CD9, a tetraspanin in cancer: biology and therapeutic promise in acute leukemia

Tetraspanins are transmembrane proteins that organize into functional structures known as tetraspanin-enriched microdomains, where they coordinate interactions with key partner proteins and modulate cellular processes such as adhesion, signaling, and motility. Among them, CD9 is a widely expressed member, also recognized as a classical marker of exosomes. Beyond its role in development and tissue homeostasis, CD9 has emerged as a modulator of the crosstalk between cancer cells and their microenvironment. It can contribute to processes such as cell migration, invasion, and resistance to therapy. Mechanistically, CD9 interacts with many partners including integrins, metalloproteinases, and signaling receptors to influence cell behavior. However, its functional contribution to tumor progression remains controversial. While CD9 expression is associated with enhanced dissemination in certain cancers, it appears to restrain motility and invasion in others. This likely reflects the complexity of its context-dependent functions, influenced by cell type, microenvironmental cues, and molecular partners. A deeper understanding of the regulatory mechanisms is therefore essential. In this review, we overview the tetraspanin family and summarize current knowledge on CD9 regulation and function across cancers, with a focus on leukemia. While its role in tumorigenesis remains debated, CD9 is a reliable biomarker of leukemic cells and can be used for diagnosis and MRD monitoring in acute lymphoblastic and myeloid leukemia, particularly in patients lacking molecular markers. We also discuss emerging therapeutic strategies that aim to target CD9 in cancer. CD9 gene regulation in cancer, and biological implication in acute lymphoblastic leukemia. Created with BioRender.com.