Self-amplifying nicotinamide N-methyltransferase feedback loops: Drivers of anticancer drug resistance and therapeutic opportunities

Drug resistance poses a significant challenge in cancer therapy, undermining treatment efficacy and patient survival. Nicotinamide N-methyltransferase (NNMT), a pivotal cytoplasmic enzyme, plays a crucial role in mediating drug resistance by linking nicotinamide adenine dinucleotide (oxidized form) (NAD + ) metabolism and the S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) methylation cycle. Notably, self-amplifying NNMT feedback loops in cancer cells drive the development of resistance to anticancer drugs. NNMT reduces the cytotoxicity of chemotherapeutic agents, drives resistance to targeted therapies such as kinase inhibitors and monoclonal antibodies, and facilitates immune evasion, thereby diminishing the efficacy of immunotherapy. It also amplifies resistance through self-reinforcing feedback loops, including the NNMT/aldehyde dehydrogenase 3 family member A1 (ALDH3A1)/lactate/NNMT and early growth response 1 (EGR1)/NNMT/EGR1 circuits, which intensify resistance signaling within the tumor microenvironment. While novel therapeutic strategies targeting NNMT, such as gene silencing, small-molecule inhibitors, and feedback circuit interventions, show promise in reversing resistance, their clinical translation remains challenging. Future research should focus on elucidating the interplay between NNMT and lactate metabolism (including exercise-modulated lactylation), identifying additional NNMT-associated feedback loops, and investigating NNMT's regulatory roles in alternative metabolic pathways. These efforts may yield new insights and therapeutic targets to overcome drug resistance and improve clinical outcomes for cancer patients. • NNMT promotes drug resistance via multiple mechanisms. • NNMT's self-activating feedback loops amplify resistance signals. • NNMT significantly increases the risk of cancer cell drug resistance. • High NNMT levels diminish anticancer drug sensitivity and treatment efficacy. • NNMT-targeted therapies restore anticancer drug sensitivity in preclinical models.