Targeting the RNA m(6)A modification for cancer immunotherapy

N(6)-methyladenosine (m(6)A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription and translation programs that promote cancer occurrence and progression. Although defective gene regulation resulting from m(6)A often affects oncogenic and tumor-suppressing networks, m(6)A can also modulate tumor immunogenicity and immune cells involved in anti-tumor responses. Understanding this counterintuitive concept can aid the design of new drugs that target m(6)A to potentially improve the outcomes of cancer immunotherapies. Here, we provide an up-to-date and comprehensive overview of how m(6)A modifications intrinsically affect immune cells and how alterations in tumor cell m(6)A modifications extrinsically affect immune cell responses in the tumor microenvironment (TME). We also review strategies for modulating endogenous anti-tumor immunity and discuss the challenge of reshaping the TME. Strategies include: combining specific and efficient inhibitors against m(6)A regulators with immune checkpoint blockers; generating an effective programmable m(6)A gene-editing system that enables efficient manipulation of individual m(6)A sites; establishing an effective m(6)A modification system to enhance anti-tumor immune responses in T cells or natural killer cells; and using nanoparticles that specifically target tumor-associated macrophages (TAMs) to deliver messenger RNA or small interfering RNA of m(6)A-related molecules that repolarize TAMs, enabling them to remodel the TME. The goal of this review is to help the field understand how m(6)A modifications intrinsically and extrinsically shape immune responses in the TME so that better cancer immunotherapy can be designed and developed.