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KAIST Awakens dormant immune cells inside tumors to attack cancer
<(From Left) Professor Ji-Ho Park, Dr. Jun-Hee Han from the Department of Bio and Brain Engineering>
Within tumors in the human body, there are immune cells (macrophages) capable of fighting cancer, but they have been unable to perform their roles properly due to suppression by the tumor. KAIST researchers have overcome this limitation by developing a new therapeutic approach that directly converts immune cells inside tumors into anticancer cell therapies.
KAIST (President Kwang Hyung Lee) announced on the 30th that a research team led by Professor Ji-Ho Park of the Department of Bio and Brain Engineering has developed a therapy in which, when a drug is injected directly into a tumor, macrophages already present in the body absorb it, produce CAR (a cancer-recognizing device) proteins on their own, and are converted into anticancer immune cells known as “CAR-macrophages.”
Solid tumors—such as gastric, lung, and liver cancers—grow as dense masses, making it difficult for immune cells to infiltrate tumors or maintain their function. As a result, the effectiveness of existing immune cell therapies has been limited.
CAR-macrophages, which have recently attracted attention as a next-generation immunotherapy, have the advantage of directly engulfing cancer cells while simultaneously activating surrounding immune cells to amplify anticancer responses.
However, conventional CAR-macrophage therapies require immune cells to be extracted from a patient’s blood, followed by cell culture and genetic modification. This process is time-consuming, costly, and has limited feasibility for real-world patient applications.
To address this challenge, the research team focused on “tumor-associated macrophages” that are already accumulated around tumors.
They developed a strategy to directly reprogram immune cells in the body by loading lipid nanoparticles—designed to be readily absorbed by macrophages—with both mRNA encoding cancer-recognition information and an immunostimulant that activates immune responses.
In other words, in this study, CAR-macrophages were created by “directly converting the body’s own macrophages into anticancer cell therapies inside the body.”
<Figure . Schematic illustration of the strategy for in vivo CAR-macrophage generation and cancer cell eradication via co-delivery of CAR mRNA and immunostimulants using lipid nanoparticles (LNPs)>
When this therapeutic agent was injected into tumors, macrophages rapidly absorbed it and began producing proteins that recognize cancer cells, while immune signaling was simultaneously activated. As a result, the generated “enhanced CAR-macrophages” showed markedly improved cancer cell–killing ability and activated surrounding immune cells, producing a powerful anticancer effect.
In animal models of melanoma (the most dangerous form of skin cancer), tumor growth was significantly suppressed, and the therapeutic effect was shown to have the potential to extend beyond the local tumor site to induce systemic immune responses.
Professor Ji-Ho Park stated, “This study presents a new concept of immune cell therapy that generates anticancer immune cells directly inside the patient’s body,” adding that “it is particularly meaningful in that it simultaneously overcomes the key limitations of existing CAR-macrophage therapies—delivery efficiency and the immunosuppressive tumor environment.”
This research was led by Jun-Hee Han, Ph.D., of the Department of Bio and Brain Engineering at KAIST as the first author, and the results were published on November 18 in ACS Nano, an international journal in the field of nanotechnology.
※ Paper title: “In Situ Chimeric Antigen Receptor Macrophage Therapy via Co-Delivery of mRNA and Immunostimulant,” Authors: Jun-Hee Han (first author), Erinn Fagan, Kyunghwan Yeom, Ji-Ho Park (corresponding author), DOI: 10.1021/acsnano.5c09138
This research was supported by the Mid-Career Researcher Program of the National Research Foundation of Korea.
2025.12.31 View 1762 -
Depression is Not Only a Disease of the Mind. KAIST Discovers the Immune-Brain Connection
<(From Left) Ph.D candidate Insook Ahn from KAIST, Professor Jinju Han from KAIST, (Upper Left) Yangsik Kim from Inhan University School of Medicine, Ph.D candidate Soyeon Chang(psychiatrist)>
Major depressive disorder (MDD) is characterized by a lowered mood and loss of interest, contributing not only to difficulties in academic and professional life but also as a major cause of suicide in South Korea. However, there are currently no objective biological markers that can be used for diagnosis or treatment. Amidst this, a research team from KAIST has revealed that depression is not merely a problem of the mind or brain, but is deeply connected to abnormalities in the body's overall immune response. They found that this immune abnormality affects brain function, and the 'Immune Neural Axis' imbalance is the core mechanism of depression, opening up the possibility for the discovery of new biomarkers and the development of new drugs for depression treatment.
KAIST announced on the November 20th that Professor Jinju Han's research team from the Graduate School of Medical Science and Engineering (GSMSE) at KAIST, in collaboration with Professor Yangsik Kim's research team (Ph.D., KAIST GSMSE) from Inha University School of Medicine, performed a multi-omics analysis combining plasma proteomic analysis, WBC single-cell analysis, and patient-derived brain organoids (mini-brains). This study focused on female patients with MDD who exhibited 'Atypical Features' (such as hypersomnia and overeating) and 'Psychotic Symptoms'(such as auditory hallucinations and idea of reference), which are different from typical depression symptoms, and who also had impaired reality judgment.
Sduio
■ "Immune Cells and Brain Function are Altered Together" A New Biological Clue for Depression
The research team simultaneously examined genetic changes in immune cells in the blood and changes in nervous-system-related proteins. The results confirmed a breakdown in the balance of immune-neural interaction in patients with depression.
MDD, especially in young women, often presents with atypical symptoms (hypersomnia, overeating, mood reactivity, etc.), which increases the risk of a later diagnosis of bipolar disorder. Furthermore, about 40% of patients are classified as treatment-resistant depression, showing no response to various antidepressants.
Consequently, there has been a continuous call for the development of new therapeutic strategies and the discovery of biomarkers based on immunity and metabolism, moving beyond the traditional drug-centric approach.
■ World's First Integration of "Leukocyte Single-Cell Analysis + Brain Organoid" A New Paradigm for Psychiatric Research
The research team presented the world's first precision medicine approach by integrating plasma proteomics, leukocyte single-cell transcriptome analysis, and analysis of brain organoids created from patient-derived induced pluripotent stem cells (iPSCs).
