ZBP1 identified as immunoregulator reshaping 'cold' tumour microenvironments in head and neck cancer

Researchers have identified Z-DNA binding protein 1 (ZBP1) as a candidate immunoregulatory hub in head and neck squamous cell carcinoma (HNSCC), a cancer type that frequently resists programmed cell death protein 1 (PD-1) checkpoint blockade due to an immunologically 'cold' tumour microenvironment (TME). The paper, authored by Yu Min and colleagues and published in *PLOS Genetics* on 26 May 2026, used integrated analysis of The Cancer Genome Atlas (TCGA) and SangerBox datasets alongside multiplex immunofluorescence on patient tumour samples.

The study found that high ZBP1 expression correlated with increased infiltration of cytotoxic CD8-positive T cells (Pearson r = 0.48) and was associated with improved predicted responses to immunotherapy. Mechanistically, the authors show that ZBP1 reprogrammes the immunosuppressive TME, increasing the ratio of CD8-positive to CD4-positive T cells and modulating CD68-positive macrophage populations. Clinically, high ZBP1 expression predicted better outcomes in patients treated with PD-1 blockade in the datasets examined.

The findings are based on retrospective genomic and transcriptomic analyses and correlative immunofluorescence data. Experimental validation in model systems and prospective clinical evidence would be needed to determine whether ZBP1 status has utility in stratifying patients for immunotherapy or as a therapeutic target. The research contributes to ongoing efforts to identify molecular determinants of immunotherapy response in HNSCC, where treatment options for non-responders remain limited.