USP25 attenuates the immunosuppressive tumor microenvironment via the deubiquitination of TAB2 in head and neck squamous cell carcinoma

The role of deubiquitinating enzymes in the tumor immune microenvironment (TIME) remains understudied. Here, we sought to identify the mechanisms of USP25 modulation in the TIME of head and neck squamous cell carcinoma (HNSCC). Bioinformatics analysis was performed to screen differentially expressed novel deubiquitinases (DUBs) in HNSCC. The importance of USP25 in clinical practice was assessed in the TCGA dataset and tissue microarrays. Single-cell RNA-sequencing was applied to profile the TIME. The function of USP25 was determined through loss-of-function assays. Reduced expression of USP25 was associated with the malignant progression of HNSCC and further indicated poor prognosis. USP25 protein levels were positively correlated with CD8⁺ T-cell infiltration in HNSCC tissue cohorts, suggesting its role in modulating the TIME. Concordantly, this study revealed a reduction in myeloid-derived suppressor cells (MDSCs), concomitant with increased numbers of cytotoxic T cells in tumors with high USP25 expression. Mechanistically, we revealed that USP25 binds to TAB2, removes K63-linked ubiquitination chains, and subsequently activates MAPK signaling and the secretion of IL-6, which increases MDSCs migration. Increased MSDCs in turn antagonized functional CD8⁺ T cells in the TIME. Importantly, overexpression of USP25 increased anti-PD1 therapeutic efficacy in HNSCC in vivo. These results underscore the critical role and mechanism of USP25 in modulating the TIME in HNSCC, suggesting its potential as a therapeutic target in immune checkpoint blockade therapy.