The results showed that patients with atypical depression exhibited high levels of stress, anxiety, and depression. Furthermore, proteins crucial for inter-neuronal signaling (DCLK3 and CALY) were significantly elevated compared to normal levels, and Complement Protein C5, which strongly enhances the body's immune response, was also increased. This indicates that both 'brain function' and 'immune function' are excessively activated and out of balance within the body.
This finding confirms a clue that depression is not merely a mood issue but is connected to biological changes occurring throughout the entire body. Upon examining the immune cells of depression patients, genetic changes were found that make inflammatory responses in the body occur more easily and strongly than usual. This implies that the entire bodily immune system is in a state of excessive activation, and this immune/inflammatory abnormality may influence the development of depression.
The patient-derived brain organoids showed accompanying growth retardation and abnormal neural development, supporting the possibility that immune abnormalities interact with changes in brain function to exacerbate the disease.
■ "Immune-Neural Axis Imbalance is the Core Mechanism of Atypical Depression"
This study integrated clinical data, single-cell omics, proteomics, and brain organoids to demonstrate that the 'Imbalance of the Immune-Neural Axis' is the core mechanism of MDD accompanied by atypical and psychotic symptoms.
<Integration of clinical symptoms, blood analysis, and patient-derived brain organoid analysis in women with major depressive disorder>
Professor Jinju Han stated, "This achievement presents a new precision medicine model for psychiatric research," adding, "We anticipate that this will actively lead to biomarker discovery and new drug development."
This accomplishment was published online in the world-renowned international scientific journal, Advanced Science, on October 31st.
※ Paper Title: Exploration of Novel Biomarkers through a Precision Medicine Approach Using Multi-omics and Brain Organoids in Patients with Atypical Depression and Psychotic Symptoms DOI: https://doi.org/10.1002/advs.202508383
※ Author Information: Soyeon Chang (Inha University, Co-First Author), Seok-Ho Choi, Jiyoung Lee, Yangsik Kim (Inha University, Corresponding Author), Insook Ahn (KAIST, Co-First Author), and Jinju Han (KAIST, Corresponding Author)
This research was supported by the National Research Foundation of Korea and the Korea Health Industry Development Institute.
2025.11.20 View 17243 -
KAIST Uncovers the Mechanism Behind Overactive Immune Cells
<(From Right) Professor Eui-Cheol Shin, Ph.D candidate So-Young Kim, Professor Su-Hyung Park, Professor Hyuk Soo Eun, Dr. Hoyoung Lee>
“Why do immune cells that are supposed to eliminate viruses suddenly turn against our own body?”
There are instances where killer T cells—which are meant to precisely remove virus-infected cells—malfunction like overheated engines, attacking even healthy cells and damaging tissues. A KAIST research team has now identified the key mechanism that regulates this excessive activation of killer T cells, offering new insights into controlling immune overreactions and developing therapies for immune-related diseases.
KAIST (President Kwang Hyung Lee) announced on November 5 that a research team led by Professors Eui-Cheol Shin and Su-Hyung Park from the Graduate School of Medical Science and Engineering, in collaboration with Professor Hyuk Soo Eun from Chungnam National University College of Medicine, has uncovered the molecular basis of nonspecific activation in killer T cells and proposed a new therapeutic strategy to control it.
Killer T cells (CD8⁺ T cells) selectively eliminate infected cells to prevent viral spread. However, when excessively activated, they can attack uninfected cells, causing inflammation and tissue damage. Such overactive immune responses can lead to severe viral infections and autoimmune diseases.
In 2018, Professor Shin’s team was the first in the world to discover that killer T cells can be nonspecifically activated by cytokines and randomly attack host cells—a phenomenon they termed “bystander activation of T cells”. The current study builds on that discovery by revealing the molecular mechanism driving this abnormal process.
The team focused on a cytokine called interleukin-15 (IL-15). Experiments showed that IL-15 can abnormally excite killer T cells by a bystander activation mechanism, causing them to attack uninfected host cells. However, when there is a concurrent antigen-specific stimulation, IL-15-induced bystander activation is suppressed.
The researchers further identified that this suppression occurs through an intracellular signaling process. When the concentration of calcium ions (Ca²⁺) changes, a protein called calcineurin activates, which in turn triggers a regulatory protein known as NFAT, suppressing IL-15-induced bystander activation of killer T cells. In other words, the calcineurin–NFAT pathway activated by antigen stimulation acts as a brake on overactivation by a bystander mechanism.
The team also discovered that some immunosuppressants, which are known to block the calcineurin pathway, may not always suppress immune responses—in certain contexts, they can instead promote IL-15-induced bystander activation of killer T cells. This finding underscores that not all immunosuppressants work the same way and that treatments must be carefully tailored to each patient’s immune response.
Through gene expression analysis, the researchers identified a gene set that increase only in abnormally activated killer T cells induced by IL-15 as markers. They further confirmed that these same markers were elevated in bystander killer T cells from patients with acute hepatitis A, suggesting that the markers could be used for disease diagnosis.
<In a normal immune response, killer T cells are activated by antigen stimulation and selectively eliminate only virus-infected cells, thereby controlling viral replication and promoting the patient’s rapid recovery. However, when killer T cells are nonspecifically overactivated by interleukin-15, they may randomly attack normal cells as well, causing excessive tissue damage and leading to severe disease. Future research may identify diseases in which such nonspecific hyperimmune responses occur, making it possible to develop new drugs to control them>
This study provides crucial clues for understanding the pathogenesis of various immune-related diseases, including severe viral infections, chronic inflammatory disorders, autoimmune diseases, and organ transplant rejection. It also paves the way for developing novel immunoregulatory therapies targeting IL-15 signaling.
Professor Eui-Cheol Shin explained that, “this study shows that killer T cells are not merely defenders—they can transform into ‘nonspecific attackers’ depending on the inflammatory environment. By precisely regulating this abnormal activation, we may be able to develop new treatments for intractable immune diseases.”
This research was published in the journal Immunity on October 31, with Dr. Hoyoung Lee and Ph.D. candidate So-Young Kim as co–first authors.
