The mechanistic role of Wilms tumor 1-associated protein in cancer pathogenesis, immunity, immunotherapy, and therapy resistance.

Wilms' tumor 1-associated protein 1 (WTAP) is an epitranscriptomic regulator with multifaceted roles in cancer biology. Acting beyond its function in the m6A methyltransferase complex, WTAP governs RNA splicing, stability, and translation, influencing oncogenic signaling, immune modulation, and therapy resistance. Recent evidence reveals its dynamic involvement in diverse malignancies, where it can act as both an oncogene and tumor suppressor depending on the cellular context. WTAP promotes tumor progression through epithelial-mesenchymal transition (EMT), metabolic reprogramming, angiogenesis, and immune evasion, and contributes to resistance against chemotherapy and immunotherapy by regulating DNA repair, ferroptosis, and immune checkpoint pathways. However, studies have also demonstrated that WTAP can exert tumor-suppressive effects under specific physiological conditions, such as hepatocyte-specific WTAP loss leading to extracellular-signal regulated kinases (ERK)-driven hepatocarcinogenesis, and WTAP-mediated m6A regulation restraining oncogenic signaling in some prostate cancers. Moreover, by enhancing ferroptosis resistance, WTAP may weaken ferroptosis-driven antitumor immunity and contribute to immune-checkpoint resistance. Understanding these mechanisms offers opportunities for exploiting WTAP as a biomarker and therapeutic target across multiple cancer types. This review explores the multifaceted role of WTAP in cancer, focusing on its mechanisms of action in tumorigenesis, immune modulation, and therapy resistance, and offers insights into potential therapeutic strategies targeting WTAP in cancer treatment.