Mutant IDH1 inhibition induces dsDNA sensing to activate tumor immunity
mIDH1 generates the oncometabolite (R)-2-hydroxyglutarate (R-2HG), which is a key factor in promoting tumorigenesis and enabling immune evasion in solid tumors. To understand how mIDH1 inhibition restores immune surveillance, a series of investigations were carried out.Employing a mouse model of liver cancer, the study reveals that mIDH1 inhibition precipitates a prompt and significant DNA demethylation event within tumor cells. Concurrently, this inhibition curtails tumor cell proliferation and instigates a remarkable influx of CD8+ T cells. Transcriptional analysis uncovers the early activation of a constellation of genes integral to type I interferon and viral response pathways.The root cause of this transcriptional upheaval lies in the epigenetic induction of viral mimicry. This entails the awakening of dormant transposable elements (TEs), which, once liberated, are detected by cytosolic dsDNA sensors, thereby kindling the innate immune response.A critical revelation is that mIDH1 tumors are marred by a congenital defect in their innate immune signaling apparatus, manifested as the hypermethylation and silencing of the cGAS locus. However, the inhibition of mIDH1 emerges as a panacea, reversing the DNA hypermethylation and reanimating the cGAS-STING-IRF3 signaling axis. This resuscitation is driven by dsDNA originating from TE-derived reverse transcriptase activity, culminating in a fortified antitumor immunity.The veracity of these findings is corroborated in human intrahepatic cholangiocarcinoma and glioma models. In these human counterparts,mIDH1 inhibition recapitulates the key immunological events witnessed in the murine model, encompassing the upregulation of cGAS and STING, the ignition of type I interferon and viral response gene signatures, and the augmentation of antitumor immunity.In sum, this study has unearthed a dual therapeutic modality underpinning mIDH1 inhibition. This entails the induction of viral mimicry signaling and the restitution of the interferon-γ response. By illuminating these complex pathways, the research not only enriches our understanding of the tumor-immune dialogue but also charts a course for the rational design of combination therapies. Such strategies, engineered to amplify the viral mimicry response in mIDH1 cancers, hold the potential to redefine cancer treatment paradigms and herald a new era of improved patient outcomes.DOI: 10.1126/science.adl6173
Tumor cells impair immunological synapse formation via central nervous system-enriched metabolite
![]()
Yihong Li. et al.
In the pursuit of understanding cancer's evasion tactics from immune surveillance, this comprehensive study uncovers a remarkable phenomenon by meticulously analyzing multi-omics data sourced from HER2+ breast cancer patients subjected to trastuzumab and anti-PD-L1 antibody regimens. The CNS-enriched N-acetyltransferase 8-like (NAT8L) and its metabolite N-acetylaspartate (NAA) are found to be highly overexpressed in tumors that exhibit resistance. Intriguingly, within the CNS context, NAA is liberated during episodes of brain inflammation. NAT8L, through the action of NAA, plays a dual role: it mitigates brain inflammation and concurrently undermines anti-tumor immunity by suppressing the cytotoxic capabilities of natural killer (NK) cells and CD8+ T cells. Delving deeper into the molecular machinery, NAA emerges as a disruptor of the immunological synapse formation process. It achieves this by facilitating the PCAF-induced acetylation of lamin A-K542. This acetylation event has far-reaching consequences, as it impedes the seamless integration between lamin A and SUN2 and throws off the delicate balance of lytic granule polarization. The implications of these findings are profound, revealing that tumor cells have ingeniously co-opted the CNS's anti-inflammatory strategy to elude the clutches of the immune system. Of particular significance is the identification of NAT8L as a promising target. By targeting NAT8L, there lies the potential to enhance the effectiveness of anti-cancer agents and tip the scales in favor of the immune system in its battle against cancer. In summary, this research not only enriches our understanding of the complex and elusive mechanisms governing tumor immune evasion but also shines a light on a potential therapeutic avenue. It thus holds the promise of revolutionizing cancer immunotherapy strategies and opening new doors for the development of more potent and targeted treatments, offering hope for improved cancer management and patient outcomes.
DOI: 10.1016/j.ccell.2024.05.006
Editor & Reviewer: Congci Yu
