Effect of PTEN Overexpression Plus Anti‐PD‐1 on Immune Escape in Oral Squamous Cell Carcinoma

ABSTRACT Objectives Phosphatase and tensin homolog (PTEN) is an essential regulator of tumor proliferation, apoptosis, and migration. However, the mechanisms by which PTEN regulates immune escape and its implications in immune checkpoint inhibitor combination therapy in oral squamous cell carcinoma (OSCC) remain unclear. Methods We analyzed the expression of PTEN and PD‐L1 in OSCC tissues and cell lines, and their associations with clinicopathological characteristics. The role of PTEN in modulating PD‐L1 expression and facilitating tumor immune evasion was investigated using western blotting and T‐cell cytotoxicity assays. PTEN regulation efficacy, alone or with immune checkpoint inhibitors, was evaluated in humanized xenograft mice. Results Reduced PTEN and increased PD‐L1 were strongly correlated with high clinical stage, positive lymph node metastasis, and lower CD8 + T‐cell infiltration. Patients with lower PTEN, higher PD‐L1, higher clinical stage, and positive lymph node metastasis experienced shorter overall survival. PTEN overexpression suppressed PD‐L1 levels and promoted cytotoxic T‐cell activity in OSCC cells by inhibiting PI3K/AKT signaling in vitro. Upregulating PTEN alone or combined with anti‐PD‐1 treatment effectively inhibited OSCC tumor progression and promoted CD8 + T‐cell infiltration in tumors in vivo. Conclusions PTEN upregulation enhances the antitumor immune response of CD8 + T‐cells, suggesting a potential OSCC immunotherapy strategy.