Title: “TCR signaling via NFATc1 constrains IL-15-induced bystander activation of human memory CD8⁺ T cells”, DOI: doi.org/10.1016/j.immuni.2025.10.002
The study was supported by the National Research Foundation of Korea (NRF), the Korea Health Industry Development Institute (KHIDI), and the Institute for Basic Science (IBS).
2025.11.06 View 1841 -
KAIST team links early life epigenetic memory to adult brain inflammation
<(From left) Professor Won-Suk Chung, Ph.D. Ph.D candidate Hyeonji Park Dr. Seongwan Park, Professor Inkyung Jung>
Why do some people remain healthy through childhood yet become more vulnerable to brain disorders such as dementia later in life? A KAIST (President Kwang Hyung Lee) -led team has uncovered a key part of the answer: a developmental ‘switch’ in astrocytes—the brain’s most abundant support cells that shapes how strongly the brain’s immune system reacts in adulthood. The study identifies a gene, NR3C1 (encoding the glucocorticoid receptor), as a master regulator of this switch and shows how early-life epigenetic ‘memory’ can predispose the adult brain to excessive inflammation.
The work was carried out by a joint team led by Professor Inkyung Jung (Department of Biological Sciences, KAIST) and Associate Director Won-Suk Chung (Center for Vascular Research, Institute for Basic Science; Professor, KAIST Biological Sciences). Using mouse models, the researchers mapped gene-regulatory programs across multiple stages of astrocyte development and found that NR3C1 acts during a brief early-postnatal window to enforce long-term immune restraint.
<The schematic illustrates how the NR3C1 gene (glucocorticoid receptor) suppresses the immune response of astrocytes. In normal (control) astrocytes, NR3C1 binds to specific regulatory regions of DNA (nGRE) to inhibit the expression of immune-related genes, thereby maintaining brain homeostasis even under immune stimulation. In contrast, in NR3C1-deficient astrocytes (KO), this suppression is lost, leading to excessive activation of inflammation-related genes such as Gfap, Il6st, Stat2, and Cxcl10. As a result, in an autoimmune encephalomyelitis (EAE) model, pronounced neuroinflammation and clinical symptoms (paralysis and severe debilitation) are observed>
To build this map, the team combined state-of-the-art 3D epigenome profiling with RNA sequencing and chromatin accessibility analyses, capturing how DNA folds and which regulatory elements contact target genes. They identified 55 stage-specific transcription factors that guide astrocyte maturation; among them, NR3C1 emerged as the critical ‘switch’ in early life. Notably, deleting NR3C1 in astrocytes did not disrupt normal development. However, when the adult mice were challenged with an autoimmune model of multiple sclerosis, animals lacking astrocytic NR3C1 mounted exaggerated inflammatory responses and developed more severe disease.
Mechanistically, the study shows that early loss of NR3C1 epigenetically primes immune genes - keeping their regulatory elements open and ready - so that later in life these genes respond too strongly to inflammatory cues. In effect, NR3C1 serves as an early ‘brake’ that prevents over-activation of astrocyte immune programs in adulthood.
“This is the first demonstration that astrocyte immune functions are governed by epigenetic memory,” said Professor Won-Suk Chung. “Our findings offer new clues to the origins of degenerative brain disorders, including Alzheimer’s disease.”
“We reveal a temporal regulatory window in astrocyte development that can set the stage for disease vulnerability in adulthood,” added Professor Inkyung Jung. “Understanding the 3D genome logic behind these programs could open paths to therapies for immune-related brain disorders such as multiple sclerosis.”
<The figure shows the three-dimensional genome structure of astrocytes at specific gene loci, illustrating how NR3C1 regulates their expression. In normal cells, NR3C1 binds to DNA and maintains the chromatin in a closed state, thereby preventing unnecessary activation between distal regulatory elements (enhancers) and gene promoters. In contrast, when NR3C1 is absent, the chromatin becomes open, creating a state in which enhancers and genes can be more easily activated. As a result, genes such as Mxi1 are overexpressed, triggering inflammatory responses. This clearly demonstrates that NR3C1 plays an essential role in maintaining immune homeostasis by stabilizing three-dimensional gene regulatory mechanisms.>
The results of this study were published online on September 22 in the international journal Nature Communications (IF 15.7), with Dr. Seongwan Park and PhD student Hyeonji Park of KAIST’s Department of Biological Sciences as co-first authors.
※ Paper title: “NR3C1-mediated epigenetic regulation suppresses astrocytic immune responses in mice,” DOI: https://www.nature.com/articles/s41467-025-64088-5
In addition, on September 17, the journal published a commentary article introducing this research: https://www.nature.com/articles/s41467-025-64102-w
This research was supported by the Suh Kyungbae Science Foundation, the Ministry of Health and Welfare, the Ministry of Science and ICT, and IBS.
Glossary - Epigenetic priming: preparing genes for rapid future activation by altering chromatin without changing DNA sequence
2025.09.25 View 2499 -
KAIST Professors Participate in Mastering Immunity 2025 Singapore Summit
<2025 Global Infectious Diseases Summit>
KAIST is proud to announce the participation of Professors Eui-Cheol Shin and Jeong Seok Lee in the Mastering Immunity 2025: Global Infectious Diseases Summit, held on 1–2 September 2025 in Singapore. This international symposium brought together leading experts in immunology to discuss the latest advancements in infectious disease research, vaccine development, and immune response characterization.
At the summit, Professor Eui-Cheol Shin contributed as a speaker, sharing insights from his groundbreaking research in immunology, while Professor Jeong Seok Lee also presented on his latest work in the field. Professor Eui-Cheol Shin joined a panel discussion alongside other distinguished global experts, highlighting the importance of collaboration in addressing pressing infectious disease challenges.
The summit was organized by ProImmune, an international life-science company specializing in innovative immunology solutions. Through cutting-edge technologies, including Ankyron® target-binding reagents, Pro5® MHC Class I Pentamers, ProT2® MHC Class II Tetramers as well as immunology-based assays such as REVEAL® MHC Binding Assays and ProPresent® Antigen Presentation Assays are accelerating this vital research. ProImmune supports researchers worldwide in understanding immune responses and accelerating the development of vaccines and immunotherapies.
