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

This investigative endeavor focused on the intricate communications within the tumor microenvironment, a complex cellular ecosystem surrounding cancer cells. While the immune system’s cellular constituents have long been studied for their roles in either suppressing or facilitating tumor growth, the influence of nervous system components has remained enigmatic. The Crick Institute team addressed this gap by examining how specialized sensory nerves, which typically detect environmental threats such as noxious heat, physical damage, or chemical irritants, interact with immune cells within lung tumors.

Utilizing sophisticated mouse models, the researchers meticulously manipulated the activity of these sensory nerves, observing pronounced effects on tumor dynamics. Notably, sensory nerve activation bolstered tumor growth, whereas their inhibition correlated with reduced cancer progression. This bidirectional relationship was further characterized by the tumors’ capacity to induce nerve proliferation and stimulate the release of the neuropeptide calcitonin gene-related peptide (CGRP), a key molecular mediator in this neuroimmune dialogue.

CGRP emerged as a crucial suppressor of immune defense mechanisms in the tumor milieu. The study demonstrated that CGRP acts on tumor-associated macrophages, immune cells integral to the orchestration of antitumor responses, impeding the formation of tertiary lymphoid structures (TLS). TLS are organized clusters of immune cells renowned for their association with improved patient prognosis across various cancers, including lung carcinoma. By hindering TLS development, CGRP effectively diminishes the immune system’s capacity to mount a robust and coordinated attack against neoplastic cells.

Importantly, therapeutic interventions that either disrupted the sensory nerve signals or blocked CGRP receptors reinstated TLS formation within tumors. This immunological restructuring intensified the antitumor immune response, resulting in substantial suppression of tumor growth. Given that CGRP receptor antagonists are already utilized clinically for the treatment of migraine headache, the translational potential of repurposing these drugs for cancer therapy is both compelling and immediate.

Extending their inquiry to environmental factors, the Crick team explored the impact of cigarette smoke—a dominant risk factor for lung cancer—on this neuroimmune interface. Exposure to cigarette smoke extract was found to amplify sensory neuronal activity, thereby accelerating tumor advancement. This insight reveals an understudied pathway by which smoking exacerbates cancer progression, beyond its well-known genotoxic effects, by harnessing nerve-mediated immune suppression.

The implications of these findings extend far beyond a single malignancy. They challenge the classical paradigms of tumor immunology by integrating neuroscience, illustrating that nerve fibers and their signaling molecules are not merely bystanders but active architects in the tumor microenvironment. This intersection of disciplines suggests that cancer treatment strategies could be revolutionized by targeting neuroimmune interactions, thereby enabling modulation of the immune landscape in favor of tumor eradication.

Leanne Li, leading the Cancer-Neuroscience Laboratory at the Crick Institute, emphasized the transformative potential of these discoveries: “Our work underscores the complexity of the tumor microenvironment, revealing how neuronal components influence immune cell behavior and tumor progression. This intersection of neuroscience and immunology represents a fertile ground for innovative therapeutic development.”

Co-first authors Ya-Hsuan Ho and Giacomo Bregni further highlighted the clinical ramifications of the study. Ho noted, “Our observations that neuronal activity can reorganize the immune architecture within tumors challenge existing concepts of immune evasion in cancer.” Bregni added, “Despite advancements in immunotherapy, many lung cancer patients do not benefit due to resistance mechanisms. Targeting neuroimmune pathways offers a previously unrecognized strategy to enhance treatment responses.”

This research serves as the foundation for future work by the InteroCANCEption team, an interdisciplinary consortium funded with up to £20 million through the Cancer Grand Challenges initiative. Their mission is to decode how the nervous system’s sensory capabilities—interoception—detect tumors and modulate cancer progression. By mapping neural pathways and brain activity patterns linked to tumor signaling, the team aims to translate neurobiological insights into novel diagnostics and therapies encompassing neural modulation techniques.

Dr. David Scott, Director of Cancer Grand Challenges, reflected on the significance of harnessing the nervous system to intervene in cancer development: “Exploring how brain-tumor communications influence disease offers an exciting frontier. Funding teams like InteroCANCEption catalyzes transformative breakthroughs that redefine the boundaries of oncology and neuroscience.”

