BackgroundAttentional bias modification (ABM) training is employed to modulate attentional bias and alleviate clinical symptoms in obsessive-compulsive disorder (OCD) patients. This study aimed to develop a novel, ecologically valid ABM paradigm based on virtual reality (VR). The intent was to enhance the efficacy of traditional computerized ABM and to preliminarily examine its feasibility in patients with contamination-based obsessive-compulsive disorder (OCD).Method15 patients with OCD who were currently receiving pharmacotherapy were recruited and allocated to either an ABM group, which received VR-ABM training twice weekly for four weeks (eight sessions in total), or a TAU group, which continued their routine outpatient treatment, including pharmacotherapy, psychotherapy, and physical therapy.Result5 patients in ABM group and 5 patients in TAU group completed the 4-week follow-up. VR-ABM paradigm effectively elicited target symptoms, with virtual scenarios inducing moderate levels of obsessive-compulsive symptoms and anxiety. Notably, all participants in the VR-ABM group reported the program to be appropriately challenging, effectively eliciting obsessive-compulsive symptoms and improving subjective concentration.ConclusionThese preliminary findings support the feasibility of the novel VR-ABM training in OCD and warrant further investigation in larger, controlled trials to rigorously evaluate its therapeutic efficacy.
Systematic review of animal studies on the use of herbal medicine for attention-deficit/hyperactivity disorder
BackgroundAttention-deficit/hyperactivity disorder (ADHD), a common neurodevelopmental condition, often requires treatment with stimulants such as methylphenidate and nonstimulants such as atomoxetine. Despite their effectiveness, medication-related side effects, adherence and symptom control issues have increased the interest in alternative therapies, especially herbal medicine. However, existing preclinical studies vary in quality and relevance. This systematic review evaluates animal studies investigating herbal medicines for ADHD; identifies limitations in experimental models, behavioral assessments, safety evaluation, and methodological rigor; and proposes a framework to guide future research.MethodsFollowing PRISMA 2020 guidelines, PubMed and Web of Science were systematically searched for eligible studies published between 1995 and March 2025 that used animal models to interventions for the treatment of ADHD-like symptoms.ResultsAnalysis of 25 studies revealed a strong reliance on a limited range of animal models, particularly the spontaneously hypertensive rat (48%), with 88% of studies using male animals exclusively. Behavioral assessments predominantly focused on hyperactivity (72%), whereas evaluations of inattention and impulsivity were comparatively limited. Herbal interventions were associated with improvements in ADHD-like behaviors and modulation of catecholaminergic neurotransmission, including increased dopamine and norepinephrine levels in the prefrontal cortex. Additional mechanisms included activation of neurotrophic signaling pathways (brain-derived neurotrophic factor/TrkB) and suppression of proinflammatory mediators such as TNF-α and IL-1β. However, 80% of the studies did not report safety outcomes, and no study clearly described randomization or blinding procedures, limiting the translational relevance of the findings. Despite these limitations, several formulations, including the Long Mu Qing Xin mixture, An Shen Ding Zhi Ling demonstrated promising multitarget effects.ConclusionAlthough herbal medicines demonstrate promising multipathway effects for ADHD, progress remains constrained by the limited diversity of animal models and narrow scope of behavioral assessments. Future research should prioritize the use of diverse models, more comprehensive assessments, and the implementation of rigorous methodological standards.
Super-potent synthetic opioids called nitazenes are spreading across the U.S.
In high school, Ashley Delgado dreamed of becoming a doctor and one day buying her father a Rolls-Royce. “She wanted to heal people,” said her father, James Taylor. She had a high GPA, Taylor added, and did especially well in science and Latin.
In her mid-20s, Ashley suffered a leg injury and was prescribed OxyContin. The painkiller marked the beginning of a yearslong descent through addiction — from prescription opioids to methamphetamine, then heroin, and finally, fentanyl.
Have Microbubbles Burst Through the Barriers of Genetic Medicine Delivery?
After more than 20 years working on viral and nonviral delivery modalities, Kenneth Greenberg, PhD, thought he had seen it all in genetic medicine delivery—until he met Steve Feinstein, MD, and Michael Davidson, MD, in 2021. Feinstein, a clinical cardiologist, had been working with ultrasound and contrast ultrasound for decades.
“Steve was scratching his head in the 90s trying to better diagnose heart disease patients, wondering why there’s a contrast agent for every other imaging modality except ultrasound,” Greenberg told Inside Precision Medicine.
Feinstein’s solution was microbubbles. These tiny gas-filled spheres (1-10 μm) with lipid, protein, or polymer shells can safely circulate through capillaries and resonate in response to ultrasound waves when injected intravenously, improving blood flow and tissue perfusion visualization before being cleared by the lungs and liver.
