Targeting PERP promotes anti-tumor immunity in HNSCC by regulating tumor immune microenvironment and metabolic homeostasis.

Background: PERP may have the potential to function as an oncogene. However, the precise function, prognostic value, and predictive significance remain shrouded in ambiguity.

Methods: We conducted an in-depth analysis using pan-cancer RNA sequencing data and various online web tools to investigate the correlation between PERP and crucial clinical outcomes such as prognosis, tumor microenvironment, and tumor metabolism. In addition, we explored the tumor-promoting role of PERP and its potential mechanisms through models such as immunofluorescence staining, flow cytometry, cell proliferation assays, wound healing assays, cell migration assays, mass spectrometry analysis and isotope tracing. Further in vivo models confirmed the functional consistency of PERP across pan-cancer. Finally, we analyzed the potential of PERP as a predictive factor for immunotherapy sensitivity in a clinical cohort.

Results: PERP exhibits elevated expression in the majority of cancer types and impedes immune cell infiltration as well as immune checkpoint reactivity in pan-cancer. We confirmed that PERP can promote tumor progression by tumor cell proliferation, scratch and transwell experiments. Meanwhile, the absence of PERP restricts the flux of C-glucose into glycolysis and the tricarboxylic acid (TCA) cycle. Importantly, the deficiency of PERP enhances the in vivo anti-tumor efficacy of PD1 monoclonal antibodies. In addition, low PERP expression is highly correlated with the response of head and neck squamous cell carcinoma (HNSCC) patients to immunotherapy.

Conclusions: PERP represents a promising predictive/diagnostic biomarker and therapeutic target for HNSCC patients.