Clinical and translational medicine · 2026
Lactate-induced metabolic reprogramming of TAMs impairs antigen presentation capacity via C/EBPα-CD74 axis in oral squamous cell carcinoma.
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Wang Mengyao, Wang Mengqi, Gong Zizhen, Zeng Fanrui, Ni Zihui, Zhai Rundong, Zhu Weiwen, Zhang Jiayi, Liu Laikui
Аннотация
BACKGROUND: Throughout oral squamous cell carcinoma (OSCC) progression, tumor-associated macrophages (TAMs) lose their antigen-presenting capacity and anti-tumor function. The mechanisms that cause this dysfunction are not fully understood. CD74 is essential for antigen-presenting process, while little direct evidence describes its role in TAMs' immune function.
METHODS: We integrated single-cell transcriptomic analysis, clinical cohort validation and CD74 conditional knockout mouse model to investigate the role of CD74 in TAMs during OSCC progression. Metabolomic analysis and mechanistic studies were performed to dissect how lactate-mediated metabolic reprogramming regulates CD74 expression.
RESULTS: We demonstrate that lactate accumulation in TME induces metabolic reprogramming of TAMs, which drives the acetylation of C/EBPα, and consequently suppresses CD74 expression. This downregulation of CD74 impairs the antigen-presenting capacity of TAMs, suppresses T cell activation, and ultimately promotes OSCC progression and recurrence.
CONCLUSIONS: Our findings reveal the critical role of the lactate-C/EBPα-CD74 axis in shaping TAMs function, and provide potential therapeutic target for OSCC immunotherapy.
KEY POINTS: CD74hi TAMs decrease during OSCCprogression and are associated with patient prognosis. Loss of CD74 impairs antigen presentation andsuppresses T cell activation. Tumor-derived lactateinhibits CD74 transcription via C/EBPα acetylation.
METHODS: We integrated single-cell transcriptomic analysis, clinical cohort validation and CD74 conditional knockout mouse model to investigate the role of CD74 in TAMs during OSCC progression. Metabolomic analysis and mechanistic studies were performed to dissect how lactate-mediated metabolic reprogramming regulates CD74 expression.
RESULTS: We demonstrate that lactate accumulation in TME induces metabolic reprogramming of TAMs, which drives the acetylation of C/EBPα, and consequently suppresses CD74 expression. This downregulation of CD74 impairs the antigen-presenting capacity of TAMs, suppresses T cell activation, and ultimately promotes OSCC progression and recurrence.
CONCLUSIONS: Our findings reveal the critical role of the lactate-C/EBPα-CD74 axis in shaping TAMs function, and provide potential therapeutic target for OSCC immunotherapy.
KEY POINTS: CD74hi TAMs decrease during OSCCprogression and are associated with patient prognosis. Loss of CD74 impairs antigen presentation andsuppresses T cell activation. Tumor-derived lactateinhibits CD74 transcription via C/EBPα acetylation.