It was Feinstein that got the FDA to approve the first two ultrasound contrast imaging agents. Beyond diagnostics, he found new uses for microbubbles. Certain acoustic conditions could allow them to deliver therapeutic payloads directly into tissues.
Together with Davidson, a lipidologist and preventive cardiology specialist, Feinstein formed a long-term research partnership in Chicago’s academic medical community that resulted in the founding of SonoGene in 2000 to translate and commercialize ultrasound-mediated gene delivery.
Though SonoGene never made a splash, Feinstein and Davidson were able to generate preclinical data, which Greenberg found “mindblowing.”
“It showed me that you could use ultrasound and nonviral DNA payloads to achieve delivery and gene expression,” said Greenberg. “This is in rodents, but it was enough to persuade me that if it worked in humans anywhere near as well as it does in rodents, it could completely change the landscape of gene delivery. I thought it was just such an elegant idea. These components have been available for years, and we can repurpose them in a creative way to accomplish things that you could never do with existing modalities.”
In 2022, Greenberg, Feinstein, and Davidson joined forces to launch SonoThera, backed by a $60.75 million Series A financing with the goal of developing a nonviral, ultrasound-mediated gene delivery platform capable of producing safe, targeted, redosable, and cost-effective genetic medicines.
Four years later, investors are reaffirming that vision. SonoThera closed an oversubscribed $125 million Series B financing to advance its lead programs to the clinic and develop its ultrasound-enabled delivery platform. The funding comes at a crucial time for genetic medicine, where delivery challenges continue to temper therapeutic innovation.
RIPPLE effect
The genetic medicine revolution has produced transformative therapies across rare diseases, oncology, and metabolic disorders. Yet despite the success of viral vectors such as adeno-associated virus (AAV) and nonviral systems such as lipid nanoparticles (LNPs), researchers continue to grapple with payload-size constraints, limited tissue targeting, inability to redose, manufacturing complexity, and immune-related toxicities.
For Kenneth Greenberg, PhD, those challenges create an opening for a fundamentally different delivery strategy. “The field and investors recognize that this is a big problem, and no one has yet been able to solve it,” he said. “Coming up from a very different angle, I think it is getting people excited that this could ever come.”
Rather than engineering new viral capsids or nanoparticle chemistries, SonoThera has built its platform around two technologies already widely used in medicine: ultrasound systems and microbubble contrast agents. The company’s innovation lies in combining them with naked DNA payloads and proprietary ultrasound waveforms, called RIPPLE, to drive gene transfer into tissues.
“Our strategy has been to use the existing infrastructure as much as possible and not to develop bespoke hardware or novel microbubbles,” Greenberg said. “We want this to be widely utilized and have great patient access and clinicians to be familiar with the systems and the components.”
Unlike AAVs or LNPs, SonoThera does not package DNA inside a carrier. Instead, naked DNA and microbubbles circulate independently in the bloodstream until ultrasound is applied to a target organ. “There are some common misconceptions about the mechanism,” Greenberg said. “The mechanism basically involves taking the genetic payload, which is naked DNA. It’s not encapsulated in anything.”
The ultrasound activates circulating microbubbles in a multi-step process. First, acoustic energy creates temporary gaps in the endothelial lining of blood vessels, allowing DNA to access target tissues. The microbubbles are then collapsed, creating transient pores in cell membranes that permit intracellular entry of the payload. Finally, ultrasound-driven modulation of the nuclear pore complex facilitates transport of DNA into the nucleus for transcription and protein production. “The ultrasound can basically do everything in one single profile,” Greenberg said. “We can modulate the waveform in ways to drive this mechanism of delivery. We don’t need receptors, endosomes, or anything like that, which gives the platform a huge advantage in versatility to target different organs.”
That receptor-independent mechanism may offer one of the platform’s biggest advantages. Existing delivery systems typically depend on receptor-mediated cellular uptake, which can activate innate immune pathways and restrict tissue tropism. According to Greenberg, microbubbles largely avoid those limitations. “It’s also key to how we avoid the immune system, the innate immune system’s response that typically gets triggered by viruses and LNPs,” Greenberg said.
Because microbubbles are micron-sized rather than nanosized, they never enter the cell and are destroyed extracellularly after ultrasound activation. The DNA itself enters cells independently. While naked DNA degrades relatively quickly in circulation, Greenberg said its half-life of roughly 30 to 60 minutes is sufficient because infusion and ultrasound delivery occur simultaneously.
In contrast, LNPs enter cells through endocytosis, carrying lipids and genetic cargo that can activate innate immune sensors such as cGAS-STING and TLR9. AAVs similarly rely on receptor-mediated uptake pathways that can provoke immune responses and limit redosing.
