m6A Modification Enhances Immune Checkpoint Therapy

Immune checkpoint therapies are challenged by low response rates, innate or acquired resistance, and immunotherapy-related adverse events that challenge the utility of clinical application. Therefore, the discovery of novel strategies that can be combined with ICI is crucial.

The functions of m6A modifications and immune checkpoints have been extensively studied in recent decades. A range of immune checkpoints have been reported to be supervised in an m6A-dependent manner. Creative Biolabs describes recent advances in understanding the molecular mechanisms behind m6A-modified immune checkpoints.

Introduction to m6A Modifications

The m6A modification is a dynamic RNA epigenetic mark located in complex molecular biological structures. This chemical modification involves adenosine methylation at the N6 position within the RNA molecule. It plays a key role in the regulation of gene expression, RNA processing, and ultimately protein translation.

The m6A modification acts as a finely regulated molecular switch that determines when and how genes are expressed. Recent studies have revealed its involvement in a wide range of biological processes, including cell differentiation, stress response and immunity.

m6A Code in Immune Checkpoint Regulation

One of the remarkable features of m6A modification is its role in shaping the immune response. It significantly affects the expression of immune checkpoint molecules and influences the outcome of immune checkpoint therapy. By modifying the RNA transcripts of checkpoint genes, m6A can either enhance or block their translation. m6A modifications play a dual role in cancer.

Fig. 1 m6A regulatory factors alter immune checkpoint expression in tumors.¹

• If m6A modification increases translation of a checkpoint protein, it can enhance immunosuppression and create an environment conducive to cancer growth.
• On the other hand, a decrease in site-specific m6A modifications may lead to increased translation of immune checkpoint proteins, ultimately improving the response to immune checkpoint therapy.

Therapeutic Potential of m6A Modifications in Immune Checkpoint Therapy

Scientists are exploring various strategies to capitalize on the potential of m6A modifications to enhance the effectiveness of immune checkpoint therapy.

• m6A regulation of PD-L1 expression - By understanding the precise mechanisms by which m6A modification regulates PD-L1, researchers can develop targeted therapies that manipulate m6A modification to increase PD-L1 expression on cancer cells. This, in turn, could enhance the efficacy of PD-1/PD-L1 checkpoint inhibitors.
• Enhancing the efficacy of CTLA-4 blockade - By manipulating m6A modifications to control CTLA-4 expression, researchers aim to tip the balance in favor of the immune system. This may lead to more effective CTLA-4 checkpoint blockade therapies and higher success rates in treating various cancers.

Challenges and Future Directions

• Minimize off-target effects
• Understand how m6A modifications affect the development of resistance and develop strategies to counteract it
• Determine the safety and efficacy of therapies based on m6A modifications

As researchers continue to unravel the complexity of how m6A modifications affect the immune checkpoint pathway, the potential for innovative and more effective cancer therapies becomes increasingly apparent.

Reference

1. Zhou, Xianyong, et al. "Targeting RNA N6-methyladenosine to synergize with immune checkpoint therapy." Molecular Cancer 22.1 (2023): 36.

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