Cancer researchers are turning renewed attention to one of the most versatile molecules on the surface of malignant cells: CD44. A review published in Experimental & Molecular Medicine examines how this cell-surface receptor can influence nearly every stage of cancer development, from the earliest changes in tumour biology to invasion, metastasis, treatment resistance and immune escape. Rather than acting as a simple marker of cancer cells, CD44 appears to function as a dynamic communication platform that links the tumour cell to its surrounding tissue.

CD44 is best known as a receptor for hyaluronan, a large sugar-rich molecule found in the extracellular matrix—the structural network that surrounds cells. When hyaluronan binds to CD44, it can activate intracellular signalling pathways that regulate proliferation, survival, migration and changes in cell identity. These signals may involve pathways such as PI3K–AKT, RAS–RAF–MEK–ERK, Wnt–β-catenin, NF-κB and YAP–TAZ. The result is a molecular system capable of translating physical and chemical changes in the tumour environment into instructions that help cancer cells adapt.

The receptor is also unusually complex because the CD44 gene can produce multiple protein forms through alternative splicing. The standard form, often called CD44s, is found in many normal tissues, while variant forms, known as CD44v, contain additional extracellular regions generated by the inclusion of variable exons. These variants can alter how the receptor interacts with growth factors, matrix components and signalling proteins. In several cancers, particular CD44 variants have been associated with aggressive disease, although their abundance and biological significance can differ between tumour types and even between regions of the same tumour.

One of the most closely studied functions of CD44 is its connection to cancer stem-like cells. These cells are not necessarily permanent or identical to stem cells in healthy tissue, but they can display enhanced abilities to self-renew, initiate new tumours and survive stress. CD44-positive populations have been reported in cancers including breast, colorectal, gastric, pancreatic, head and neck and liver malignancies. The review highlights that CD44 is not a universal or definitive cancer-stem-cell marker; instead, its importance depends on the tissue, the CD44 isoform, the surrounding microenvironment and the other markers present on the cell.

CD44 may also help cancer cells undergo epithelial–mesenchymal transition, or EMT, a developmental programme that can give stationary epithelial cells more mobile and invasive properties. During EMT-like changes, tumour cells may lose strong cell-to-cell adhesion and acquire the ability to move through tissue, enter blood vessels and establish distant colonies. CD44 signalling can interact with transcriptional regulators such as Snail, Slug, Twist and ZEB proteins, which are known to control EMT-associated gene expression. This interaction creates a potential molecular bridge between altered cell identity and metastatic behaviour.

The receptor’s effects extend beyond tumour cells themselves. CD44 is present on immune cells, fibroblasts and other stromal populations that occupy the tumour microenvironment. By influencing interactions among these cells, CD44 can contribute to a local environment that supports tumour growth. Its signalling has been linked to inflammatory responses, extracellular-matrix remodelling and the recruitment or functional alteration of immune populations. In some settings, these processes may reduce effective anti-tumour immunity, allowing malignant cells to persist despite the presence of immune surveillance.

Another concern is the relationship between CD44 and resistance to treatment. Cancer cells that express certain CD44 forms may be better equipped to withstand chemotherapy, radiation or targeted drugs through enhanced DNA-repair capacity, altered drug transport, antioxidant protection and survival signalling. CD44-positive cells can also occupy protected niches within tumours, where limited oxygen, nutrient changes and matrix interactions promote a more resilient state. These observations have made CD44 an attractive candidate for therapeutic intervention, but they also underline why simply eliminating CD44-bearing cells may not be sufficient.

Several strategies are being investigated to target the CD44 system. Antibodies and antibody–drug conjugates aim to recognise CD44 or selected CD44 variants and deliver toxic payloads directly to tumour cells. Hyaluronan-based nanoparticles and drug-delivery systems seek to exploit the receptor’s natural binding properties, potentially concentrating treatment in CD44-rich tumours. Other approaches attempt to block the interaction between CD44 and hyaluronan, inhibit downstream signalling, degrade hyaluronan in the tumour environment or target CD44-positive cancer stem-like populations. Each strategy faces technical barriers, including variable CD44 expression, the presence of the receptor in normal tissues and the difficulty of distinguishing malignant from healthy CD44-positive cells.

The review by Oh, Kim, Kim and colleagues presents CD44 as a promising but highly context-dependent therapeutic target. Its expression alone may not reliably predict prognosis or treatment response, because CD44 is shaped by alternative splicing, post-translational modification, cellular location and signals from the surrounding microenvironment. Future treatments may therefore need to combine CD44 targeting with immunotherapy, chemotherapy, radiation or inhibitors of specific signalling pathways. The broader message is that cancer biology cannot be reduced to a single marker: CD44 is better understood as a flexible molecular hub whose effects change with tumour type and disease stage. Mapping those differences could help researchers design more selective therapies while limiting damage to healthy tissues.

Subject of Research: CD44’s roles in cancer progression, metastasis, tumour microenvironment interactions, treatment resistance and targeted therapeutic strategies

Article Title: Multifaceted roles of CD44 in cancer progression and targeted therapeutic strategies

Article References: Oh, HJ., Kim, ST., Kim, HJ. et al. “Multifaceted roles of CD44 in cancer progression and targeted therapeutic strategies.” Experimental & Molecular Medicine (2026). https://doi.org/10.1038/s12276-026-01797-x

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01797-x

Keywords: CD44, cancer progression, hyaluronan, cancer stem cells, metastasis, epithelial–mesenchymal transition, tumour microenvironment, drug resistance, targeted therapy, immunotherapy

Tags: cancer progression mechanismsCD44 cell surface receptorCD44 variant isoformsextracellular matrix in tumor developmenthyaluronan-CD44 interactionsimmune escape in cancerintracellular signaling pathways in cancermolecular signaling pathways in cancerrole of CD44 in treatment resistancetargeted cancer therapy strategiestumor invasion and metastasistumor microenvironment communication