From sonoporation to clinical translation
The platform’s flexibility has become increasingly apparent as SonoThera expanded beyond its initial liver studies. The company subsequently evaluated delivery to kidney, skeletal muscle, heart, brain, and adipose tissue. “What we’ve found is that the delivery technology works in all organs in the body, as far as we can tell,” Greenberg said. The notable exception is the lung, where air attenuates ultrasound energy.
Perhaps most striking is the company’s work in the brain. The SonoThera platform can temporarily open the blood-brain barrier and deliver payloads using the same mechanism as other tissues. “A common misconception is that the bone can attenuate the ultrasound energy. But that’s not the case,” Greenberg said. “The frequencies are such that they can penetrate easily through the skull and get into the brain.”
If that capability translates clinically, it could represent a significant advantage over delivery technologies that remain largely confined to the liver or a limited set of tissues.
SonoThera’s initial pipeline targets diseases where current delivery systems struggle. In Duchenne muscular dystrophy (DMD), the full-length dystrophin gene is too large for AAV vectors. The company’s ADPKD program has a larger payload.
“The overarching strategy when we’ve approached indications is that it’s challenging to get access to large payloads that are prohibitively large for AAVs,” Greenberg said. “With our ADPKD program, the payloads are even larger. That’s about a 22 KB payload, while the DMD payload is about 13 kb.”
Redosing is also important. Many genetic diseases require long-term treatment, especially in children whose tissues grow. AAV therapies are rarely administered again due to immune responses, making therapeutic expression difficult. “There are indications where the disease really requires redosing over time,” Greenberg said. “DMD is a good example because we’re treating really young boys as their bodies grow.”
SonoThera delivers mutation-agnostic full-length dystrophin with redoseability. The company also targets skeletal muscle, heart, and diaphragm simultaneously to address cardiopulmonary complications that kill many DMD patients.
The platform uses episomal DNA rather than genome editing. Greenberg believes the DNA behaves like AAV-delivered episomes, becoming chromatinized in the nucleus and maintaining expression. “We’ve got durability data out to a year so far with a single treatment,” he said.
Target tissue will determine redosing frequency: rapidly dividing cells may dilute episomal DNA, but quiescent tissues may maintain expression longer. Despite its focus on gene replacement, SonoThera has shown compatibility with gene editing and targeted integration methods. “For us, it’s really about using the right tool for the right job,” Greenberg said. “We don’t want to do gene editing just because it’s sexy.”
The scientific foundation for SonoThera’s platform is rooted in sonoporation, a concept that has been explored academically for decades but has never successfully reached the clinic. Greenberg believes the field historically struggled with two major hurdles: achieving sufficient transfection efficiency and broad biodistribution. “In the first two years of the company, we basically focused on solving those problems and really innovating to achieve extremely high delivery efficiency and broad organ biodistribution,” he said.
Those advances have now positioned the company to enter clinical development. SonoThera is conducting IND-enabling studies, manufacturing activities, and GLP toxicology work while refining clinical trial designs with physician and disease-area experts. The initial studies will focus primarily on safety while also evaluating biomarkers and early signs of efficacy. In DMD, the company has already generated preclinical biopsies showing expression of full-length dystrophin protein in muscle tissue.
Although SonoThera’s internal pipeline currently focuses on rare diseases, Greenberg sees broader opportunities ahead. Pharmaceutical companies have increasingly shifted attention toward common diseases with larger commercial potential, and many are searching for delivery platforms that can overcome the limitations of AAV-based therapies.
Investor confidence—but can it scale?
Greenberg says industry interest in nonviral, redosable systems may be better for common diseases, especially when manufacturing costs and reimbursement issues make one-time treatments unsustainable. SonoThera will advance its pipeline and partner with larger companies seeking platform access to capitalize on those opportunities. “Our strategy as a small biotech company has been to have our internal pipeline but, in parallel, be able to have licensing deals and partnerships that allow us to expand the reach of the technology and the much larger patient populations.”
The oversubscribed $125 million Series B financing suggests investors increasingly view delivery as the next major frontier in genetic medicine. As SonoThera approaches the clinic, it faces many of the same questions every new gene-delivery platform has faced for creating a paradigm-shifting delivery modality: safety, durability, and scale.
Because SonoThera’s platform relies on ultrasound-driven physical mechanisms rather than biological targeting, factors such as organ size, anatomy, blood flow, and patient variability could provide challenges to translatability.
Delivering DNA to a mouse liver or muscle is very different from delivering therapeutic amounts of genetic cargo throughout the muscles, heart, and diaphragm of a growing child with Duchenne muscular dystrophy. While microbubbles have a decades-long track record as imaging agents, repeated therapeutic delivery tools are a different proposition.
