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

Gastric cancer remains one of the leading causes of cancer-related mortality worldwide, with cisplatin—a platinum-based chemotherapeutic agent—serving as a cornerstone in its systemic treatment. Despite initial responses, many patients eventually succumb to the disease due to acquired drug resistance. Adding complexity, tumors adopt sophisticated immune evasion tactics, blunting the effectiveness of emerging immunotherapies. This double jeopardy has spurred intense scientific efforts to identify molecular culprits underpinning these resistance mechanisms.

The investigative team spearheaded by Qian, Gao, and Wang deployed cutting-edge genomics combined with proteomic analyses to dissect the contributions of NAT10, an acetyltransferase previously implicated in RNA modification and cellular stress responses. They demonstrated that elevated NAT10 expression in gastric cancer cells correlates strongly with diminished cisplatin sensitivity and heightened PD-L1-mediated immune checkpoint activation. This dual role positions NAT10 as a master regulator, deftly modulating cancer cell fate and immune engagement.

Mechanistically, the study elucidates that NAT10 promotes the transcriptional and post-transcriptional augmentation of DUSP1, a dual-specificity phosphatase with known roles in attenuating MAPK signaling pathways. By bolstering DUSP1 levels, NAT10 effectively dampens pro-apoptotic signals traditionally triggered by cisplatin, thereby enabling malignant cells to circumvent the cytotoxic stresses induced by chemotherapy. Concurrently, NAT10 upregulates PD-L1, a cell surface protein that binds PD-1 receptors on T cells, effectively disarming immune surveillance mechanisms.

This nuanced interplay between NAT10, DUSP1, and PD-L1 reveals an intricate axis of resistance that allows gastric tumors not only to survive chemotherapy but also to evade cytotoxic T cell-mediated destruction. The findings suggest that NAT10 acts as a molecular switch, coordinating cell-intrinsic survival programs with immune checkpoint activation, thereby fortifying tumor resilience on multiple fronts.

Importantly, the authors utilized gastric cancer patient-derived xenograft models to validate their in vitro observations. These models recapitulated the aggressiveness and treatment resistance observed clinically, reinforcing the therapeutic relevance of targeting the NAT10-DUSP1-PD-L1 axis. Pharmacological inhibition of NAT10 in these models restored cisplatin sensitivity and reinvigorated antitumor immune responses, highlighting it as a promising therapeutic target.

Additionally, advanced transcriptomic profiling unraveled the broader impact of NAT10 dysregulation on the tumor microenvironment. NAT10 overexpression was linked to a suppressive milieu characterized by reduced infiltration of cytotoxic lymphocytes and increased presence of regulatory T cells, further emphasizing its multifaceted contribution to immune escape.

This research resonates deeply in the context of current oncology paradigms, where the integration of chemotherapy with immune checkpoint blockade aims to amplify antitumor efficacy. However, resistance remains a formidable obstacle. By illuminating NAT10’s role in orchestrating both chemoresistance and immune escape, the study paves the way for developing combination therapies that target this enzyme alongside conventional treatments.

Moreover, the study raises intriguing questions about the broader implications of RNA modification enzymes like NAT10 in cancer biology. As RNA epigenetics emerges as a critical frontier, understanding how such modifications influence gene expression and protein function could unlock novel avenues to combat refractory cancers.

The discovery also underscores the importance of personalized medicine. Measuring NAT10 expression levels may serve as a biomarker to stratify gastric cancer patients likely to benefit from combined cisplatin and immune checkpoint inhibitor therapies. Such stratification could optimize treatment regimens, reduce unnecessary toxicity, and improve patient outcomes.

Furthermore, this research prompts the exploration of NAT10 inhibitors currently in preclinical development, which could be repurposed or refined for gastric cancer applications. The notion of dual targeting—simultaneous modulation of chemotherapy response and immune evasion—embodies a sophisticated therapeutic strategy that aligns with the complexity of tumor biology.

While these findings mark a substantial leap forward, the study also highlights the necessity for future investigations to elucidate the structural basis of NAT10 interactions with its substrates and regulators. Deciphering this could expedite the design of highly specific inhibitors with minimal off-target effects.

In addition, expanding this research to other cancer types characterized by cisplatin resistance and immune checkpoint activation could reveal whether the NAT10-mediated pathway is a universal mechanism or specific to gastric carcinoma. Such comparative studies would broaden the therapeutic impact.

This seminal work not only advances scientific knowledge but offers tangible hope for patients battling gastric cancer. As drug resistance and immune escape continue to thwart conventional and emerging treatments, innovative approaches targeting fundamental molecular drivers like NAT10 usher in a new era in cancer therapy.

In essence, the discovery of NAT10’s role provides a key piece in the complex puzzle of cancer resilience. It exemplifies how unraveling molecular crosstalk within tumors can translate into groundbreaking clinical interventions, reinforcing the relentless pursuit of more effective and durable cancer treatments.

Subject of Research: Mechanisms underlying cisplatin resistance and immune escape in gastric cancer via NAT10-mediated regulation.

Article Title: NAT10 promotes cisplatin resistance and immune escape by increasing the expression of DUSP1 and PD-L1 in gastric cancer.

Article References:
Qian, L., Gao, W., Wang, X. et al. NAT10 promotes cisplatin resistance and immune escape by increasing the expression of DUSP1 and PD-L1 in gastric cancer. Cell Death Discov. (2026). https://doi.org/10.1038/s41420-026-03107-w

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-026-03107-w