Scientists develop molecules that may treat Crohn’s disease

Broad scientists designed molecules (pictured in teal) that can bind CARD9 (white with red and blue), a protein linked to inflammatory bowel disease.
Image Credit: Rush et al. Cell. DOI: 10.1016/j.cell.2025.12.013

Scientific Frontline: "At a Glance" Summary

• Main Discovery: Researchers developed small-molecule drug candidates that mimic a rare, protective variant of the CARD9 gene to treat Crohn's disease and other inflammatory bowel diseases.
• Methodology: The team utilized a "binder-first" strategy, screening 20 billion molecules to identify binders to the CARD9 coiled-coil domain, followed by X-ray crystallography and competitive binding assays to isolate compounds that block inflammatory signaling.
• Key Data: The initial library screen evaluated over 20 billion compounds, ultimately yielding molecules that significantly reduced inflammation in both human immune cells and a mouse model expressing the human CARD9 gene.
• Significance: This work validates a complete "genetics-to-therapeutics" pipeline, proving that scaffolding proteins previously considered "undruggable" can be effectively targeted by mimicking naturally occurring protective variants.
• Future Application: Immediate efforts focus on optimizing these compounds for human clinical trials, while the broader methodology provides a blueprint for developing drugs against other difficult genetic targets.
• Branch of Science: Chemical Biology, Immunology, Genetics, and Molecular Biology.
• Additional Detail: The development strategy parallels the success of PCSK9 inhibitors for cholesterol, leveraging the safety profile of a natural genetic variant to guide drug design.

“Recipe book” for reprogramming immune cells

Filipe Pereira, professor of molecular medicine at Lund University
Photo Credit: Courtesy of Lund University

Scientific Frontline: "At a Glance" Summary

• Main Discovery: Researchers at Lund University established a high-throughput screening platform and a library of over 400 immune-related transcription factors to decode the specific "recipes" required to reprogram accessible somatic cells into distinct immune cell identities.
• Methodology: The study utilized unique DNA barcodes attached to each transcription factor, allowing the simultaneous tracking of thousands of combinatorial possibilities to determine which specific factor groups drive conversion to desired immune lineages.
• Key Data: This four-year project successfully identified reprogramming protocols for six different immune cell types, including Natural Killer (NK) cells, which were previously impossible to generate through direct reprogramming.
• Context: Prior to this breakthrough, the specific reprogramming factors had been mapped for only four of the human body's more than 70 distinct immune cell types, limiting the development of synthetic immunotherapies.
• Significance: The platform enables the production of rare, patient-specific immune cells from abundant sources like skin fibroblasts, potentially expanding immunotherapy applications from cancer treatment to autoimmune diseases and regenerative medicine.

A bacterial toxin can counteract colorectal cancer growth

Sun Nyunt Wai
Photo Credit: Mattias Pettersson

Scientific Frontline: "At a Glance" Summary

• Discovery of Anti-Tumor Toxin: The purified cytotoxin MakA, secreted by the cholera bacterium Vibrio cholerae, has been identified as an agent that significantly inhibits the growth of colorectal cancer tumors.
• Mechanism of Action: MakA accumulates specifically within tumor tissue, inducing cancer cell death and suppressing proliferation while simultaneously recruiting innate immune cells, such as macrophages and neutrophils, to the tumor microenvironment.
• Safety and Specificity: In murine models, systemic administration of MakA targeted tumors locally without causing harmful systemic inflammation, weight loss, or organ dysfunction, indicating a high degree of specificity for cancerous tissue.
• Immune Modulation: The toxin alters the cellular composition of the tumor environment, stimulating the production of immune mediators that promote apoptosis while preserving regulatory mechanisms to protect surrounding healthy tissue.
• Therapeutic Potential: This study highlights a novel therapeutic avenue utilizing bacterial toxins to both directly target cancer cells and enhance the host's immune response, offering a potential alternative to traditional treatments like chemotherapy and radiation.

