PA28gamma coordinates the cross-talk between cancer-associated fibroblasts and tumor cells to promote OSCC progression via HDAC1/E2F3/IGF2 signaling.

PA28gamma overexpression is aberrant and accompanied by poor patient prognosis in various cancers, the precise regulatory mechanism of this crucial gene in the tumor microenvironment remains incompletely understood. In this study, using oral squamous cell carcinoma as a model, we demonstrated that PA28gamma exhibits high expression in cancer-associated fibroblasts (CAFs), and its expression significantly correlates with the severity of clinical indicators of malignancy. Remarkably, we found that elevated levels of secreted IGF2 from PA28gamma(+) CAFs can enhance stemness maintenance and promote tumor cell aggressiveness through the activation of the MAPK/AKT pathway in a paracrine manner. Mechanistically, PA28gamma upregulates IGF2 expression by stabilizing the E2F3 protein, a transcription factor of IGF2. Further mechanistic insights reveal that HDAC1 predominantly mediates the deacetylation and subsequent ubiquitination and degradation of E2F3. Notably, PA28gamma interacts with HDAC1 and accelerates its degradation via a 20S proteasome-dependent pathway. Additionally, PA28gamma(+) CAFs exert an impact on the tumor immune microenvironment by secreting IGF2. Excitingly, our study suggests that targeting PA28gamma(+) CAFs or secreted IGF2 could increase the efficacy of PD-L1 therapy. Thus, our findings reveal the pivotal role of PA28gamma in cell interactions in the tumor microenvironment and propose novel strategies for augmenting the effectiveness of immune checkpoint blockade in oral squamous cell carcinoma.