While the company argues that naked DNA and ultrasound avoid many of AAV’s payload limitations, questions remain about the doses required for large organs and whether manufacturing and administration can scale efficiently. Relatedly, SonoThera has reported preclinical expression lasting up to a year after a single treatment, but long-term persistence remains unknown. If repeat dosing is required, the company will need to demonstrate that repeated ultrasound exposure and cycles of vascular permeabilization can be performed safely over time.
SonoThera’s appeal reflects a broader reality: despite decades of innovation, delivery remains genetic medicine’s biggest unsolved problem. The company’s platform is scientifically elegant and potentially transformative, but only clinical data will determine whether ultrasound-mediated gene transfer represents a true breakthrough—or simply the latest attempt to solve one of biotechnology’s most stubborn challenges.
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OLE Identified as a Potential Alzheimer’s Therapy Targeting Microglia
A research collaboration between investigators from the Spanish National Research Council (CSIC), the Miguel Hernández University of Elche (UMH), and the École Polytechnique Fédérale de Lausanne (EPFL) has identified a molecule that may could be a new approach to treating Alzheimer’s disease (AD) by restoring the protective functions of microglia, immune cells found in the brain. The findings, published in Cell Death & Disease, said the molecule N-oleoyl-Leucine (OLE), which is derived from the Alzheimer’s disease-associated gene PM20D1, was shown to reduce amyloid pathology, improve cognition, and promote neuroprotection.
“One of the most significant findings is that we have identified a molecule capable of restoring microglia’s protective function,” said senior author José Vicente Sánchez Mut, PhD, principal investigator at the Functional Epi-Genomics of Aging and Alzheimer’s Disease laboratory at the Institute for Neurosciences, a joint CSIC-UMH center. “In Alzheimer’s disease, these cells become progressively impaired. Our results suggest that this process can be reversed, pointing to new therapeutic and research avenues to counteract the disease.”
In recent years, there has been a surge of research into microglia’s role in AD. As the researchers noted, genetic risk variants associated with AD are enriched in regions that regulate microglial function, and microglial gene-expression programs have been shown to be altered during disease progression. As the disease advances, microglia proliferate and accumulate around amyloid plaques, but lose their ability to maintain tissue homeostasis and clear amyloid beta (Aβ). At the same time these immune cells take on inflammatory and neurotoxic characteristics.
PM20D1 has been identified recently as a risk gene in the development of AD. It is a quantitative trait locus associated not only with Alzheimer’s disease but also with diabetes, obesity, and other disorders. People exhibiting lower PM20D1 expression have a higher risk of developing metabolic disorders and Alzheimer’s disease. Other prior research studies also showed that PM20D1 overexpression in mouse models reduced amyloid levels and cognitive deficits, making it a potentially fruitful area for additional study.
PM20D1 encodes a secreted enzyme that regulates the conjugation of fatty acids with amino acids, generating compounds known as N-acyl amino acids (NAAA). OLE is one of these amino acids and was selected for further investigation because PM20D1 activity in living organisms appears to favor its production and because OLE levels are strongly correlated with PM20D1 expression in both humans and mice.
“There is increasing evidence of microglia participation in Alzheimer’s disease (AD), which incentives their modulation to intercept the disease,” the researchers wrote. “Here, we describe a new mechanism by which the recently AD-associated Peptidase M20 Domain Containing 1 (PM20D1) instructs microglia to tackle AD.”
To evaluate OLE’s therapeutic potential, the team first tested it in genetically engineered Caenorhabditis elegans worms that produce beta-amyloid, where they showed that OLE treatment reduced protein aggregation and improved mobility. The researchers then administered OLE to APP/PS1 mouse models of AD for three months. Again, the mice demonstrated better performance in memory tests and showed reductions in amyloid plaque burden.
A cellular analyses found that microglia were the cells most responsive to OLE treatment.
“Single-cell analysis allowed us to determine that microglia were the cells that responded most strongly to the treatment,” said first author Victoria Pozzi, PhD, a postdoctoral researcher working in the Sánchez Mut lab. “From there, we observed that the compound helped these cells move toward beta-amyloid plaques and better contain the damage associated with the disease.”
The study also found that OLE increased Aβ chemotaxis and clearance in cultured microglia. In neuronal cultures exposed to Alzheimer’s-related stressors, OLE enhanced cell survival, indicating that the molecule may have direct neuroprotective effects in addition to its effects on immune cells.
The team believes OLE may function as a disease-modifying therapy by altering microglial behavior and reducing amyloid-associated damage, but because OLE was administered systemically in their experiments, more work is needed to determine whether its primary effects occur in microglia or whether it acts independently on multiple cell types. They also plan to investigate whether other N-acyl amino acids have therapeutic potential and whether OLE can influence tau pathology and neurodegeneration.
