The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Heide, J. et al. Nature. 645:1051-1059. (2025).
doi: 645(8082):1051-1059.
Summary of the findings
Nicotinamide N-methyltransferase (NNMT) is a metabolic and epigenetic regulator that reprograms normal fibroblasts into cancer-associated fibroblasts (CAFs) across various types of cancer (Eckert et al., 2019). Mechanistically, high NNMT expression in CAFs depletes the universal methyl donor S-adenosylmethionine (SAM) to produce 1-methylnicotinamide, creating a metabolic sink. This decrease in SAM availability results in a global loss of H3K27me3, an epigenetic change that encourages a pro-tumorigenic CAF phenotype.
NNMT-activated CAFs create an immunosuppressive tumor microenvironment by secreting complement factors. Activation of the complement cascade activation recruits Ly6Chigh monocytes to the tumor site and promotes their differentiation into PD-L1+ monocytic myeloid-derived suppressor cells (M-MDSCs). These MDSCs directly inhibit the proliferation and effector functions of CD8+ T cells, thereby shielding the tumor from antitumor immunity. Nnmt knockout in the non-immune stroma of immunocompetent mice significantly reduces tumor growth and restores CD8+ T cell activity in syngeneic models of ovarian, breast, and colon cancer.
To translate these findings into a therapeutic strategy, we developed a potent, specific, and orally bioavailable NNMT inhibitor (NNMTi). X-ray crystallography revealed that this inhibitor effectively occupies both the cofactor- and substrate-binding pockets of the enzyme. In vivo, NNMTi treatment reverses the epigenetic reprogramming of CAFs, reduces C3 secretion, and decreases the recruitment of immunosuppressive M-MDSCs, while increasing CD8+ T cell activation.
Consequently, NNMTi treatment decreased tumor burden and metastasis in multiple mouse models. We further show that NNMTi treatment sensitized tumors to immune checkpoint blockade, such as anti-PD-1 and anti-CD47, by restoring CD8+ T cell activation. These findings establish NNMT as a key epigenetic regulator of CAF activation and a promising therapeutic target to reduce stroma-driven immunosuppression and enhance the effectiveness of immunotherapies.
