On November 7, 2025, scientists investigating the mechanisms and clinical applications of GMI, an immunomodulatory protein derived from Ganoderma microsporum, gathered with medical professionals and health specialists interested in GMI at the National Taiwan University Hospital International Convention Center for an interdisciplinary academic exchange. This was the first scholarly symposium devoted exclusively to a single Ganoderma constituent since the world's first Ganoderma symposium in November 1987. Although the focus was a single ingredient, GMI's reported range of activities rivals that of Ganoderma as a whole.
Truly effective substances invite a clear scientific explanation. Yet the reasons behind GMI's effects cannot be summed up in a few words. We have therefore divided the speakers' findings and reflections into three in-depth articles, seeking both breadth and depth, so readers can gain a fuller understanding of GMI—a remarkable gift from Ganoderma.
Text and photos by Ting-Yao Wu（中文版） Translated by Manen Fong
On the 2025 International Conference on GMI was jointly organized by the Sun Ya Fu Medical Foundation and the Taiwan GMI Industry Development Association. (Image courtesy of the Taiwan GMI Industry Development Association.)
The reasons for convening this conference were described in the conference handbook by Professor Ruey-Shyang Hseu, chair of the Taiwan GMI Industry Development Association, one of its organizers:
“More than 40 years ago, I happened upon a strain of Ganoderma microsporum growing on a willow-tree stump. Twenty years later, we isolated the gene for a protein with immunomodulatory activity from G. microsporum and successfully introduced it into food-grade yeast. By cultivating the yeast in bioreactors, we established standardized, large-scale production of this valuable immunomodulatory protein—GMI—and made this cross-species signaling factor available to numerous research institutions for further investigation.
“Over the past decade and more, many research teams have demonstrated activities of GMI that include immune modulation, cancer inhibition, promotion of cellular regeneration, mitochondrial activation, and wound healing. Today, we are honored to welcome these distinguished scholars to discuss GMI’s unique mechanisms and their experiences of clinical application, so that this Taiwan-developed ingredient, bringing together the essence of Eastern medicine and Western biotechnology, can be seen and used by more people.”
Reflecting on more than a decade of GMI research, Professor Hseu believes that the novel protein is “not only a key component in regulating cellular immunity, but also a cross-species signaling factor that enables every living organism or cell to achieve a more harmonious and stable balance through different pathways.”
In his view, “The discovery of GMI is a scientific breakthrough; applying GMI is an expression of respect for life.” He welcomes additional researchers and partners to join in opening new opportunities in biomedicine, advancing a new era of health, and working together to promote well-being and protect life. (Photo by Ting-Yao Wu)
Professor Low-Tone Ho, chair of the conference and chairman of the Sun Ya Fu Medical Foundation, opened the meeting with brief remarks. He drew an apt parallel between Professor Hseu’s discovery of GMI and Hungarian biologist Albert Szent-Györgyi’s discovery of vitamin C.
“Szent-Györgyi was awarded the 1937 Nobel Prize in Physiology or Medicine for isolating vitamin C from animal adrenal glands and red peppers and determining its chemical structure. In his Nobel lecture, he remarked that everyone had been looking at the same things, yet he saw something others had not—and that was how he discovered vitamin C.
“Many medicines are discovered rather than invented. The GMI we are discussing today has a similar story: people walked around the NTU campus and saw things growing on its trees, but only Professor Hseu noticed Ganoderma microsporum and went on to discover GMI in it.
“GMI is a relatively small protein discovered in G. microsporum, but it has a great many functions. Numerous patents have been filed, and structural analyses and experiments have suggested substantial benefits in cancer treatment. Its effects have attracted the interest of many scientists, and several professors have published findings on its activities and mechanisms of action against cancer cells.
“Today’s conference centers on this novel protein. We will hear outstanding presentations by some of its researchers and learn about their knowledge, experience, and vision for GMI.”
Professor Ho spent 15 years in leadership positions in research divisions at Taiwan’s National Health Research Institutes (NHRI), a major center of biomedical and pharmaceutical research. In his opening remarks, he noted that one of the NHRI’s ambitions is to discover a clearly characterized chemical molecule suitable for development as a new drug.