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AI Discovers Two New Antibiotics for Drug-Resistant Gonorrhea
Scientists have developed a deep learning model that could significantly accelerate the discovery of novel antibiotic compounds. In a study published today in Science Translational Medicine, the AI algorithm was able to identify two compounds effective against gonorrhea infections, each operating through mechanisms unlike those of any antibiotics in use today.
“Faced with the threat of untreatable gonorrhea, new antibiotics are urgently needed,” writes James J. Collins, PhD, professor of medical engineering and science at the Broad Institute of MIT and Harvard. “Our work establishes a much-needed hit discovery tool to address the growing crisis of antimicrobial resistance for this pathogen.”
According to the CDC and WHO, gonorrhea is one of the most urgent antibiotic-resistant threats worldwide. When left untreated, this sexually transmitted infection can lead to serious health complications. Yet treatment is becoming increasingly challenging as strains of Neisseria gonorrhoeae continue to develop resistance to existing antibiotics.
“Previous first-line therapies for gonorrhea—including penicillin, tetracycline, ciprofloxacin, cefixime, and azithromycin among others—are no longer recommended because of excessively high resistance rates in circulating strains,” says Collins. “The last remaining first-line monotherapy, ceftriaxone, is at risk of becoming obsolete, with resistance rates of over 10% in parts of the world.”
Traditional antibiotic discovery relies on high-throughput screening methods that search large chemical libraries for promising compounds. However, this approach cannot keep pace with the fast expansion of chemical space, which today englobes over 75 billion compounds.
To overcome this limitation, Collins and colleagues turned to deep learning algorithms capable of making large-scale screening significantly more time- and cost-efficient. They selected a predictive graph neural network (GNN), a model that represents molecules as graphs and can virtually screen thousands of molecules per second. Compared to large language models, the GNN more accurately identified molecules with activity against gonorrhea that were structurally different from both the training data and existing antibiotics.
To train the model, the team screened 38,650 small molecules with diverse structures and identified those capable of inhibiting the growth of N. gonorrhoeae. The model was then able to virtually screen through nearly six million compounds, which led to identification of 83 antibiotic candidates with confirmed activity against N. gonorrhoeae.
Among them, two compounds stood out for having distinct structures from existing antibiotics, known as MP20 and A1. In mice and an organ-on-a-chip model of vaginal gonorrhea infection, both molecules rapidly and selectively killed the bacteria without inducing drug resistance.
Proteomics analyses revealed the mechanism of action of each antibiotic candidate. MP20 was found to disrupt the bacterial membrane and damage DNA, while A1 targeted an enzyme essential for the synthesis of the bacterial cell wall.
“There is a critical need to fill the trickling antimicrobial development pipeline with promising antibiotic candidates, especially ones with distinct mechanisms of action,” says Collins. “We have shown that these compounds can retain potency against even the most highly resistant strains of N. gonorrhoeae, exhibit selective killing toward bacteria, and act through orthogonal mechanisms from those of existing first-line antibiotics.”
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GLP-1 Drugs Reduce Crime-Linked Behavior
GLP-1 drugs could act upon impulsive behavior that leads to violence and criminal acts, research suggests.
The study adds to evidence suggesting that these drugs could have benefits outside their widely used action on diabetes and obesity.
Specifically, it suggests that GLP-1 drugs could act upon impulse control and stress-reward systems in the brain relating to substance and alcohol misuse.
The findings appear in the journal Criminology.
“As GLP-1 medications become increasingly widespread, understanding their broader behavioral effects becomes an important public health and criminological question that requires careful study,” said researcher Daniel Semenza, PhD, from Rutgers University.
Recent research has suggested that GLP-1 receptor agonists (RAs) such as exenatide, liraglutide, semaglutide, and dulaglutide have benefits beyond glycemic control and weight loss.
These include reducing the risk of multiple psychiatric and neurocognitive conditions and improving impulse control.
Semenza and Christopher Thomas, also from Rutgers, examined the relationship between the use of GLP-1 drugs and violent behavior using recent survey data from 821 U.S. adults in a 2025 nationally representative survey who had used these medications at some point in their lives. Of these, 597 were current users and 224 were former users.
Given established connections between aggression, alcohol use, and impulsivity, they also investigated whether current GLP-1 use was associated with a lower risk of violence by moderating the associations of impulsivity and alcohol use with violent crime.
The team found that impulsivity and alcohol use were strongly associated with committing violent crime. Each standard deviation increase in impulsivity was associated with a 1.9-fold increase in violence, and each unit increase in an alcohol use index was associated with a 1.8-fold increase.