The revelation that sensory neurons and their secreted factors contribute dynamically to immune suppression within tumors not only reshapes our understanding of lung cancer biology but also signals a turning point in cancer research. Therapeutic targeting of neuroimmune crosstalk, particularly leveraging existing pharmacological agents that inhibit CGRP signaling, holds promise for augmenting immunotherapy efficacy, which remains suboptimal for many patients.

Moreover, the identification of cigarette smoke’s role in modulating this neuroimmune nexus provides a molecular explanation for the exacerbation of lung cancer progression by smoking. This newfound knowledge underlines the urgency of integrating preventative measures with innovative therapeutic strategies to confront lung cancer—a disease that continues to pose substantial global health challenges.

In summary, the Francis Crick Institute’s landmark study charts a new path by elucidating how sensory nerve signals regulate immune architecture in lung cancer and identifying CGRP as a key inhibitory messenger. The potential to repurpose CGRP receptor antagonists to reinvigorate antitumor immunity offers a compelling translational direction. As neuroscience and immunology converge, future cancer treatments may harness the nervous system’s influence to tip the balance against malignancy, transforming patient outcomes in the years to come.

Subject of Research: The neuroimmune interactions between sensory nerves and immune cells within the lung tumor microenvironment and their implications for cancer progression and therapy.

Article Title: Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer.

News Publication Date: Tuesday, May 19, 2026.

References: Ho et al. (2026). Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer. Cell.

Extracellular vesicles, small lipid-bound packages secreted by cells, have emerged as crucial mediators of cellular crosstalk. These vesicles ferry diverse molecular cargo, including proteins, RNA, and DNA fragments, enabling communication that transcends physical barriers. In cancer, extracellular vesicles facilitate the horizontal transfer of oncogenic signals, remodeling stromal components and modulating immune responses. Despite burgeoning interest, the precise epigenetic landscapes of vesicular DNA, especially their methylation profiles, have remained largely unexplored—until now.

The research team embarked on a comprehensive profiling of whole-genome methylation marks present on DNA encapsulated within extracellular vesicles derived from gastric cancer patients. Their approach utilized state-of-the-art sequencing technology combined with meticulous vesicle isolation, ensuring the fidelity and relevance of the DNA analyzed. By characterizing the methylomic signatures at a genome-wide scale, they mapped a refined epigenetic blueprint reflecting both intrinsic tumor biology and the extrinsic influence exerted via vesicle-mediated communication.

This epigenetic cartography unveiled methylation patterns divergent from those observed in tumor cellular DNA alone, suggesting that extracellular vesicle DNA harbors unique signatures possibly tailored for intercellular signaling purposes. Such methylation signatures could influence gene expression profiles once taken up by recipient cells, thereby modulating pathways critical to tumor invasion, immune evasion, and microenvironment remodeling. This revelation marks a paradigm shift, underscoring the functional relevance of evDNA methylation beyond a mere byproduct of cellular turnover.

Of particular interest, the investigators identified distinct differential methylation regions enriched in genes governing immune modulation, extracellular matrix remodeling, and cell adhesion. These findings hint at a sophisticated epigenetic strategy employed by tumor cells to manipulate neighboring cells and distant niches, fostering a milieu conducive to cancer progression and metastasis. The epigenetic plasticity encoded in vesicle DNA may thus represent a stealth mechanism by which tumors propagate malignancy signals.

The methodology developed for this study exemplifies meticulous attention to isolating high-purity extracellular vesicles from patient plasma samples, circumventing common contaminants that could skew DNA methylation readings. Employing bisulfite conversion coupled with next-generation sequencing facilitated high-resolution detection of methylated cytosines across the genome. Computational analysis then integrated these data into interpretable epigenomic maps that highlight key regulatory regions perturbed in cancer.

Importantly, through comparative analysis with matched tumor tissue and normal controls, the researchers demonstrated that evDNA methylation profiles not only reflect tumor-specific alterations but may also capture dynamic aspects of tumor heterogeneity and evolution. This dual representation enhances the potential utility of vesicle DNA methylation as a minimally invasive biomarker for early detection, prognosis, and therapeutic monitoring.