He hopes future research will examine the concentration of GMI reaching the bloodstream, given the reported observation that it is not degraded by stomach acid. GMI can already be marketed as a food ingredient; Ho is optimistic about its possible future development as a pharmaceutical. (Photo by Ting-Yao Wu)
Tsai’s research focuses on virology and immunology. His laboratory has developed a series of virus research platforms for screening compounds with antiviral activity. “The ultimate purpose of studying viruses is to solve the problems they cause. How should we design drugs against them? We can screen existing drugs, but I am more interested in herbal medicine, because herbal materials may be more suitable for routine preventive use.”
During the COVID-19 pandemic, as the world struggled with continually mutating SARS-CoV-2—including variants capable of immune escape—Tsai’s laboratory joined the search for anti–SARS-CoV-2 agents. He obtained numerous traditional Chinese medicinal materials from his university’s Institute of Traditional Medicine. Professor Tung-Yi Lin supplied Ganoderma-derived constituents, including GMI.
This was Tsai’s first encounter with GMI. The article describes it as having received US FDA clearance as a new dietary ingredient and therefore regards its safety for consumption as well established. Previous studies had examined its immunomodulatory and antitumor properties, but no one had investigated whether GMI might have antiviral effects. Could it be the kind of herbal medicine Tsai was looking for?
The results were surprising. With the original Wuhan strain of SARS-CoV-2 as well as the Beta, Delta, Omicron, and other variants available at the time, GMI was able to almost completely prevent the virus from entering cells in the experiments. It also inhibited the spread of infection from infected cells to healthy cells.
Tsai explained that after a cell becomes infected with SARS-CoV-2, it displays viral spike proteins on its surface. These spike proteins can bind to ACE2 receptors on neighboring cells, allowing infected and healthy cells to merge through cell fusion. Infected cells can thus rapidly draw surrounding healthy cells into the infection, one reason SARS-CoV-2 can produce extensive tissue damage in a short period.
In Tsai’s experiments, GMI effectively prevented infected cells from fusing with healthy cells, regardless of whether the virus was the original strain or a variant. It also showed additive or synergistic effects when combined with antibodies or antiviral drugs, blocking this shortcut by which the virus could otherwise spread rapidly through the body.
Tsai’s analysis indicates that GMI prevents viral entry and inhibits fusion between infected and healthy cells partly by disrupting the interaction between viral spike protein and the host ACE2 receptor. More importantly, it induces the internalization of ACE2 by host cells, reducing the number of entry points available to the virus. Animal experiments performed with Professor Lin further showed that inhaled, nebulized GMI reduced ACE2 receptors in mouse lung tissue by more than 60%.
Vaccines and certain drugs are designed to target viral spike protein, so mutations that change the spike may reduce their preventive or therapeutic effectiveness. GMI, by contrast, modulates ACE2. Because the SARS-CoV-2 variants examined still relied on ACE2 to infect cells, reducing receptor availability or making binding more difficult could lower the risk of viral entry and spread. This is presented as the key to GMI’s activity against multiple variants.
Tsai’s laboratory is among the relatively few groups able to establish a genetically engineered EBV platform for screening antiviral agents. After completing its SARS-CoV-2 studies, the team also tested whether GMI could inhibit the cancer-associated EBV.
The studies showed that GMI effectively inhibited EBV infection of kidney and gastric epithelial cells. This effect was seen against EBV strains derived from nasopharyngeal carcinoma (M81), gastric carcinoma (YCCEL1), and lymphoma (MSHJ). Further analysis suggested that GMI acts primarily at the membrane-fusion stage, when the virus is about to enter a cell.
To cause infection, a virus must first bind to a cellular receptor (recognizing its host cell), then fuse with the cell membrane (opening the door) to gain entry. For EBV, this fusion process involves viral glycoprotein B (gB) and the cellular EphA2 receptor. Because GMI can bind both gB and EphA2, it can obstruct infection from both the viral and host-cell sides. In these experiments, its inhibitory effect was even stronger than that of the EBV antibody comparator.