However, current GLP-1 receptor agonist use was associated with significantly weaker associations between either impulsivity or alcohol use and violent crime compared with former GLP-1 drug use, attenuating these by approximately 62% and 52%, respectively.
This meant that even when users of GLP-1 receptor agonists drank alcohol or acted impulsively, it would be less likely to lead to violent crime.
The relationship was particularly strong relating to impulsivity and less so with alcohol use.
“Understanding the neurobiological mechanisms by which GLP-1 receptor signaling may moderate impulsivity-related risk pathways represents an important research opportunity,” the researchers concluded.
“Given the rapidly expanding use of GLP-1 receptor agonists throughout the United States and the rest of the world, this pattern of reduced violence risk warrants ongoing attention from both researchers and policymakers.”
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Macrophage EGFR Activity Linked to Immune Suppression, Tumor Growth in Colorectal Cancer
Researchers at the Medical University of Vienna have identified a new role played by epidermal growth factor receptor (EGFR) signaling in metastatic colorectal cancer (mCRC), finding that its activity in myeloid immune cells helps shape the tumor microenvironment and influences tumor growth. The study, published in Cell Death & Differentiation, indicates that EGFR signaling does not affect only cancer cells but contributes to how immune cells regulate anti-tumor responses.
“Our results show that EGFR in myeloid cells is a key regulator of the tumor-promoting immune landscape,” said senior author Maria Sibilia, PhD, a professor of tumor biology and director of the Center for Cancer Research at Medical University of Vienna.
Metastatic colorectal is a leading cause of cancer-related deaths worldwide. EGFR-blocking antibody treatments are already part of standard first-line therapy for patients with wild-type KRAS/BRAF tumors, but not all patients respond to this form of treatment, and even among those that do respond, resistance frequently develops. The new findings help clarify why EGFR expression in tumor cells alone does not fully predict therapeutic outcomes and suggest that immune-cell signaling is an important factor in treatment response.
While, EGFR has been broadly studied as a tumor cell receptor, earlier research has suggested that EGFR-positive myeloid cells are associated with worse prognosis in CRC and hepatocellular carcinoma. Studies in mice had also shown that deleting EGFR in myeloid cells reduced tumor burden, while deleting it in tumor epithelial cells had limited effect. However, the contribution of immune-cell EGFR signaling on the response to anti-EGFR therapy has not been broadly studied or understood.
To address this, the Sibilia lab used genetically engineered mouse models of colorectal cancer with single-cell RNA sequencing, proteomic profiling, and combined it with analysis of patient-derived datasets. The team focused on tumor-associated myeloid cells, including macrophage subsets known to shape immune suppression within the tumor microenvironment. To allow direct comparison of outcomes, EGFR was selectively deleted in either myeloid cells or tumor epithelial cells in preclinical models.
Single-cell analyses showed that loss of EGFR in myeloid cells reduced populations of tumor-promoting macrophages, including Spp1+ and C1qc+ subsets, and altered signaling pathways linked to inflammation and immune regulation. Reduced activity in TGFβ, IFNγ, and JAK/STAT pathways was associated with decreased expression of immune checkpoint molecules and changes in myeloid–T cell communication. CD8+ T cells in EGFR-deficient tumors showed lower expression of exhaustion markers such as Pdcd1 and Havcr2, suggesting a shift in T cell functional state.
A key finding was the identification of thrombospondin-1 (THBS1) as a myeloid-derived ligand regulated by EGFR signaling. Further analysis confirmed that EGFR activity influences THBS1 expression in macrophages and patient data also showed that high expression of both EGFR and THBS1 correlated with poorer outcomes, and combined gene signatures were associated with reduced survival.
The researchers also noted that tumor-associated macrophages and other myeloid populations can shift between anti-tumor and tumor-promoting states, and that their role in EGFR-targeted therapy response had not been fully defined.
One conclusion drawn by the researchers based on their work is that myeloid EGFR signaling contributes to immunosuppression in mCRC and may affect treatment response to both targeted therapy and immunotherapy approaches. “These findings strongly suggest that targeting EGFR specifically in myeloid cells may be of great therapeutic benefit for patients with CRC,” the researchers wrote.
The data also indicate that therapeutic strategies that only address tumor cell EGFR likely don’t address the full landscape of its effects and may not indicate the extent of treatment response. Instead, the investigators suggested, modulation of EGFR signaling in immune cells, particularly macrophage populations, could improve the effectiveness of existing EGFR inhibitors and may enhance response to immune checkpoint blockade by reducing T cell exhaustion and checkpoint expression.
