NSUN2, short for NOP2/Sun RNA methyltransferase family member 2, is a key 5-methylcytosine (m5C) RNA methyltransferase. m5C modification is an epigenetic modification on various RNA species such as tRNAs, mRNAs, and non-coding RNAs, which impacts RNA stability, translation efficiency, and cellular stress responses, thus influencing cell proliferation, differentiation, and survival [3]. NSUN2-related pathways are involved in many biological processes and are closely associated with tumorigenesis [3]. Genetic models, like KO/CKO mouse models, are valuable for studying NSUN2's functions.

In esophageal squamous cell carcinoma (ESCC), NSUN2 knockout mouse models demonstrated that silencing NSUN2 suppressed tumorigenesis and progression. Mechanistically, NSUN2 induced m5C modification of GRB2, stabilizing its mRNA through LIN28B, and activating PI3K/AKT and ERK/MAPK signalling [4]. In endometrial cancer, knockdown of NSUN2 increased lipid peroxides and lipid ROS, augmenting susceptibility to ferroptosis. NSUN2 promoted m5C modification of SLC7A11 mRNA, recognized by YBX1, increasing SLC7A11 stability and levels [2]. Also, genetic deletion of the glucose/NSUN2/TREX2 axis in "cold tumors" suppressed tumorigenesis and overcame anti-PD-L1 immunotherapy resistance via cGAS/STING activation [1].

In conclusion, NSUN2 is crucial for maintaining RNA m5C methylation, which affects multiple biological processes. Through model-based research, especially KO/CKO mouse models, we've seen its significant roles in various cancers including ESCC, endometrial cancer, and in modulating tumorigenesis and immunotherapy resistance in "cold tumors". Understanding NSUN2 provides insights into disease mechanisms and potential therapeutic targets.