N6 methyladenosine (m6A) is currently the most abundant mRNA modification found, typically associated with mRNA stability, splicing, and protein translation. This dynamic modification is accomplished by METTL3 (the enzyme active component of m6A written complex). METTL3 and its heterodimer component METTL14 are essential genes for cell survival, and the genetic regulatory mechanism of METTL3 has shown the role of m6A in regulating normal and malignant hematopoiesis. And these findings have driven drug discovery work, using inhibition of METTL3 to treat hematological cancer, and have been shown to improve the survival rate of mouse models in this situation.
The emergence of immunotherapy has greatly improved the natural history of cancer, including melanoma and lung cancer, among which the most successful type of anti-cancer immunotherapy targets key immune checkpoint molecules on tumor cells or T cells. Although these drugs have been successful in many individuals, the majority of patients treated with these advanced immunotherapies have not been cured and exhibit primary resistance, partial remission, or late recurrence of drug-resistant diseases. Therefore, utilizing non overlapping mechanisms to further enhance the immunogenicity of tumor cells remains a priority option.
Based on the above mechanism, it can be inferred that T cells can further kill tumor cells using this mechanism. As a result, the research team pre incubated tumor cells with METTL3 inhibitors and then co cultured them with T cells. It was found that the inhibitor group had a significant increase in killing ability compared to the control group (Figure 1), and this effect originated from the endogenous nature of tumor cells and was dependent on the antigen presentation mechanism. Based on the above in vitro data, the research team explored the efficacy evaluation of STM2457 (the PK data of STM3006 is too poor) and anti-PD1 in combination with the Cdx model in mice. The study found that the combination of the two drugs can significantly prolong the survival of mice compared to single drug use (Figure 2). Further single-cell analysis revealed significant differences in the signaling pathways targeted by STM2457 and anti-PD1, which can complement each other and synergistically target tumor inhibition, achieving the therapeutic effect of combination therapy.
Figure 1: Inhibition of METTL3 promotes the killing effect of T cells on tumors
Figure 2: Combination therapy prolongs the survival period of mice
In summary, the research team found that inhibiting METTL3 can stimulate cells to produce endogenous interferon responses through the formation of double stranded RNA. Through random CRISPR screening, it was determined that dsRNA sensing and interferon signaling are the main factors that enhance T cell killing of cancer cells after METTL3 inhibition. This immune regulatory mechanism is different from current immunotherapy drugs and provides an early preclinical scientific basis for enhancing anti-tumor effects when combined with anti PD1 immune checkpoint blockade.
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