PTEN loss drives B7H3 upregulation via the mTORC2/FOXO/c-Myc axis to promote tumor immune escape in ovarian cancer

Immune checkpoint blockade (ICB) therapy has shown limited efficacy in ovarian cancer (OC). PTEN loss is a common driver in OC, yet its impact on ICB efficacy remains poorly understood. Utilizing the single-cell RNA sequencing data and performing multiplex immunohistochemical staining on treatment-naive OC clinical specimens, we showed that PTEN reduction resulted in an immunosuppressive tumor microenvironment associated with upregulated B7H3. Mechanistically, PTEN depletion activates mTORC2, which phosphorylates FOXO1/3, thereby inhibiting their transcriptional activity and reducing MXI1 expression. This, in turn, diminishes the inhibitory effect on c-Myc, leading to enhanced c-Myc transcriptional activity and subsequent upregulation of B7H3. Notably, in mouse models, anti-B7H3 therapy exhibits heightened effectiveness in OC with PTEN loss. This enhanced response can be abrogated by removing CD8⁺ T cells. Our findings elucidate an immune evasion mechanism in PTEN-loss OC and suggest B7H3 blockade as a potent therapeutic strategy specifically for these tumors.