<Presentation at the Summit>
KAIST celebrates the contributions of Professors Shin and Lee in representing Korean science on the global stage and advancing the understanding of infectious diseases.
For more information about the Mastering Immunity 2025 summit and to view the recorded talks, visit: https://www.proimmune.com/conference-videos
2025.09.13 View 1463 -
Why Do Plants Attack Themselves? The Secret of Genetic Conflict Revealed
<Professor Ji-Joon Song of the KAIST Department of Biological Sciences>
Plants, with their unique immune systems, sometimes launch 'autoimmune responses' by mistakenly identifying their own protein structures as pathogens. In particular, 'hybrid necrosis,' a phenomenon where descendant plants fail to grow healthily and perish after cross-breeding different varieties, has long been a difficult challenge for botanists and agricultural researchers. In response, an international research team has successfully elucidated the mechanism inducing plant autoimmune responses and proposed a novel strategy for cultivar improvement that can predict and avoid these reactions.
Professor Ji-Joon Song's research team at KAIST, in collaboration with teams from the National University of Singapore (NUS) and the University of Oxford, announced on the 21st of July that they have elucidated the structure and function of the 'DM3' protein complex, which triggers plant autoimmune responses, using cryo-electron microscopy (Cryo-EM) technology.
This research is drawing attention because it identifies defects in protein structure as the cause of hybrid necrosis, which occurs due to an abnormal reaction of immune receptors during cross-breeding between plant hybrids.
This protein (DM3) is originally an enzyme involved in the plant's immune response, but problems arise when the structure of the DM3 protein is damaged in a specific protein combination called 'DANGEROUS MIX (DM)'.
Notably, one variant of DM3, the 'DM3Col-0' variant, forms a stable complex with six proteins and is recognized as normal, thus not triggering an immune response. In contrast, another 'DM3Hh-0' variant has improper binding between its six proteins, causing the plant to recognize it as an 'abnormal state' and trigger an immune alarm, leading to autoimmunity.
The research team visualized this structure using atomic-resolution cryo-electron microscopy (Cryo-EM) and revealed that the immune-inducing ability is not due to the enzymatic function of the DM3 protein, but rather to 'differences in protein binding affinity.'
<Figure 1. Mechanism of Plant Autoimmunity Triggered by the Collapse of the DM3 Protein Complex>
This demonstrates that plants can initiate an immune response by recognizing not only 'external pathogens' but also 'internal protein structures' when they undergo abnormal changes, treating them as if they were pathogens.
The study shows how sensitively the plant immune system changes and triggers autoimmune responses when genes are mixed and protein structures change during the cross-breeding of different plant varieties. It significantly advanced the understanding of genetic incompatibility that can occur during natural cross-breeding and cultivar improvement processes.
Dr. Gijeong Kim, the co-first author, stated, "Through international research collaboration, we presented a new perspective on understanding the plant immune system by leveraging the autoimmune phenomenon, completing a high-quality study that encompasses structural biochemistry, genetics, and cell biological experiments."
Professor Ji-Joon Song of the KAIST Department of Biological Sciences, who led the research, said, "The fact that the immune system can detect not only external pathogens but also structural abnormalities in its own proteins will set a new standard for plant biotechnology and crop breeding strategies. Cryo-electron microscopy-based structural analysis will be an important tool for understanding the essence of gene interactions."
This research, with Professor Ji-Joon Song and Professor Eunyoung Chae of the University of Oxford as co-corresponding authors, Dr. Gijeong Kim (currently a postdoctoral researcher at the University of Zurich) and Dr. Wei-Lin Wan of the National University of Singapore as co-first authors, and Ph.D candidate Nayun Kim, as the second author, was published on July 17th in Molecular Cell, a sister journal of the international academic journal Cell.
This research was supported by the KAIST Grand Challenge 30 project.
Article Title: Structural determinants of DANGEROUS MIX 3, an alpha/beta hydrolase that triggers NLR-mediated genetic incompatibility in plants DOI: https://doi.org/10.1016/j.molcel.2025.06.021
2025.07.21 View 3275 -
KAIST Discovers Protein Switch that Turns Anti-Viral Immune Response On and Off
Even after the COVID-19 pandemic, various new infectious diseases continue to emerge, posing ongoing viral threats that demand robust and sustained immune defenses. However, excessive immune reactions can also harm body tissues, causing significant health issues. KAIST and an international research team have discovered a critical protein that acts as a 'switch' regulating immune responses to viruses. This breakthrough is expected to lay the groundwork for future infectious disease responses and autoimmune disease treatment strategies.
KAIST (President Kwang-Hyung Lee) announced on May 14 that a joint research team led by Professor Yoosik Kim from the Department of Chemical and Biomolecular Engineering at KAIST and Professor Seunghee Cha from University of Florida has discovered the mechanism by which double-stranded RNA derived from mitochondria amplifies immune responses. They identified the protein SLIRP as an 'immune switch' that regulates this process, playing a crucial role in both viral infections and autoimmune diseases.
< (From left) Master's candidate Yewon Yang, Professor Yoosik Kim and Ph.D. candidate Doyeong Ku of the Department of Chemical and Biomolecular Engineering >
Autoimmune diseases arise when the immune system fails to differentiate between external pathogens and the body's own molecules, leading to self-directed attacks. Despite extensive research, the precise causes of excessive inflammatory conditions like Sjögren’s syndrome and systemic lupus erythematosus remain unclear, and effective treatments are still limited.
To uncover the molecular mechanisms driving immune hyperactivation and to identify potential regulatory factors, the research team led by Professor Yoosik Kim focused on mitochondrial double-stranded RNA (mt-dsRNA), a genetic immunogenic material produced within cellular organelles. Since mt-dsRNA structurally resembles viral RNA, it can mistakenly trigger immune responses even in the absence of an actual viral infection.