When a virus releases the immune brake: New evidence on the onset of multiple sclerosis

Fluorescence microscope image of a mouse brain. The protective myelin layer (red) surrounds the nerve cell extensions. Cells infected with a virus are visible in light blue. Such infections cause immune cells to invade the brain and attack the myelin layer.
Image Credit: Hyein Kim, University of Basel

Scientific Frontline: "At a Glance" Summary

• Discovery of Initiation Mechanism: Researchers have identified a specific biological sequence where the Epstein-Barr virus (EBV) triggers early multiple sclerosis (MS)-like damage by allowing self-reactive B cells to bypass immune checkpoints.
• Molecular Mimicry: The mechanism relies on a viral protein (Latent Membrane Protein 1) that mimics a crucial "approval" signal usually provided by other immune cells, preventing the programmed elimination of B cells that target the body's own proteins.
• Localized Pathogenesis: Experimental mouse models demonstrated that these "out-of-control" B cells capture myelin antigens and cause localized demyelinating lesions in the central nervous system, mirroring the earliest stages of MS.
• B Cell Direct Action: The study shifts the understanding of B cells from indirect influencers of inflammation to direct agents of lesion formation, suggesting they are the primary "spark" for chronic brain inflammation.
• Therapeutic Correlation: The findings explain the clinical efficacy of current B-cell depleting therapies and emphasize that MS risk is shaped by the timing and sequence of rare immune events rather than infection alone.
• Future Prevention: This discovery highlights the potential for preventive strategies, such as targeted vaccinations designed to inhibit severe EBV infections and prevent the subsequent invasion of the brain by pathogenic B cells.

TB harnesses part of immune defence system to cause infection

Photo Credit: Thirdman

Scientific Frontline: "At a Glance" Summary

• Mycobacterium tuberculosis (MTB) Subverts Immune Defense: The bacterium exploits Dectin-1, an immune receptor typically tasked with anti-fungal defense, to facilitate its own survival and replication within host cells rather than being destroyed.
• Mechanism of Action: Research reveals that MTB produces a unique alpha-glucan molecule that specifically targets the Dectin-1 receptor, manipulating host cell responses to create a favorable environment for infection.
• Experimental Evidence: In controlled studies involving human and mouse cells, the absence of the Dectin-1 pathway allowed for better control of the infection; specifically, mice lacking this receptor were found to be significantly more resistant to MTB.
• Global Context: This discovery addresses a critical knowledge gap regarding why humans and animals are highly susceptible to TB, a disease responsible for approximately 1.5 million deaths annually.
• Future Implications: Identifying this pathway offers potential for new therapeutic interventions and preventive strategies, such as genetically modifying livestock to remove the Dectin-1 receptor and increase herd resistance.

Stanford Medicine study identifies immune switch critical to autoimmunity, cancer

Edgar Engleman, MD, professor of pathology
Photo Credit: Courtesy of Stanford School of Medicine

A single signaling pathway controls whether immune cells attack or befriend cells they encounter while patrolling our bodies, researchers at Stanford Medicine have found. Manipulating this pathway could allow researchers to toggle the immune response to treat many types of diseases, including cancers, autoimmune disorders and those that require organ transplants.

The research, which was conducted in mice, illuminates the mechanism of an important immune function that prevents inappropriate attacks on healthy tissue. Called peripheral immune tolerance, the key cellular players, known as regulatory T cells (or Tregs, pronounced “tee-regs”), were first described in the late 1990s in a series of discoveries that were recently recognized with the 2025 Nobel Prize in physiology or medicine.

A platform to test new cancer treatments

Differentiated hepatic cells growing in a flask re-gain the appearance of cells present in liver.
Image Credit: © FAMOL, UNIGE

Overcoming acquired treatment resistance is one of the major challenges in the fight against cancer. While combination therapies hold promise, their toxicity to healthy tissue remains a major hurdle. To anticipate these risks, researchers at the University of Geneva (UNIGE) have developed in vitro models of the kidneys, liver, and heart – three organs particularly sensitive to such therapies. This fast, animal-free approach paves the way for safer evaluation of new treatments. The findings are published in Biomedicine & Pharmacotherapy. 

Recent advances in immunotherapy, targeted therapies, and gene therapies have significantly improved survival rates for patients with cancer. However, over time, many tumors develop resistance to these treatments, undermining their effectiveness. This phenomenon, known as ‘acquired resistance’, has become one of the major challenges in oncology. 