Tsai was concurrently searching for antiviral agents against HSV-1 in a separate project and screened the various medicinal materials he had collected. To his surprise, GMI emerged again, prompting him to remark, “We really seem to have a special connection.”
HSV-1 commonly causes herpes lesions on or around the lips and mouth, nose, and sometimes the genitals. GMI also blocked HSV-1 infection of cells, with an effect that reportedly exceeded that of a leading neutralizing antibody comparator. As with EBV, the proposed mechanism was GMI binding to viral gB and preventing fusion with the host cell: the virus could attach to the cell but could not enter it.
Eight herpesviruses are known to infect humans. They are grouped into three major subfamilies—alpha, beta, and gamma—according to their biology and cellular tropism. Their gB proteins share similar three-dimensional structures. In the EBV (gamma) and HSV-1 (alpha) experiments, GMI showed strong and specific affinity for gB on the viral surface. Tsai therefore proposed that GMI might have a similar effect against beta-herpesviruses.
Experiments confirmed that GMI binds strongly to the gB protein of human herpesvirus 5 (cytomegalovirus, CMV). This suggests that GMI may have broad antiviral potential across different herpesvirus subfamilies.
As Tsai observed in his lecture, humans encounter many different viruses throughout their lives. Some, such as SARS-CoV-2 and influenza viruses, cause “acute” infections with symptoms appearing soon after infection. Others, including herpesviruses and hepatitis viruses, can establish persistent or latent infections that may later contribute to chronic disease or cancer.
A major challenge with acute viruses is that vaccine and drug development may struggle to keep pace with viral mutations, while the optimal window for antiviral treatment can easily be missed. A food-grade agent that is less vulnerable to mutations, can prevent infection, and can stop viral spread in the body could therefore help reduce the harm caused by disease.
With chronic viral infections, the difficulty is that viruses may remain in the body for life and reactivate to cause illness. Even when antiviral drugs are available, they cannot simply be taken every day as though they were candy. A safe and effective substance suitable for daily use might help reduce the risk of disease following viral reactivation.
By examining SARS-CoV-2 and herpesviruses, Tsai’s research suggests that GMI could offer leads for overcoming some of the difficulties of preventing acute and chronic viral infections. Does its broad antiviral activity extend to other viruses? Could GMI be used clinically as a last-minute preventive measure during a COVID-19 wave, or as a daily supplement to help prevent recurrence in carriers of herpesviruses? These questions merit further investigation.
Because another acute infectious-disease outbreak caused by a coronavirus is considered likely in the future, Tsai hopes to test GMI against SARS and MERS coronaviruses, which previously caused major outbreaks, to learn whether its antiviral activity extends across coronavirus species.
He also hopes to conduct clinical research on preventing recurrent HSV-1 infection with GMI: participants could use GMI oral dissolving tablets, with saliva collected periodically to measure viral load. As neither blood draws nor invasive procedures would be necessary, he regards this as a promising first step in clinical antiviral research on GMI. (Photo by Ting-Yao Wu)
【Further Reading】
2. 2022| Ganoderma microsporum immunomodulatory protein acts as a multifunctional broad-spectrum antiviral against SARS-CoV-2 by interfering virus binding to the host cells and spike-mediated cell fusion
3. 2025| Broad-spectrum antiviral activity of Ganoderma microsporum immunomodulatory protein: Targeting glycoprotein gB to inhibit EBV and HSV-1 infections via viral fusion blockage
Professor Lin specializes in investigating how Chinese herbal medicines inhibit tumor growth and metastasis and has studied GMI’s anticancer properties for more than a decade. In this lecture he discussed GMI’s inhibitory effects on two types of lung adenocarcinoma: tumors expressing EGFR, common among Asian patients, and tumors with KRAS mutations, seen more frequently in European and North American patient populations.
In his early work, Lin tested GMI against cancer cells originating from lung, brain, oral, pancreatic, and other tumors. The cancer cells that responded to GMI shared a feature: they expressed EGFR on their surfaces.
