N⁶-methyladenosine (m⁶A) represents the most abundant and functionally significant RNA modification implicated in epigenetic regulation, significantly impacting gene expression through the selective recognition by m⁶A reader proteins. Aberrant expression of m⁶A readers has been associated with cancer progression, contributing to tumor growth, metastasis, drug resistance, and immune evasion. With the increasing research on m⁶A readers, the discovery of small-molecule inhibitors targeting these proteins has emerged as a promising avenue for cancer therapy. This review delineates the classification and functional roles of m⁶A readers across various cancers. Furthermore, we summarize and discuss the recent progress in the development of small-molecule inhibitors, with a focus on the medicinal chemistry perspectives. We hope to provide valuable insights to guide future efforts in drug discovery and rational design targeting m⁶A readers for innovative cancer therapeutics.

m⁶A readers  /  m⁶A reader inhibitors  /  Cancer treatment  /  YTH family proteins  /  IGF2BPs  /  RNA-binding proteins  /  Targeted therapy  /  Immunotherapy