Immune system keeps mucosal fungi in check

The yeast fungus Candida albicans (blue) breaks out of human immune cells (red) by forming long thread-like cells called hyphae. The part of the hypha that has already left the immune cells is colored yellow.
Image Credit: Erik Böhm, Leibniz-HKI

The yeast Candida albicans colonizes mucosal surfaces and is usually harmless. However, under certain conditions it can cause dangerous infections. A research team at the University of Zurich has now discovered how the immune system prevents the transformation from a harmless colonizer to a pathogenic mode. This happens, among other things, by sequestering zinc. 

The microbiome not only consists of bacteria, but also of fungi. Most of them support human and animal health. However, some fungi also have pathogenic potential. For instance, the yeast Candida albicans can grow in an uncontrolled manner on the oral mucosa, causing oral thrush. 

In severe cases by growing in a filamentous form, it can enter the bloodstream and cause systemic infections, which account for over one million deaths per year. This happens primarily in people with a weakened immune system on intensive care units, for instance individuals who are immunosuppressed because of a transplantation or cancer. 

New Method Uncovers How Viruses Evade Immune Responses — and How We Might Fight Back

Co-first authors Erin Doherty (left) and Jason Nomburg (right)
Photo Credit: Courtesy of Innovative Genomics Institute

Viruses and their hosts — whether bacteria, animals, or humans — are locked in a constant evolutionary arms race. Cells evolve defenses against viral infection, viruses evolve ways around those defenses, and the cycle continues.

One important weapon that cells use in the fight against viruses is a set of tiny molecular “alarm signals” made of nucleotides: the same chemical building blocks that make up DNA and RNA. When a virus infects a cell, these nucleotide messengers activate powerful immune defenses. To survive, viruses must find ways to shut these signals down. In a new study published in the journal Cell Host & Microbe, IGI researchers reveal that viruses have evolved a surprisingly large and diverse set of enzymes specifically designed to destroy these immune alarm signals, helping them hide from or disable the host’s antiviral defenses.

Immune cells turn damage into repair

Intestines one week after abdominal irradiation, showing proliferating epithelial cells (in brown).
Image Credit: Julius Fischer / TUM 

Patients receiving intensive cancer treatments often suffer from severe damage to the intestinal lining. Researchers from the Technical University of Munich (TUM) and the Leibniz Institute for Immunotherapy (LIT) have discovered that certain immune cells can trigger healing processes. They use inflammatory signals to do so - which is surprising, as inflammation in the intestine was previously thought to be primarily harmful. This finding could open new possibilities for therapies. 

Regulatory T cells (Tregs), a specialized type of immune cells, are usually seen as “peacekeepers” that prevent excessive immune attacks. In a study  published in Signal Transduction and Targeted Therapy, researchers from the Department of Radiation Oncology at the TUM University Hospital and the LIT Cooperation Group “Innate Immune Sensing in Cancer and Transplantation” uncovered how the body's own immune system can be harnessed to repair the intestinal lining and improve survival.  

Immunology: In-Depth Description

Image Credit: Scientific Frontline / AI generated

Immunology is the branch of biomedical science concerned with the structure, function, and disorders of the immune system—the complex network of cells, tissues, and organs that protect an organism from foreign invaders. Its primary goal is to understand how biological systems identify and eliminate pathogens (such as bacteria, viruses, fungi, and parasites) while maintaining tolerance for the body's own healthy tissue (distinguishing "self" from "non-self").

Why the "gut brain" plays a central role for allergies

This tissue section, taken from the intestine of a mouse unable to produce the neuropeptide VIP, clearly shows the striking frequency with which certain cell types occur on the intestine's surface. These include villous cells (red), mucus-producing goblet cells (yellow), Paneth cells (pink) and stem cells (green).
Image Credit: © Charité | Luisa Barleben

The intestinal nervous system, often referred to as the "gut brain", is essential in controlling digestion and maintaining the intestinal barrier. This protective layer, made up of the intestinal mucosa, immune cells and the microbiome, shields the body from the contents of the gut. Its effectiveness depends on the delicate balance among these components. If this balance is disrupted, inflammation, allergies, or chronic intestinal diseases can arise. The intestinal mucosa serves as the body’s primary defense against pathogens. While previous studies have shown that the intestinal nervous system is involved in immune responses in addition to digestion, its role in the development of intestinal epithelial cells has remained largely unclear until now. 