EGFR is a cell-surface receptor that receives growth signals. Wild-type EGFR activates in response to epidermal growth factor and transmits signals that promote cell proliferation. Mutant EGFR, by contrast, can become constitutively active, stimulating cell growth around the clock.
Lin’s research found substantial inhibitory effects of GMI on both kinds of lung adenocarcinoma cells: it effectively inhibited the growth of wild-type EGFR cells and strongly promoted apoptosis in EGFR-mutant cells. This suggests that EGFR is an important target of GMI’s anticancer activity.
Further analysis showed that GMI not only binds EGFR on the cell surface and suppresses its activation (turning off the signaling switch), but also induces cancer cells to internalize and degrade EGFR. This sharply reduces the amount of EGFR on the surface (leaving fewer switches that can activate signaling). The mechanism differs considerably from that of existing EGFR-targeted drugs, which act inside cells to block EGFR signaling.
EGFR-targeted drugs have reached their third generation, but cancer cells can still acquire successive EGFR mutations that render previously effective therapies ineffective. Could GMI, by causing cancer cells to degrade their own EGFR and thereby disarm themselves, offer a more fundamental solution?
At the very least, several animal studies by Lin have shown that GMI can target EGFR in vivo. In mouse models bearing wild-type EGFR (LLC1) or double-mutant EGFR (H1975) lung adenocarcinoma, GMI administered by injection or orally significantly reduced EGFR expression in tumor cells, inhibited tumor growth or metastasis, improved survival rates, and prolonged survival, without observed liver or kidney toxicity. Whether such results can be reproduced in humans warrants detailed investigation.
KRAS is an important protein involved in transmitting growth signals inside cells. When mutated, it can continuously instruct cancer cells to grow. Among KRAS mutations in lung cancer, KRAS G12C—a substitution affecting amino acid 12 of the KRAS protein—is relatively common. Although targeted agents have been developed against it in recent years, resistance can emerge after treatment, just as it does with EGFR-targeted agents.
Lin’s research indicates that GMI alone can suppress the growth of KRAS G12C-mutant lung adenocarcinoma cells, but does not significantly induce their apoptosis. Combining GMI with clinically used KRAS G12C inhibitors (AMG 510 or MRTX849), however, substantially enhances drug activity and accelerates cancer-cell apoptosis.
In animal studies, human KRAS G12C-mutant lung adenocarcinoma cells (H358) were transplanted into mice, which then received GMI injections. Tumor growth was indeed inhibited, though less strongly than in the EGFR models. When mice received oral AMG 510, tumor growth was initially well controlled, but began accelerating in the middle-to-late stages of the experiment.
The combination of GMI and the targeted drug produced the best results: tumor-growth suppression was more sustained than with either treatment alone, more apoptotic cells were detected in tumor tissue, and there was no observed liver or kidney toxicity. These findings suggest that GMI, with its reported safety profile, may have potential as an adjunct to targeted drugs to improve outcomes for patients with KRAS G12C-mutant lung cancer.
From asking why certain cancer cells fail to respond to GMI, to identifying EGFR as a target and combining GMI with targeted agents against KRAS-mutant tumors, Lin’s team has uncovered part of the explanation for GMI’s anticancer effects. Its studies also provide evidence of an absence of observed liver or kidney toxicity during extended administration in the experimental settings examined.
Although these findings come from experimental models of lung adenocarcinoma, Lin has also observed EGFR inhibition by GMI in cell-based experiments involving EGFR-expressing brain, oral, pancreatic, and colorectal cancers, pointing to possible activity across cancer types and many questions still to explore. At the conference, a participant asked: “Normal cells also express EGFR. What effects does GMI have on them?” Lin replied:
“One indication that a clinically used EGFR-targeted drug is working is the appearance of a skin rash, because the skin contains a great deal of EGFR. If a rash appears, it is a sign that the drug is exerting its effect. Since GMI targets EGFR, in theory it ought also to affect EGFR in skin cells and cause a rash. But we have not observed this.