The translational implications of this work are profound. Liquid biopsy approaches leveraging extracellular vesicle analysis could revolutionize cancer diagnostics by offering a snapshot of tumor epigenomic state with greater sensitivity than circulating cell-free DNA alone. Furthermore, monitoring evDNA methylation patterns longitudinally could uncover shifts in tumor behavior or emergence of resistant clones, thereby guiding personalized treatment strategies.

Beyond diagnostics, the study opens new horizons for therapeutic intervention. Targeting the biogenesis, release, or uptake of epigenetically programmed vesicles might disrupt malignant communication networks, sensitizing tumors to existing therapies or preventing metastasis. Additionally, synthetic vesicles engineered to deliver corrective epigenetic payloads could emerge as novel anti-cancer platforms.

This research also invites fascinating questions about the biology of extracellular vesicles in the cancer ecosystem. The selective packaging of specific DNA fragments with defined methylation states implies active regulation rather than passive shedding. Understanding the molecular machineries governing this specificity may reveal new vulnerabilities in cancer cells.

Moreover, the interaction between evDNA methylation and recipient cell chromatin landscapes merits deeper investigation. How vesicle-derived methylation states influence gene expression programs in recipient cells — possibly reprogramming stromal fibroblasts, endothelial cells, or immune populations — is a compelling avenue. Unlocking these mechanisms could shed light on the complexity of tumor microenvironment shaping.

The current study further underscores the significance of epigenetic heterogeneity within tumor-derived extracellular vesicles. Such diversity may reflect different subpopulations within the tumor, each equipped with distinct communication strategies. Profiling this heterogeneity can enrich our understanding of tumor ecology and therapeutic resistance.

As the field rapidly evolves, integrating methylation profiling of extracellular vesicle DNA with other omics data—such as proteomics and transcriptomics—will be crucial. Multimodal analyses promise a holistic view of vesicle-mediated intercellular dialogues, enhancing our ability to map disease networks and identify intervention points.

While the study focused on gastric cancer, the principles elucidated likely extend across multiple solid tumor types and hematologic malignancies. Future work exploring evDNA methylation across diverse cancers may delineate universal versus cancer-specific communication patterns, refining biomarker panels and therapeutic targets.

In conclusion, by charting the whole-genome methylation landscape of extracellular vesicle DNA in gastric cancer, the researchers have unveiled a hidden epigenetic communicative language that tumor cells exploit to influence their environment. This breakthrough not only enriches our molecular understanding but propels us toward innovative liquid biopsy modalities and epigenetically informed therapeutic approaches. The study heralds a new era in cancer precision medicine wherein extracellular vesicle methylomes serve as both messengers and maps of malignancy.

Subject of Research:
Epigenetic profiling of extracellular vesicle DNA in gastric cancer to understand intercellular communication and identify novel biomarkers.

Article Title:
Whole-genome methylation profiling of extracellular vesicle DNA in gastric cancer identifies intercellular communication features.

Article References:
Lin, B., Jiao, Z., Dong, S. et al. Whole-genome methylation profiling of extracellular vesicle DNA in gastric cancer identifies intercellular communication features. Nat Commun 16, 8084 (2025). https://doi.org/10.1038/s41467-025-63435-w

Image Credits: AI Generated

Exosomal RNA serves as a potent biomarker, capturing the complexities of tumor behavior and enabling a non-invasive approach to cancer management. Unlike traditional methods that rely on invasive biopsies, the detection and analysis of exRNA from non-invasive sources such as saliva and blood open new avenues for early diagnosis. This innovative method significantly reduces patient discomfort and risks associated with surgical biopsies, allowing for timely intervention and better clinical outcomes.

The mechanisms through which exRNAs drive tumor progression are intricate and multifaceted. Exosomes, the extracellular vesicles that carry exRNA, facilitate communication between cells in the tumor microenvironment, leading to critical alterations in cellular behavior. Within the realm of HNCs, exosomal miRNAs, mRNAs, and long non-coding RNAs (lncRNAs) play crucial roles in modulating key signaling pathways. Notably, these pathways include NF-κB, EGFR, and PI3K/AKT/mTOR, which are intimately linked to tumor survival, proliferation, and metastasis.

