Fig. 1

Pro- and anti-tumor effects of NMD inhibition. NMD has been shown to play a critical role in tumors, displaying, at the same time, a pro-tumor and tumor suppressor activity, depending on the genetic context and tumor microenvironment. NMD, degrading mRNAs with a PTC, protects cells from the formation of potentially toxic proteins. Indeed NMD pathway inhibition results in tumor cell toxicity due to the accumulation of mutated protein. Moreover, immunogenic peptides, derived from these proteins, could act as neoantigens able to activate T-cell response against tumor cells, inducing so an immune-dependent reduction of tumor growth. Furthermore, NMD physiologically regulates genes involved in DNA damage response, so NMD inhibition results in a reduction of tumor capacity to respond to DNA damage and in a greater sensitivity to chemotherapy. On the other hand, for its tumor-suppressor role, NMD is often inhibited by microenvironmental cues, as hypoxia or oxidative stress, determining an increased expression of ISR components, like ATF3 and CHOP, or antioxidant agent such as SLC7A11. In this way, NMD inhibition protects cancer cells from elevated level of ROS and reduced oxygen concentration allowing tumor adaptation to stress conditions. Moreover, impaired NMD was found to favor activation of the NF-kB pathway so inducing an inflammatory state and favoring tumor cell survival. Adapted from BioRender.com