The team discovered that SLIRP, a key regulator of mt-dsRNA, amplifies immune responses by stabilizing the RNA. They confirmed that SLIRP expression increases in experimental models simulating the tissues of autoimmune disease patients and viral infections. Conversely, suppressing SLIRP significantly reduced the immune response, underscoring its role as a critical factor in immune amplification.
This study also demonstrated the dual function of SLIRP in different contexts. In cells infected with human beta coronavirus OC43 and encephalomyocarditis virus (EMCV), SLIRP suppression led to reduced antiviral responses and increased viral replication. Meanwhile, in the blood and salivary gland cells of Sjögren’s syndrome patients, where both SLIRP and mt-dsRNA levels were elevated, suppressing SLIRP alleviated the abnormal immune response.
These findings highlight SLIRP as a key molecular switch that regulates immune responses in both infections and autoimmune diseases.
< Figure 1. Schematic diagram of antiviral signal amplification by SLIRP: SLIRP-based mt-dsRNA induction, cytoplasmic accumulation, and strong interferon response induction by positive feedback of immune response activation. Confirmation of the immune regulatory function of SLIRP in defense against autoimmune diseases Sjögren's syndrome, coronavirus, and encephalomyocarditis virus infection. >
Professor Yoosik Kim remarked, "Through this study, we have identified SLIRP as a crucial protein that drives immune amplification via mt-dsRNAs. Given its dual role in autoimmune diseases and viral infections, SLIRP presents a promising target for immune regulation therapies across various inflammatory disease contexts."
The study, with Ph.D. student Do-Young Ku (first author) and M.S. student Ye-Won Yang (second author) from the Department of Chemical and Biomolecular Engineering at KAIST as primary contributors, was published online in the journal Cell Reports on April 19, 2025.
※ Paper title: SLIRP amplifies antiviral signaling via positive feedback regulation and contributes to autoimmune diseases※ Main authors: Do-Young Ku (KAIST, first author), Ye-Won Yang (KAIST, second author), Seunghee Cha (University of Florida, corresponding author), Yoosik Kim (KAIST, corresponding author)
This study was supported by the Ministry of Health and Welfare's Public Health Technology Research Program and the National Institutes of Health (NIH) through Research Project (R01) funding.
2025.05.14 View 7206 -
KAIST Identifies Master Regulator Blocking Immunotherapy, Paving the Way for a New Lung Cancer Treatment
Immune checkpoint inhibitors, a class of immunotherapies that help immune cells attack cancer more effectively, have revolutionized cancer treatment. However, fewer than 20% of patients respond to these treatments, highlighting the urgent need for new strategies tailored to both responders and non-responders.
KAIST researchers have discovered that 'DEAD-box helicases 54 (DDX54)', a type of RNA-binding protein, is the master regulator that hinders the effectiveness of immunotherapy—opening a new path for lung cancer treatment. This breakthrough technology has been transferred to faculty startup BioRevert Inc., where it is currently being developed as a companion therapeutic and is expected to enter clinical trials by 2028.
< Photo 1. (From left) Researcher Jungeun Lee, Professor Kwang-Hyun Cho and Postdoctoral Researcher Jeong-Ryeol Gong of the Department of Bio and Brain Engineering at KAIST >
KAIST (represented by President Kwang-Hyung Lee) announced on April 8 that a research team led by Professor Kwang-Hyun Cho from the Department of Bio and Brain Engineering had identified DDX54 as a critical factor that determines the immune evasion capacity of lung cancer cells. They demonstrated that suppressing DDX54 enhances immune cell infiltration into tumors and significantly improves the efficacy of immunotherapy.
Immunotherapy using anti-PD-1 or anti-PD-L1 antibodies is considered a powerful approach in cancer treatment. However, its low response rate limits the number of patients who actually benefit.
To identify likely responders, tumor mutational burden (TMB) has recently been approved by the FDA as a key biomarker for immunotherapy. Cancers with high mutation rates are thought to be more responsive to immune checkpoint inhibitors. However, even tumors with high TMB can display an “immune-desert” phenotype—where immune cell infiltration is severely limited—resulting in poor treatment responses.
< Figure 1. DDX54 was identified as the master regulator that induces resistance to immunotherapy by orchestrating suppression of immune cell infiltration through cancer tissues as lung cancer cells become immune-evasive >
Professor Kwang-Hyun Cho's research team compared transcriptome and genome data of lung cancer patients with immune evasion capabilities through gene regulatory network analysis (A) and discovered DDX54, a master regulator that induces resistance to immunotherapy (B-F).
This study is especially significant in that it successfully demonstrated that suppressing DDX54 in immune-desert lung tumors can overcome immunotherapy resistance and improve treatment outcomes.
The team used transcriptomic and genomic data from immune-evasive lung cancer patients and employed systems biology techniques to infer gene regulatory networks. Through this analysis, they identified DDX54 as a central regulator in the immune evasion of lung cancer cells.
In a syngeneic mouse model, the suppression of DDX54 led to significant increases in the infiltration of anti-cancer immune cells such as T cells and NK cells, and greatly improved the response to immunotherapy.
Single-cell transcriptomic and spatial transcriptomic analyses further showed that combination therapy targeting DDX54 promoted the differentiation of T cells and memory T cells that suppress tumors, while reducing the infiltration of regulatory T cells and exhausted T cells that support tumor growth.
< Figure 2. In the syngeneic mouse model made of lung cancer cells, it was confirmed that inhibiting DDX54 reversed the immune-evasion ability of cancer cells and enhanced the sensitivity to anti-PD-1 therapy >
In a syngeneic mouse model made of lung cancer cells exhibiting immunotherapy resistance, the treatment applied after DDX54 inhibition resulted in statistically significant inhibition of lung cancer growth (B-D) and a significant increase in immune cell infiltration into the tumor tissue (E, F).
The mechanism is believed to involve DDX54 suppression inactivating signaling pathways such as JAK-STAT, MYC, and NF-κB, thereby downregulating immune-evasive proteins CD38 and CD47. This also reduced the infiltration of circulating monocytes—which promote tumor development—and promoted the differentiation of M1 macrophages that play anti-tumor roles.
