A robust risk signature based on transient receptor potential family genes (TFGs) for prognosis evaluation in head and neck squamous cell carcinoma (HNSCC) was developed, and the TFGs-based signature (TFBS) proposed herein could be a favorable indicator to predict the survival outcome in HNSCC and provides prominent treatment guidance.

• Using HNSCC sample data from the TCGA website, experts integrated expression profiles of TFGs for 490 HNSCC cases.

• Screening of 6 TFGs (TRPC1, TRPC3, TRPC6, TRPV2, TRPV4, and TRPM8) closely linked with prognosis of HNSCC cases was conducted to construct TFBS.

• A dismal patient outcome in the TFBS-high group was predicted by TFBS.

• On Cox regression, favorable independent value of TFBS was evident.

• In receiver operating characteristic analysis, TFBS demonstrated robust power for predicting prognosis.

• In gene set enrichment analysis, various important pathways associated with HNSCC were unveiled, including the p53 pathway, TNF-alpha signaling via NFKB, and hypoxia.

• Patients in the TFBS-high group were more likely in immunosuppressive status.