RUVBL1-mediated mTORC1 activation drives tumour progression and immune evasion for oral squamous cell carcinoma.

BACKGROUND AND AIMS: Oral squamous cell carcinoma (OSCC) is a prevalent head and neck malignancy for which surgical resection remains the primary therapeutic approach. Although immunotherapy, particularly immune checkpoint blockade targeting PD-1/PD-L1, has been revolutionary, only a small number of patients with OSCC have clinically benefited from it. Therefore, elucidating the molecular mechanisms underlying OSCC progression and immune evasion is crucial. RuvB-like AAA ATPase 1 (RUVBL1) has been implicated in diverse biological processes and modulates tumour immunity. Little is known regarding the function of RUVBL1 and its mechanism of action in OSCC. In this study, we aimed to understand RUVBL1 regulation in OSCC tissues and how expression correlates with patient prognosis.

MATERIALS AND METHODS: We conducted bioinformatics analysis, functional assays in vitro, co-culture experiments, and murine xenograft models, along with validation in clinical samples. To investigate the underlying mechanism, transcriptome sequencing and biochemical as well as molecular analyses were utilized.

KEY FINDINGS: RUVBL1 promotes tumour growth and regulates the tumour microenvironment by controlling PD-L1 expression by targeting the rapamycin kinase (mTOR) pathway, thereby impairing both the infiltration and effector function of T cells in OSCC. Pharmacological inhibition of RUVBL1 with CB6644 suppressed tumour growth and synergised with PD-L1 blockade and conventional therapy. Collectively, these findings identify RUVBL1 as a critical driver of OSCC progression and immune modulation.

SIGNIFICANCE: Our findings highlight the potential of RUVBL1 as a prognostic biomarker and therapeutic target to enhance treatment efficacy.