Professor Kwang-Hyun Cho stated, “We have, for the first time, identified a master regulatory factor that enables immune evasion in lung cancer cells. By targeting this factor, we developed a new therapeutic strategy that can induce responsiveness to immunotherapy in previously resistant cancers.”
He added, “The discovery of DDX54—hidden within the complex molecular networks of cancer cells—was made possible through the systematic integration of systems biology, combining IT and BT.”
The study, led by Professor Kwang-Hyun Cho, was published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) on April 2, 2025, with Jeong-Ryeol Gong being the first author, Jungeun Lee, a co-first author, and Younghyun Han, a co-author of the article.
< Figure 3. Single-cell transcriptome and spatial transcriptome analysis confirmed that knockdown of DDX54 increased immune cell infiltration into cancer tissues >
In a syngeneic mouse model made of lung cancer cells that underwent immunotherapy in combination with DDX54 inhibition, single-cell transcriptome (H-L) and spatial transcriptome (A-G) analysis of immune cells infiltrating inside cancer tissues were performed. As a result, it was confirmed that anticancer immune cells such as T cells, B cells, and NK cells actively infiltrated the core of lung cancer tissues when DDX54 inhibition and immunotherapy were concurrently administered.
(Paper title: “DDX54 downregulation enhances anti-PD1 therapy in immune-desert lung tumors with high tumor mutational burden,” DOI: https://doi.org/10.1073/pnas.2412310122)
This work was supported by the Ministry of Science and ICT and the National Research Foundation of Korea through the Mid-Career Research Program and Basic Research Laboratory Program.
< Figure 4. The identified master regulator DDX54 was confirmed to induce CD38 and CD47 expression through Jak-Stat3, MYC, and NF-κB activation. >
DDX54 activates the Jak-Stat3, MYC, and NF-κB pathways in lung cancer cells to increase CD38 and CD47 expression (A-G). This creates a cancer microenvironment that contributes to cancer development (H) and ultimately induces immune anticancer treatment resistance.
< Figure 5. It was confirmed that an immune-inflamed environment can be created by combining DDX54 inhibition and immune checkpoint inhibitor (ICI) therapy. >
When DDX54 inhibition and ICI therapy are simultaneously administered, the cancer cell characteristics change, the immune evasion ability is restored, and the environment is transformed into an ‘immune-activated’ environment in which immune cells easily infiltrate cancer tissues. This strengthens the anticancer immune response, thereby increasing the sensitivity of immunotherapy even in lung cancer tissues that previously had low responsiveness to immunotherapy.
2025.04.08 View 12236 -
KAIST Unveils New Possibilities for Treating Intractable Brain Tumors
< Photo 1. (From left) Professor Heung Kyu Lee, KAIST Department of Biological Sciences, and Dr. Keun Bon Ku >
Immunotherapy, which enhances the immune system's T cell response to eliminate cancer cells, has emerged as a key approach in cancer treatment. However, in the case of glioblastoma, an aggressive and treatment-resistant brain tumor, numerous clinical trials have failed to confirm their efficacy. Korean researchers have recently analyzed the mechanisms that cause T cell exhaustion, which is characterized by a loss of function or a weakened response following prolonged exposure to antigens in such intractable cancers, identifying key control factors in T cell activation and clarifying the mechanisms that enhance therapeutic effectiveness.
KAIST (represented by President Kwang Hyung Lee) announced on the 6th of November that Professor Heung Kyu Lee’s team from the Department of Biological Sciences, in collaboration with the Korea Research Institute of Chemical Technology (represented by President Young Kuk Lee), has confirmed improved survival rates in a glioblastoma mouse model. By removing the inhibitory Fc gamma receptor (FcγRIIB), the research team was able to restore the responsiveness of cytotoxic T cells to immune checkpoint inhibitors, leading to enhanced anticancer activity.
The research team examined the effect of FcγRIIB, an inhibitory receptor recently found in cytotoxic T cells, on tumor-infiltrating T cells and the therapeutic effectiveness of the anti-PD-1 immune checkpoint inhibitor.
< Figure 1. Study results on improved survival rate due to increased antitumor activity of anti-PD-1 treatment in inhibitory Fc gamma receptor(Fcgr2b) ablation mice with murine glioblastoma. >
Their findings showed that deleting FcγRIIB induced the increase of tumor antigen-specific memory T cells, which helps to suppress exhaustion, enhances stem-like qualities, and reactivates T cell-mediated antitumor immunity, particularly in response to anti-PD-1 treatment. Furthermore, FcγRIIB deletion led to an increase in antigen-specific memory T cells that maintained continuous infiltration into the tumor tissue.
This study presents a new therapeutic target for tumors unresponsive to immune checkpoint inhibitors and demonstrates that combining FcγRIIB inhibition with anti-PD-1 treatment can produce synergistic effects, potentially improving therapeutic outcomes for tumors like glioblastoma, which typically show resistance to anti-PD-1 therapy.
< Figure 2. Overview of the study on the enhanced response to anti-PD-1 therapy for glioblastoma brain tumors upon deletion of the inhibitory Fc gamma receptor (FcγRIIB) in tumor microenvironment. When the inhibitory Fc gamma receptor (FcγRIIB) of cytotoxic T cells is deleted, an increase in tumor-specific memory T cells (Ttsms) was observed. In addition, this T cell subset is identified as originating from the tumor-draining lymph nodes(TdLNs) and leads to persistent infiltration into the tumor tissue. Anti-PD-1 therapy leads to an increased anti-tumor immune response via Ttsms, which is confirmed by increased tumor cell toxicity and increased cell division and decreased cell de-migration indices. Ultimately, the increased cytotoxic T cell immune response leads to an increase in the survival rate of glioblastoma. >
Professor Heung Kyu Lee explained, "This study offers a way to overcome clinical failures in treating brain tumors with immune checkpoint therapy and opens possibilities for broader applications to other intractable cancers. It also highlights the potential of utilizing cytotoxic T cells for tumor cell therapy."
