<p>RNA modifications serve as critical regulators of gene expression, providing an additional layer of control beyond the genetic code. Among these, N⁶-methyladenosine (m⁶A) is the most prevalent and functionally significant epitranscriptomic mark in eukaryotes. This review explores the dynamic role of m⁶A in immune regulation within host-microbe interactions and cancer. Specifically, we describe how m⁶A influences both innate and adaptive immune responses in animals and its role in pathogen recognition and defense mechanisms in plants. By integrating insights from both plant and animal immune systems, this review offers a comprehensive perspective on the function of m⁶A in host-microbe interactions. We also discuss emerging research directions and the potential of RNA modifications as targets for developing innovative disease resistance strategies in medicine and agriculture. Understanding the regulatory influence of m⁶A could pave the way for novel therapeutic and crop improvement approaches, enhancing resilience against diseases in both plants and humans.</p>