Building on this, the team will now investigate myeloid-specific EGFR inhibition strategies and explore targeted delivery methods, such as nanoparticles directed toward EGFR-positive macrophage populations. Additional work will also seek to validate THBS1 as a biomarker for patient stratification and to determine how targeting this pathway might be integrated with immunotherapy regimens.
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Unexpected Role for RNA Editing in Cancer Immune Evasion Uncovered
A new study in Science Immunology has uncovered a previously unrecognized mechanism by which cancer cells may evade immune detection, identifying the RNA helicase DDX6 as a key regulator of RNA editing and innate immune suppression.
The research, led by Larry Ng, PhD, of the Cancer Science Institute of Singapore, found that DDX6 represses a specific form of double-stranded RNA (dsRNA) editing that would otherwise stabilize dsRNA molecules and promote immune activation. When DDX6 was depleted, dsRNA accumulated, triggering innate immune signaling, increasing immune cell infiltration, and reshaping the tumor microenvironment in both patient-derived organoids and mouse models.
The findings provide new insight into how tumors exploit RNA-editing pathways to suppress immune responses and suggest that targeting DDX6 could represent a new strategy for cancer immunotherapy.
“Our cells are equipped with this double-stranded RNA sensing mechanism,” Ng explained. “It is actually a mechanism against viruses.” Cells contain specialized sensors that recognize dsRNA, a molecular pattern commonly associated with viral infection. Activation of these sensors triggers inflammatory responses, including type I interferon signaling, that help eliminate infected cells.
However, dsRNA is not exclusively produced by viruses. Normal cells also generate endogenous RNA transcripts capable of forming double-stranded structures. To prevent inappropriate immune activation, cells rely on RNA-editing enzymes such as adenosine deaminase acting on RNA 1 (ADAR1), which modify dsRNA molecules and reduce their ability to activate immune sensors.
“What RNA editing does is to actually prevent this autoimmunity from happening,” Ng said. “Editing marks our own RNA with this modification, so it will help to prevent the recognition by the sensors.”
This protective mechanism becomes particularly important in cancer. Tumor cells often exhibit extensive chromosomal instability, producing abundant abnormal RNA transcripts and dsRNA structures that could otherwise trigger immune responses.
“Cancers actually have a lot of these double-stranded RNA structures due to chromosomal instability,” Ng said. “But they survive.” According to Ng, tumors accomplish this by co-opting RNA-editing pathways that normally protect healthy cells. “What they do is that they actually hijack this editing function to help them survive,” he said. “If we could target or prevent this editing from happening, we can actually reactivate the covert RNA sensing, and this might help to trigger tumor cell death.”
The study focused on DDX6, an RNA helicase previously linked to cancer development but not fully understood in the context of immune regulation. Ng and colleagues discovered that DDX6 interacts directly with ADAR1 and suppresses a specific category of ADAR1-mediated RNA editing events.
The finding challenges a longstanding assumption in the RNA-editing field.
For years, researchers believed that RNA editing primarily suppresses immune activation by destabilizing dsRNA structures, making them less recognizable to innate immune sensors. Ng’s study reveals that some RNA-editing events have the opposite effect.
“Not all of this editing can actually prevent the recognition of these RNA structures,” Ng said. “It actually helps to stimulate the interferon response.”
These editing events appear to stabilize dsRNA rather than destabilize it, promoting activation of innate immune pathways. DDX6 suppresses these immunostimulatory editing events, thereby preventing immune activation.
“DDX6 actually helps to prevent this potent editing event from happening—this immunostimulatory RNA editing event,” Ng said.
The discovery represents what Ng described as a significant shift in understanding RNA editing biology. “For a very long time, people in the RNA editing field think that editing actually helps to prevent the recognition of double-stranded RNA structures,” he said. “But in this paper we showed that not all of these editing events can actually destabilize. Some of them can help to stabilize.”
The biological consequences of DDX6 suppression were evident in both normal tissues and tumors. Mice lacking DDX6 accumulated dsRNA and developed widespread interferon activation, demonstrating the protein’s importance in preventing excessive innate immune responses in healthy cells.
Within tumors, however, DDX6-mediated suppression appeared to benefit cancer cells by limiting immune activation. “The immune activation actually will result in cell death,” Ng said. “Too much activation is not good for cancer.”
The researchers found that reducing DDX6 levels promoted dsRNA-driven innate immune responses and increased immune cell infiltration within tumors. Nevertheless, Ng emphasized that the study was designed primarily to investigate innate immunity rather than directly demonstrate enhanced antitumor immune activity.
“We see increased immune cell infiltration, and there is evidence of immune cell activation,” he said. “But whether or not this increased immune cell infiltration is causing the tumor to shrink, I do not have the definite evidence yet.”
