This study investigates the relationship between metabolic characteristics and the tumor immune microenvironment (TME) in oral squamous cell carcinoma (OSCC) using spatial transcriptomics and single-cell sequencing. The researchers found that metabolic heterogeneity within OSCC tissues is associated with distinct TME compositions. Hypermetabolic regions, dominated by epithelial tissues, showed higher infiltration of CD4 T cells and regulatory T cells (Tregs), leading to increased TGF-β secretion and immune suppression. Fibroblasts in these regions transformed into inflammatory cancer-associated fibroblasts (iCAFs) through lactate utilization, promoting the expression of CXCL12, which recruits Tregs. This process is regulated by the PI3K-Akt-HIF1A axis. The study highlights the importance of metabolic characteristics in defining the TME and suggests potential therapeutic targets, such as targeting lactate utilization and CXCL12 expression, to enhance immune checkpoint blockade therapy.This study investigates the relationship between metabolic characteristics and the tumor immune microenvironment (TME) in oral squamous cell carcinoma (OSCC) using spatial transcriptomics and single-cell sequencing. The researchers found that metabolic heterogeneity within OSCC tissues is associated with distinct TME compositions. Hypermetabolic regions, dominated by epithelial tissues, showed higher infiltration of CD4 T cells and regulatory T cells (Tregs), leading to increased TGF-β secretion and immune suppression. Fibroblasts in these regions transformed into inflammatory cancer-associated fibroblasts (iCAFs) through lactate utilization, promoting the expression of CXCL12, which recruits Tregs. This process is regulated by the PI3K-Akt-HIF1A axis. The study highlights the importance of metabolic characteristics in defining the TME and suggests potential therapeutic targets, such as targeting lactate utilization and CXCL12 expression, to enhance immune checkpoint blockade therapy.