HMMR in human cancers: regulatory mechanism and biological function

Hyaluronan-mediated motility receptor (HMMR), also referred to as RHAMM or CD168, has gained recognition as a multifunctional protein that mediates the transmission of extracellular matrix-derived hyaluronan (HA) signals to intracellular pathways regulating tumor growth, migration, and mitosis. Overexpression of HMMR is observed in various cancers, including head and neck squamous cell carcinoma, breast cancer, lung cancer, and prostate cancer, as well as several hematologic malignancies. This elevated expression correlates with poor prognosis, rendering it a valuable marker for survival prediction and risk stratification. Functionally, HMMR facilitates tumor progression and metastasis by activating multiple oncogenic pathways and coordinating spindle assembly, cell polarity, and mitotic fidelity. Additionally, HMMR plays a key role forming an immunosuppressive tumor microenvironment and supporting the maintenance of cancer stem cells, collectively driving metastasis, therapeutic resistance, and adverse clinical outcomes. These diverse functions position HMMR as both a promising prognostic biomarker and a potential therapeutic target. However, its coiled-coil structural characteristics present significant challenges for traditional small-molecule inhibition. In response, emerging strategies such as peptide mimetics that competitively inhibit HA binding, HMMR-based tumor vaccines, and HA synthesis inhibitors are being explored to counteract HMMR-driven oncogenic activities. This review offers a comprehensive overview of HMMR‘s discovery, structural domains, isoform diversity, upstream regulatory networks, and key signaling pathways, underscoring its biological relevance and clinical significance across various cancers while clarifying the tumor and context specific roles of HMMR and its structural and functional complexity.