The study, led by Dr. Keun Bon Ku of KAIST (currently a senior researcher at the Korea Research Institute of Chemical Technology's Center for Infectious Disease Diagnosis and Prevention), along with Chae Won Kim, Yumin Kim, Byeong Hoon Kang, Jeongwoo La, In Kang, Won Hyung Park, Stephen Ahn, and Sung Ki Lee, was published online on October 26 in the Journal for ImmunoTherapy of Cancer, an international journal in tumor immunology and therapy from the Society for Immunotherapy of Cancer. (Paper title: “Inhibitory Fcγ receptor deletion enhances CD8 T cell stemness increasing anti-PD-1 therapy responsiveness against glioblastoma,” http://dx.doi.org/10.1136/jitc-2024-009449).
This research received support from the National Research Foundation of Korea, the Bio & Medical Technology Development Program, and the Samsung Science & Technology Foundation.
2024.11.15 View 10442 -
PICASSO Technique Drives Biological Molecules into Technicolor
The new imaging approach brings current imaging colors from four to more than 15 for mapping overlapping proteins
Pablo Picasso’s surreal cubist artistic style shifted common features into unrecognizable scenes, but a new imaging approach bearing his namesake may elucidate the most complicated subject: the brain. Employing artificial intelligence to clarify spectral color blending of tiny molecules used to stain specific proteins and other items of research interest, the PICASSO technique, allows researchers to use more than 15 colors to image and parse our overlapping proteins.
The PICASSO developers, based in Korea, published their approach on May 5 in Nature Communications.
Fluorophores — the staining molecules — emit specific colors when excited by a light, but if more than four fluorophores are used, their emitted colors overlap and blend. Researchers previously developed techniques to correct this spectral overlap by precisely defining the matrix of mixed and unmixed images. This measurement depends on reference spectra, found by identifying clear images of only one fluorophore-stained specimen or of multiple, identically prepared specimens that only contain a single fluorophore each.
“Such reference spectra measurement could be complicated to perform in highly heterogeneous specimens, such as the brain, due to the highly varied emission spectra of fluorophores depending on the subregions from which the spectra were measured,” said co-corresponding author Young-Gyu Yoon, professor in the School of Electrical Engineering at KAIST. He explained that the subregions would each need their own spectra reference measurements, making for an inefficient, time-consuming process. “To address this problem, we developed an approach that does not require reference spectra measurements.”
The approach is the “Process of ultra-multiplexed Imaging of biomolecules viA the unmixing of the Signals of Spectrally Overlapping fluorophores,” also known as PICASSO. Ultra-multiplexed imaging refers to visualizing the numerous individual components of a unit. Like a cinema multiplex in which each theater plays a different movie, each protein in a cell has a different role. By staining with fluorophores, researchers can begin to understand those roles.
“We devised a strategy based on information theory; unmixing is performed by iteratively minimizing the mutual information between mixed images,” said co-corresponding author Jae-Byum Chang, professor in the Department of Materials Science and Engineering, KAIST. “This allows us to get away with the assumption that the spatial distribution of different proteins is mutually exclusive and enables accurate information unmixing.”
To demonstrate PICASSO’s capabilities, the researchers applied the technique to imaging a mouse brain. With a single round of staining, they performed 15-color multiplexed imaging of a mouse brain. Although small, mouse brains are still complex, multifaceted organs that can take significant resources to map. According to the researchers, PICASSO can improve the capabilities of other imaging techniques and allow for the use of even more fluorophore colors.
Using one such imaging technique in combination with PICASSO, the team achieved 45-color multiplexed imaging of the mouse brain in only three staining and imaging cycles, according to Yoon.
“PICASSO is a versatile tool for the multiplexed biomolecule imaging of cultured cells, tissue slices and clinical specimens,” Chang said. “We anticipate that PICASSO will be useful for a broad range of applications for which biomolecules’ spatial information is important. One such application the tool would be useful for is revealing the cellular heterogeneities of tumor microenvironments, especially the heterogeneous populations of immune cells, which are closely related to cancer prognoses and the efficacy of cancer therapies.”
The Samsung Research Funding & Incubation Center for Future Technology supported this work. Spectral imaging was performed at the Korea Basic Science Institute Western Seoul Center.
-PublicationJunyoung Seo, Yeonbo Sim, Jeewon Kim, Hyunwoo Kim, In Cho, Hoyeon Nam, Yong-Gyu Yoon, Jae-Byum Chang, “PICASSO allows ultra-multiplexed fluorescence imaging of spatiallyoverlapping proteins without reference spectra measurements,” May 5, Nature Communications (doi.org/10.1038/s41467-022-30168-z)
-ProfileProfessor Jae-Byum ChangDepartment of Materials Science and EngineeringCollege of EngineeringKAIST
Professor Young-Gyu YoonSchool of Electrical EngineeringCollege of EngineeringKAIST
2022.06.22 View 16142 -
Study of T Cells from COVID-19 Convalescents Guides Vaccine Strategies
Researchers confirm that most COVID-19 patients in their convalescent stage carry stem cell-like memory T cells for months
A KAIST immunology research team found that most convalescent patients of COVID-19 develop and maintain T cell memory for over 10 months regardless of the severity of their symptoms. In addition, memory T cells proliferate rapidly after encountering their cognate antigen and accomplish their multifunctional roles. This study provides new insights for effective vaccine strategies against COVID-19, considering the self-renewal capacity and multipotency of memory T cells.
COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. When patients recover from COVID-19, SARS-CoV-2-specific adaptive immune memory is developed. The adaptive immune system consists of two principal components: B cells that produce antibodies and T cells that eliminate infected cells. The current results suggest that the protective immune function of memory T cells will be implemented upon re-exposure to SARS-CoV-2.
Recently, the role of memory T cells against SARS-CoV-2 has been gaining attention as neutralizing antibodies wane after recovery. Although memory T cells cannot prevent the infection itself, they play a central role in preventing the severe progression of COVID-19. However, the longevity and functional maintenance of SARS-CoV-2-specific memory T cells remain unknown.
Professor Eui-Cheol Shin and his collaborators investigated the characteristics and functions of stem cell-like memory T cells, which are expected to play a crucial role in long-term immunity. Researchers analyzed the generation of stem cell-like memory T cells and multi-cytokine producing polyfunctional memory T cells, using cutting-edge immunological techniques.