LJI scientists discover how T cells transform to defend our organs

The new study was led by Pandurangan Vijayanand, M.D., Ph.D., William K. Bowes Distinguished Professor at La Jolla Institute for Immunology
Photo Credit: Courtesy of La Jolla Institute for Immunology

We owe a lot to tissue resident memory T cells (TRM). These specialized immune cells are among the body’s first responders to disease. 

Rather than coursing through the bloodstream—as many T cells do—our TRM cells specialize in defending specific organs. They battle viruses, breast cancer, liver cancer, melanomas, and many other health threats. 

Pandurangan Vijayanand, M.D., Ph.D., William K. Bowes Distinguished Professor at La Jolla Institute for Immunology (LJI), has even shown that a greater density of TRM cells is linked to better survival outcomes in lung cancer patients.

Customised cells to fight brain cancer

Visualisation of cell death induced by CAR-T cells. A real-time imaging experiment (images taken at 0, 5 and 10 minutes) shows a CAR-T cell in contact with a glioblastoma cell (artificially marked in green). This contact causes the CAR-T cell to concentrate granules (lytic granules, shown in pink) containing the proteins necessary for the death of the target cell. These proteins penetrate the cancer cell and induce its death. After 10 minutes, the cancer cell begins to die, as indicated by the loss of its structure (evidenced by the appearance of "bubbles").
Image Credit: © Denis Migliorini

With a five-year survival rate of less than 5%, glioblastoma is one of the most aggressive types of brain cancer. Until now, all available treatments, including immunotherapy — which involves strengthening the immune system to fight cancer— have proved disappointing. CAR-T cells are genetically modified immune cells manufactured in the laboratory and designed to identify and destroy cancer cells. By targeting a protein present in the tumor environment, a team from the University of Geneva (UNIGE) and the Geneva University Hospital (HUG) has developed CAR-T cells capable of destroying glioblastoma cells. Their efficacy in an animal model of the disease paves the way for clinical trials in humans. These results are published in the Journal for ImmunoTherapy of Cancer. 

A cellular protein, FGD3, boosts breast cancer chemotherapy, immunotherapy

The research team included, front row, from left: graduate student Junyao Zhu, biochemistry professor David Shapiro, and senior researcher Chengiian Mao; back row, from left: graduate students Abigail Spaulding, Xinyi Dai and Qianjin Jiang.
Photo Credit: Fred Zwicky

A naturally occurring protein that tends to be expressed at higher levels in breast cancer cells boosts the effectiveness of some anticancer agents, including doxorubicin, one of the most widely used chemotherapies, and a preclinical drug known as ErSO, researchers report. The protein, FGD3, contributes to the rupture of cancer cells disrupted by these drugs, boosting their effectiveness and enhancing anticancer immunotherapies.

The new findings were the happy result of experiments involving ErSO, an experimental drug that killed 95-100% of estrogen-receptor-positive breast cancer cells in a mouse model of the disease. ErSO upregulates a cellular pathway that normally protects cancer cells from stress, said University of Illinois Urbana-Champaign biochemistry professor David Shapiro, who led the new work with Illinois graduate student Junyao Zhu. But when that protective pathway is ramped up, the system goes awry.

Combination of immunotherapy and targeted therapy improves survival for patients with advanced colorectal cancer

Human colorectal cancer cells
Image Credit: National Cancer Institute

A new study led by UCLA investigators found that combining zanzalintinib, a targeted therapy drug, and atezolizumab, an immune checkpoint inhibitor, helped patients with metastatic colorectal cancer, the second most common cause of cancer death in the U.S., live longer and control their disease better than with the standard treatment drug regorafenib. 

The findings simultaneously published in The Lancet and presented at the European Society for Medical Oncology Congress; mark the first time an immunotherapy-based regimen has demonstrated a survival benefit in the vast majority of patients with metastatic colorectal cancer.

“This study represents an important step forward for a group of patients who have historically had very few treatment options,” said Dr. J. Randolph Hecht, professor of clinical medicine at the David Geffen School of Medicine at UCLA and first author of the study. “We may finally be finding ways to make immunotherapy work for more patients with colorectal cancer.”

