# Lactate‐induced metabolic reprogramming of TAMs impairs antigen presentation capacity via C/EBPα–CD74 axis in oral squamous cell carcinoma

## TL;DR

Tumor lactate disrupts immune cell function in oral cancer by reducing CD74, offering a new target for immunotherapy.

## Contribution

Identifies the lactate-C/EBPα-CD74 axis as a novel mechanism impairing TAM antigen presentation in OSCC.

## Key findings

- Lactate accumulation in the tumor microenvironment suppresses CD74 expression via C/EBPα acetylation.
- Loss of CD74 in TAMs impairs antigen presentation and T cell activation, promoting cancer progression.
- Restoring CD74 function enhances T cell activation and limits oral cancer progression.

## Abstract

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.

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.

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.

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.

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.

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.

• CD74hi TAMs correlate with favourable prognosis in OSCC.

• Lactate reprograms TAMs metabolism and increases mitochondrial respiration.

• C/EBPα acetylation suppresses CD74 and impairs antigen presentation.

• Restoring CD74 enhances T‐cell activation and limits OSCC progression.