumulation induces metabolic reprogramming in TAMs, promoting the acetylation modification of the transcription factor C/EBPα. Acetylated C/EBPα further suppresses CD74 expression, thereby impairing the antigen-presenting capacity of TAMs and ultimately leading to cytotoxic T cell exhaustion.