NCAPH promotes immune evasion via inhibiting PD-L1 protein degradation in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is an epithelial carcinoma characterized by its distinct geographical distribution, exhibiting a higher prevalence in Southeast Asia. Despite the approval of immune checkpoint blockade (ICB) therapy for treating advanced recurrent HNSCC, the extent of patient benefit remains limited. Elucidating the molecular regulatory mechanisms of immunosuppressive tumor microenvironment in HNSCC is crucial for improving current treatment status and patient outcomes. Our findings show that knockdown of NCAPH suppresses cell proliferation, migration, and xenograft tumor growth, while enhancing radiotherapy-induced cellular apoptosis. Importantly, we found that NCAPH binds to PD-L1 and disrupts its degradation, competing with HIP1R (Huntingtin-interacting protein 1-related) and leading to the stabilization of PD-L1 protein, which contributes to the formation of immunosuppressive tumor microenvironment. To inhibit the interaction between NCAPH and PD-L1, we created a peptide known as NPIDP (NCAPH and PD-L1 Interaction Disrupting Peptide) that effectively disrupts the interaction between NCAPH and PD-L1. Furthermore, topotecan, a well-characterized topoisomerase I inhibitor, was identified to bind NCAPH and promote its proteasomal degradation. Notably, we demonstrated that NPIDP and topotecan suppress tumor immune evasion both in vitro and in vivo. In summary, our findings reveal the critical role of NCAPH in regulating tumor immune surveillance, suggesting that NCAPH could serve as a potential biomarker and therapeutic target for HNSCC in the future.