Fig. 1: Alternative pathways of TNF signalling and their alterations in HNSCC.

TNF signalling can lead to different results. It depends on the post-translational modification and activation of key molecules such as caspase-8, RIPK1 and NF-κB. While active caspase-8 triggers apoptosis and suppresses necroptosis, its inactivity (e.g. by mutations) leads to necroptosis through RIPK3 activation. If the RIPK1 signal is modified by the addition of ubiquitin, cell death can be attenuated, and the cell receives a signal for survival and proliferation by the transcription factor NF-κB. NF-κB pathway inhibitors such as LUBAC inhibitors or SMAC mimetics can sensitise HNSCC cells to necroptosis or apoptosis. For successful anticancer treatment response, the pathway marked by red exes should be inhibited (inhibition of autophagy should be also beneficial for necroptosis triggering). The TNF signalling pathways are also significantly influenced by HPV infection and by the genetic background of HNSCC. Green bubbles indicate activation and pink inhibition of the process. LUBAC linear ubiquitin chain assembly complex, c-IAPs inhibitors of apoptosis, RIPK receptor-interacting serine/threonine–protein kinases, MLKL mixed lineage kinase domain-like pseudokinase.