Instead, the data support a role for DDX6 in shaping the tumor microenvironment. “It remodels the tumor microenvironment toward the more inflamed state,” Ng said.
Additional studies, including T-cell killing assays and other functional experiments, will be required to determine whether DDX6 inhibition directly enhances immune-mediated tumor destruction.
The broader significance of the work lies in its contribution to understanding how RNA editing influences immunity. “I feel it’s more about the mechanism that I found on how DDX6 behaves or functions as an immune suppressor,” Ng said.
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Proactive Surveillance Pays Off for Patients with Li-Fraumeni Syndrome
Research presented at the annual conference of the European Society of Human Genetics shows that screening people with the rare, inherited cancer predisposition condition Li-Fraumeni syndrome (LFS) brings both medical benefits and substantial healthcare cost reductions.
The findings “could help inform future discussions about how surveillance protocols for LFS can be further optimized,” said Marion Rolain, a biomedical researcher and engineer in the genetics department at the Centre Hospitalier Universitaire Rouen in France, who presented the research.
“The goal is not necessarily to increase or decrease surveillance, but rather to ensure that screening strategies are as effective, evidence-based and personalized as possible,” she added.
Rolain explained that LFS is caused by pathogenic variants in the TP53 gene, which occur in approximately one in 5,000 to one in 20,000 individuals. It often presents as cancer, particularly rare adrenal or brain tumors, osteosarcoma, soft tissue sarcomas and/or breast cancer, that develops at an unusually young age. LFS is also suspected when a person has multiple primary cancers, including cases of childhood cancer within the same family, with diagnosis confirmed through genetic testing of the TP53 gene.
The high lifetime risk for multiple primary cancers among individuals with LFS means that their care is based on intensive multiorgan surveillance that includes annual whole-body and brain magnetic resonance imaging (MRI), regular clinical examinations of organs at risk, and age- and risk-adapted screening such as abdominal ultrasound, blood pressure measurements, breast MRI in women, and looking for signs of early puberty or virilization caused by potential adrenal tumors in children.
Carla Oliveira, PhD, from the Institute of Research and Innovation in Health at the University of Porto, in Portugal, who coordinated the study as part of the EU PREVENTABLE project, told Inside Precision Medicine that “although surveillance programs for LFS are increasingly implemented, there is still limited real-world evidence on their overall clinical, social, and economic impact.”
Her team wants to better understand and demonstrate the value of proactive prevention, early detection, and specialized care in individuals with hereditary cancer predisposition syndromes, including LFS.
“More broadly, the PREVENTABLE project aims to generate evidence to support a shift from a reactive healthcare model focused on treating advanced cancer to a more proactive approach centered on prevention and earlier diagnosis, when a genetic diagnosis is available,” Oliveira said.
The study included retrospective clinical data from 505 TP53 carriers and 361 non-carrier relatives from seven European countries.
The researchers used standardized French hospital fees to calculate the costs of each individual’s healthcare pathway then compared two groups; those without a prior cancer diagnosis who underwent proactive surveillance with regular screening, and those who received treatment after being diagnosed with cancer.
Among the 155 TP53 carriers (median age 28 years) without a prior cancer diagnosis included in the preventive arm, 18 (11.6%) developed one or more cancers during more than six years of follow-up. The mean cost of prevention was €6047 ($7007) per patient.
In the 273 patients who had already developed cancer prior to genetic testing, (median age 33 years), the mean treatment cost was €53,906 ($62,464) per patient. Within this group, 109 patients had early stage and 164 advanced stage disease.
Rolain noted that as well as a nine-fold lower cost among the patients who received screening before a cancer diagnosis, there were significant improvements in survival among the screened patients.
“From a clinical perspective, our results were not surprising, since intensive screening should enable earlier cancer detection, generally associated with better clinical outcomes. But what is particularly noteworthy is that we have been able to see this reflected in real-world data across several European countries. And we were also struck by the dramatic difference between prevention and treatment costs,” said Rolain.
She added: “While further large-scale prospective studies will be needed to confirm our findings, we believe that they are already sufficient to make the case for investing in early genetic testing in tumor risk syndromes. We have been able to show that catching cancer early or preventing it altogether is not only better for patients, but also for healthcare systems.”
The researchers hope that their study findings will contribute to future refinements of existing guidelines and help improve the balance between early cancer detection and the burden associated with intensive long-term screening for patients with LFS and other rare tumor risk syndromes.
Chair of the conference, Alexandre Reymond, PhD, who was not involved in the research, said: “With ever-increasing health system costs, it is time to change from a predominantly curative mantra and put more emphasis on prevention. This study is a beautiful example of the clinical and economic benefits of the implementation of personalized health care.”
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