This research is significant in that revealing the long-term immunity of COVID-19 convalescent patients provides an indicator regarding the long-term persistence of T cell immunity, one of the main goals of future vaccine development, as well as evaluating the long-term efficacy of currently available COVID-19 vaccines.
The research team is presently conducting a follow-up study to identify the memory T cell formation and functional characteristics of those who received COVID-19 vaccines, and to understand the immunological effect of COVID-19 vaccines by comparing the characteristics of memory T cells from vaccinated individuals with those of COVID-19 convalescent patients.
PhD candidate Jae Hyung Jung and Dr. Min-Seok Rha, a clinical fellow at Yonsei Severance Hospital, who led the study together explained, “Our analysis will enhance the understanding of COVID-19 immunity and establish an index for COVID-19 vaccine-induced memory T cells.”
“This study is the world’s longest longitudinal study on differentiation and functions of memory T cells among COVID-19 convalescent patients. The research on the temporal dynamics of immune responses has laid the groundwork for building a strategy for next-generation vaccine development,” Professor Shin added. This work was supported by the Samsung Science and Technology Foundation and KAIST, and was published in Nature Communications on June 30.
-Publication:
Jung, J.H., Rha, MS., Sa, M. et al. SARS-CoV-2-specific T cell memory is sustained in COVID-19 convalescent patients for 10 months with successful development of stem cell-like memory T cells. Nat Communications 12, 4043 (2021). https://doi.org/10.1038/s41467-021-24377-1
-Profile:
Professor Eui-Cheol Shin
Laboratory of Immunology & Infectious Diseases (http://liid.kaist.ac.kr/)
Graduate School of Medical Science and Engineering
KAIST
2021.07.05 View 20254 -
Biomarker Predicts Who Will Have Severe COVID-19
- Airway cell analyses showing an activated immune axis could pinpoint the COVID-19 patients who will most benefit from targeted therapies.-
KAIST researchers have identified key markers that could help pinpoint patients who are bound to get a severe reaction to COVID-19 infection. This would help doctors provide the right treatments at the right time, potentially saving lives. The findings were published in the journal Frontiers in Immunology on August 28.
People’s immune systems react differently to infection with SARS-CoV-2, the virus that causes COVID-19, ranging from mild to severe, life-threatening responses.
To understand the differences in responses, Professor Heung Kyu Lee and PhD candidate Jang Hyun Park from the Graduate School of Medical Science and Engineering at KAIST analysed ribonucleic acid (RNA) sequencing data extracted from individual airway cells of healthy controls and of mildly and severely ill patients with COVID-19. The data was available in a public database previously published by a group of Chinese researchers.
“Our analyses identified an association between immune cells called neutrophils and special cell receptors that bind to the steroid hormone glucocorticoid,” Professor Lee explained. “This finding could be used as a biomarker for predicting disease severity in patients and thus selecting a targeted therapy that can help treat them at an appropriate time,” he added.
Severe illness in COVID-19 is associated with an exaggerated immune response that leads to excessive airway-damaging inflammation. This condition, known as acute respiratory distress syndrome (ARDS), accounts for 70% of deaths in fatal COVID-19 infections.
Scientists already know that this excessive inflammation involves heightened neutrophil recruitment to the airways, but the detailed mechanisms of this reaction are still unclear.
Lee and Park’s analyses found that a group of immune cells called myeloid cells produced excess amounts of neutrophil-recruiting chemicals in severely ill patients, including a cytokine called tumour necrosis factor (TNF) and a chemokine called CXCL8.
Further RNA analyses of neutrophils in severely ill patients showed they were less able to recruit very important T cells needed for attacking the virus. At the same time, the neutrophils produced too many extracellular molecules that normally trap pathogens, but damage airway cells when produced in excess.
The researchers additionally found that the airway cells in severely ill patients were not expressing enough glucocorticoid receptors. This was correlated with increased CXCL8 expression and neutrophil recruitment.
Glucocorticoids, like the well-known drug dexamethasone, are anti-inflammatory agents that could play a role in treating COVID-19. However, using them in early or mild forms of the infection could suppress the necessary immune reactions to combat the virus. But if airway damage has already happened in more severe cases, glucocorticoid treatment would be ineffective.
Knowing who to give this treatment to and when is really important. COVID-19 patients showing reduced glucocorticoid receptor expression, increased CXCL8 expression, and excess neutrophil recruitment to the airways could benefit from treatment with glucocorticoids to prevent airway damage. Further research is needed, however, to confirm the relationship between glucocorticoids and neutrophil inflammation at the protein level.
“Our study could serve as a springboard towards more accurate and reliable COVID-19 treatments,” Professor Lee said.
This work was supported by the National Research Foundation of Korea, and Mobile Clinic Module Project funded by KAIST.
Figure. Low glucocorticoid receptor (GR) expression led to excessive inflammation and lung damage by neutrophils through enhancing the expression of CXCL8 and other cytokines.
Image credit: Professor Heung Kyu Lee, KAIST. Created with Biorender.com.
Image usage restrictions: News organizations may use or redistribute these figures and image, with proper attribution, as part of news coverage of this paper only.
-Publication:
Jang Hyun Park, and Heung Kyu Lee. (2020). Re-analysis of Single Cell Transcriptome Reveals That the NR3C1-CXCL8-Neutrophil Axis Determines the Severity of COVID-19. Frontiers in Immunology, Available online at https://doi.org/10.3389/fimmu.2020.02145
-Profile: Heung Kyu Lee
Associate Professor
heungkyu.lee@kaist.ac.kr
https://www.heungkyulee.kaist.ac.kr/
Laboratory of Host Defenses
Graduate School of Medical Science and Engineering (GSMSE)
The Center for Epidemic Preparedness at KAIST Institute
http://kaist.ac.kr
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon, Republic of Korea
Profile: Jang Hyun Park
PhD Candidate
janghyun.park@kaist.ac.kr
GSMSE, KAIST
2020.09.17 View 23374