Potential implementation of (p)EMT signatures in the treatment of HNSCC. Two major treatment modalities can be defined as (A) multi-modal therapy and definitive radio(chemo)therapy (B); definitive R(C)T). Multi-modal therapy includes a surgical resection of the primary tumor and the loco-regional lymph nodes, and adjuvant R(C)T. Definitive R(C)T relies on radiotherapy or radio- and chemotherapy without prior surgical removal of the primary tumor. In both treatment modalities, RNA sequencing of primary HNSCC from biopsy material at initial diagnosis can help to develop (p)EMT risk scores based on validated EMT signatures [44,67]. Bioinformatic pipelines can identify potential correlations of (p)EMT risk scores with signaling pathways that are targets for approved inhibitors, which can thereby be administered in a personalized manner in multi-modal (A) and definitive R(C)T treatment regimens (B). (Figure generated using BioRender, Toronto, ON, Canada).