“We have certainly tested normal cells as well. GMI does cause a slight reduction in their EGFR levels, but the reduction is small, because normal cells have relatively little EGFR to begin with; the impact is therefore limited. Cancer cells, by comparison, express very high levels of EGFR, so the drop after GMI treatment is much more pronounced.
“We also observed GMI accumulating at tumor sites. Because cancer cells express far more EGFR than normal cells, perhaps GMI recognizes this abnormality and selectively localizes near highly expressed or mutant EGFR, making it less likely to interact with normal EGFR. We do not yet know.”
Lin began studying GMI 18 years ago, when he joined Yang-Ming University as an assistant professor. Beyond his work on EGFR- and KRAS-mutant lung cancer, he has demonstrated effects involving heat-shock-protein targeting in lung cancer, improved sensitivity to brain-cancer drugs, stronger T-cell antitumor activity in cancer immunotherapy, suppression of the COVID-19 inflammatory storm, and reduced spinal-cord injury through anti-inflammatory mechanisms.
The last two represent downregulation of excessive immune responses, whereas the earlier effects involve enhancement of immune responses or tumor inhibition. Little wonder that Lin exclaimed, “GMI really is amazing!” (Photo by Ting-Yao Wu)
Research on GMI against lung cancer was first published in 2010–2011 by a team led by Professor Jiunn-Liang Ko (pictured at left below). Their cell-based models initially showed that GMI reduced the migratory ability of lung adenocarcinoma cells. Animal models then confirmed that GMI could activate autophagy in these cells, prompting them, in effect, to consume themselves.
Over the following decade and more, their GMI research focused primarily on supporting clinical treatments and overcoming drug resistance. These were also the main themes of the presentation by Dr. Yi-Lun Hsin, a core member of Ko’s team, at this conference. (Photo by Ting-Yao Wu)
Cisplatin is a chemotherapy drug commonly used to treat lung cancer. It primarily damages DNA, thereby triggering cancer-cell apoptosis. Ko’s team found that combining GMI with cisplatin produced a greater-than-additive inhibitory effect on the growth of lung adenocarcinoma cells (A549), with a significant increase in apoptosis. The mechanism was associated with GMI-induced autophagy in cancer cells.
Hsin explained that autophagy normally serves as a cellular recycling system: by breaking down unnecessary proteins and aging organelles, a cell recovers raw materials needed for survival. Excessive autophagy, however, can result in cell death.
The team’s early studies had already found that GMI could induce extensive autophagy and inhibit the survival of lung adenocarcinoma cells. Later studies of GMI combined with cisplatin showed that GMI-induced autophagy enhanced cisplatin’s ability to trigger lung-cancer-cell apoptosis. This could be significant for improving chemotherapy outcomes or achieving a similar effect with lower cisplatin doses—and potentially fewer adverse effects.
Pemetrexed, a chemotherapy agent often used in combination with platinum drugs, blocks intracellular folate metabolism. Deprived of the building blocks needed to make DNA, cells stop dividing and activate programmed cell death. The article notes that resistance tends to appear after about six months of clinical treatment.
To better approximate the emergence of drug resistance in patients, Ko’s team exposed lung adenocarcinoma cells to pemetrexed over an extended period, establishing the resistant A549/A400 cell line. They found that GMI reduced viability in these cells, which pemetrexed could no longer effectively inhibit, and weakened their stem-cell-like characteristics.
Stem-cell characteristics can increase cancer-cell drug resistance. One indication of such characteristics is the presence of CD133, a cell-surface protein used as a cancer stem-cell marker; its expression is often associated with cancer stemness. The studies showed that pemetrexed-resistant lung adenocarcinoma cells expressed high levels of CD133. Following GMI treatment, CD133 declined markedly, as did the cells’ capacity to form spheres, another stemness-related trait.
GMI reduces CD133 partly by directly regulating genes associated with its expression, suppressing production at the source. More importantly, it activates autophagy in cancer cells, leading to recycling and degradation of existing CD133. In mouse models of pemetrexed-resistant lung adenocarcinoma, orally administered GMI also reduced CD133 in tumor tissue and inhibited tumor growth.