Why women's brains face higher risk: scientists pinpoint X-chromosome gene behind MS and Alzheimer's

Image Credit: Scientific Frontline / AI generated

New research by UCLA Health has identified a sex-chromosome linked gene that drives inflammation in the female brain, offering insight into why women are disproportionately affected by conditions such as Alzheimer’s disease and multiple sclerosis as well as offering a potential target for intervention. 

The study published in the journal Science Translational Medicine, used a mouse model of multiple sclerosis to identify a gene on the X chromosome that drives inflammation in brain immune cells, known as microglia. Because females have two X chromosomes, as opposed to only one in males, they get a “double dose” of inflammation, which plays a major role in aging, Alzheimer’s disease and multiple sclerosis.  

When the gene, known as Kdm6a, and its associated protein were deactivated, the multiple sclerosis-like disease and neuropathology were both ameliorated with high significance in female mice.  

Checkpoint Inhibitor Promotes Tissue Repair

The illustration shows the mechanism of action of immune checkpoint inhibitors: antibodies (yellow) activate T cells (blue) enabling them to recognize and attack tumor cells (purple) more effectively. At the same time, checkpoint inhibitors accelerate tissue healing.
Image Credit: Scientific Frontline / AI generated

The body employs a protective mechanism that curbs overzealous immune responses. Known as checkpoint inhibitors, this natural braking system is located on the surface of certain immune cells. Cancer therapy often disables these inhibitors so that the immune system can fight tumor cells more effectively.

Previous observations showed that one of these inhibitors, known as TIGIT, provides a certain level of protection against tissue damage in mice infected with viruses. “We suspected that TIGIT also has something to do with tissue repair. However, the underlying mechanisms were completely unknown until now,” says Nicole Joller, Professor of Immunology at the Department of Quantitative Biomedicine at the University of Zurich (UZH). Joller’s team recently identified the signaling pathway that TIGIT uses to promote tissue repair.

A promising target for multiple sclerosis

The image depicts a neuron with its axon insulated by segments of the myelin sheath. The visible degradation and fragmentation of that sheath represent the demyelination process that is characteristic of multiple sclerosis. This process disrupts the neuron's ability to transmit signals efficiently, leading to the neurological symptoms associated with the condition.
Image Credit: Scientific Frontline / AI generated

A team from UNIGE and HUG has discovered a subgroup of immune cells particularly involved in the disease, paving the way for more precise treatments and avoiding certain side effects.

Multiple sclerosis, which affects around one in 500 people in Switzerland, is an autoimmune disease in which immune cells attack the central nervous system, causing irreversible damage. Current treatments involve blocking the immune system to prevent it from attacking the body. Although effective, these drugs can trigger potentially serious infections. A team from the University of Geneva (UNIGE) and Geneva University Hospitals (HUG), in collaboration with the University of Pennsylvania, has identified a subtype of immune cells in newly diagnosed patients that may have a decisive role in disease progression.  A treatment targeting these cells specifically could effectively control the disease while avoiding certain side effects. These findings have been published in the journal Annals of Neurology.

AI tool offers deep insight into the immune system

scHDeepInsight.
An overview of the process linking single-cell RNA input, image conversion and CNN analysis, to hierarchical immune cell classification.
Image Credit: ©2025 Tsunoda et al.
(CC BY-ND 4.0)

Researchers explore the human immune system by looking at the active components, namely the various genes and cells involved. But there is a broad range of these, and observations necessarily produce vast amounts of data. For the first time, researchers including those from the University of Tokyo built a software tool which leverages artificial intelligence to not only offer a more consistent analysis of these cells at speed but also categorizes them and aims to spot novel patterns people have not yet seen.

Our immune system is important — it’s impossible to imagine complex life existing without it. This system, comprising different kinds of cells, each playing a different role, helps to identify things that threaten our health, and take actions to defend us. They are both very effective, but also far from perfect; hence, the existence of diseases such as the notorious acquired immunodeficiency syndrome, or AIDS. And recent earth-shattering issues, such as the coronavirus pandemic, serve to highlight the importance of research around this intricate yet powerful system.