The study emphasizes that exRNAs are not merely byproducts of tumor activity; rather, they actively engage in orchestrating cancer progression. For instance, specific miRNAs such as miR-21 and miR-486 have been implicated in promoting not just tumor cell proliferation but also mechanisms that allow cancer cells to evade the host’s immune system. This significant insight alters our fundamental understanding of how tumors manage to thrive despite therapeutic interventions.

Furthermore, the impact of lncRNAs like HOTAIR and MALAT1 cannot be overlooked. These RNA species are crucial mediators of cancer cell invasion and motility, facilitating the spread of cancer within the head and neck regions. As they contribute to the transformation of benign cells into malignant entities, their potential as therapeutic targets becomes increasingly apparent. Therapies that can manipulate the activity or expression of these exosomal RNAs could pave the way for innovative treatment modalities.

A particularly exciting aspect of the study is the exploration of the clinical applications of exRNA analysis in liquid biopsies. The non-invasive collection of saliva and blood presents a formidable opportunity to implement real-time cancer diagnostics effectively. By analyzing the exRNA profile of patients, clinicians could assess cancer status, monitor response to therapy, and detect recurrence earlier than ever before. This paradigm shift towards precision medicine positions exRNAs as not only diagnostic markers but also as substantiated therapeutic targets.

The complexities of the exRNA landscape encompass various classes of RNA. For instance, circular RNAs (circRNAs) and PIWI-interacting RNAs (piRNAs) serve specialized roles in fortifying cancer cells against immune detection while also influencing their resilience against chemotherapy. This adaptation of tumor cells to therapeutic stress poses significant challenges in the effective treatment of HNCs. Nevertheless, a thorough understanding of these RNA classes offers novel opportunities to devise strategies that restore sensitivity to existing treatments.

Another focal point of the research highlights the regulatory influence of exRNAs on major oncogenic pathways. For instance, the NF-κB pathway remains a critical player in inflammation and tumor survival, wherein exRNAs significantly tilt the balance in favor of tumor growth. Considering the intricate web of interactions among the PI3K/AKT/mTOR, EGFR, and TP53 pathways, the research illustrates how exRNAs serve as vital conduits for integrating signals that can either promote or impede cancer progression.

The collaborative nature of exRNA signaling emphasizes that a singular approach may not suffice in addressing the complexities of HNCs. Future therapeutic strategies could benefit from a multimodal approach utilizing both exRNA-based diagnostics and engineered therapies aimed at restoring tumor suppressor pathways or inhibiting oncogenic signals triggered by exRNAs. The promise of engineered exosomes for targeted RNA delivery is yet another frontier that could potentially revolutionize cancer therapy.

The study concludes with a bright outlook for the integration of exRNA profiling into clinical practice, despite existing challenges such as standardizing exosome isolation techniques and pinpointing specific RNA biomarkers. Future research must prioritize these areas, alongside validating the therapeutic efficacy of targeting exRNAs in diverse patient populations. As we uncover the underlying mechanisms that drive exRNA-mediated tumor biology, we inch closer to transforming head and neck cancer management.

Ultimately, the evidence presented by Dr. Aruljothi and his team showcases exosomal RNAs as dynamic players in cancer pathogenesis and highlights their potential to revolutionize diagnostics and treatment. The journey towards harnessing these molecular messengers in the battle against head and neck cancers is just beginning, but the prospects for precision oncology have never seemed more promising. By marrying exRNA-based strategies with existing treatment modalities, clinicians can aspire to offer improved therapeutic outcomes and hope to patients navigating the challenging landscape of HNCs.

As science continues to unravel the complexities of cancer biology, exRNAs stand out as a beacon of hope—a transformative element in the quest for more effective, less invasive cancer care.

Subject of Research: Not applicable
Article Title: RNA cargo in motion: the exosomal connection to head and neck cancers
News Publication Date: 27-Mar-2025
Web References: DOI
References: None available
Image Credits: Department of Genetic Engineering, School of Bioengineering, SRM Kattankulathur, Chennai- 603203

Keywords: MicroRNA, exosomal RNA, head and neck cancers, cancer diagnostics, precision medicine, exosomes, cancer biology.