Thus, GMI-induced autophagy may do more than kill cancer cells: by degrading CD133, it can weaken the stem-cell properties on which drug-resistant cells rely. This helps explain why GMI was able to inhibit lung adenocarcinoma cells that pemetrexed could not eliminate.
Resistance is a challenge not only with chemotherapy but also with EGFR-targeted drugs. Ko’s team used H1975 lung adenocarcinoma cells bearing a double EGFR mutation, previously shown to respond to GMI in vivo, and exposed them over time to the third-generation EGFR inhibitor osimertinib. This produced a resistant cell line (H1975/TR), characterized in part by high expression of integrins αV and β1.
Integrins αV and β1 are important receptors that mediate interactions between cells and their surroundings. They contribute to cancer-cell migration and the maintenance of cancer stem-cell characteristics; stemness can, in turn, reinforce drug resistance. Clinically, high expression of integrins αV and β1 in lung cancer is also associated with poorer survival.
Ko’s research showed that GMI significantly reduced integrin αV and β1 expression in resistant cancer cells, suppressed activation of downstream integrin signaling, and consequently weakened cell migration, viability, and stem-cell properties. This suggests that GMI can act through mechanisms beyond EGFR to obstruct alternative survival routes developed by cancer cells resistant to EGFR-targeted therapies.
To escape immune-system attack, cancer cells use the surface protein CD47 to send macrophages a “don’t eat me” signal, discouraging them from engulfing the cells. CD47 is regulated by another signaling protein, STAT3. Once activated, STAT3 moves from the cytoplasm into the nucleus and promotes CD47 gene expression, allowing cancer cells to display more CD47 and evade macrophages.
Ko’s team found that in both conventional EGFR-mutant lung cancer cell lines (H1975 and HCC827) and drug-resistant lines (H1975/TR and HCC827/GR), GMI inhibited STAT3 activation and reduced CD47 expression, weakening the “don’t eat me” signal and increasing macrophage phagocytosis of the cancer cells.
Further animal experiments using lung adenocarcinoma cells resistant to gefitinib (Iressa; HCC827/GR) showed that oral GMI inhibited tumor growth and decreased STAT3 activity in tumor tissue.
Ko’s team also examined whether GMI can regulate macrophages directly. Macrophage functions are not fixed; they change in response to the local environment. Their states include the pro-inflammatory, antitumor M1 phenotype and the inflammation-suppressing, tissue-repairing M2 phenotype, which can be less favorable for tumor inhibition.
The researchers found that GMI not only obstructed cancer cells’ escape from macrophage attack but also promoted macrophage polarization toward the M1 phenotype. These complementary effects—making it harder for cancer cells to hide while strengthening macrophages’ response—could create an immune environment more favorable to suppressing tumor development.
Hsin concluded with the slide reproduced below, summarizing the multiple pathways by which GMI inhibits drug-resistant lung adenocarcinoma. Cancer is a complex disease that certainly cannot be controlled by a single mechanism. Yet GMI acts on many fronts, weakening cancer cells’ survival advantages from different directions. Calling it “amazing” hardly seems an exaggeration.
A participant then raised a question about macrophage regulation: if GMI promotes the pro-inflammatory, antitumor M1 phenotype, why do other studies report that GMI suppresses inflammation?
Drawing on his research experience, Hsin replied that whether GMI exhibits pro- or anti-inflammatory activity depends on the experimental model. Under inflammatory conditions, GMI may exert a regulatory effect.
Lin agreed, noting that his team had also observed this duality. Tumors generally exist in an immunologically inactive environment, in which GMI can stimulate immune responses. In settings such as traumatic brain injury, nerve damage, or the intense inflammatory response caused by SARS-CoV-2, however, GMI instead displays anti-inflammatory activity.
Suppressing immune activity when it is excessive and stimulating it when it is weak: this is precisely why GMI is called the Ganoderma microsporum “immunomodulatory” protein. Research presented at the 2025 International Conference on GMI’s regulation of inflammation-related diseases will be covered in another article. Stay tuned.
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