There was a 65‐fold increase in IDO1 in 10 PD‐L1+ vs 5 PD‐L1− HPV+HNSCCs (P = .004). IDO1 expression was upregulated and co‐localised in the TME of the validation cohort. IDO1 expression increased and correlated with disease progression in anti‐PD‐1 treated HNSCC patients. Here, CD274 is linked to head and neck squamous cell carcinoma.