In the following literature digest, we'll look at a review paper by Cao et al. concerning the utility of Ganoderma mushroom extracts as anticancer immunotherapy agents. I will during the digestion of the original review paper also inject understanding and context from other publications as to make it a more informative read.

I was initially interested in these mushroom extracts, because of the partial failure of alkalisation therapy. Alkalisation therapy is a powerful tool against cancer and massively improves both survival rates and survival duration in patients of various cancers (1). Alkalisation therapy in cancer works by neutralising tumour microenvironment acidosis, which in turn inhibits cancer immune evasion, disrupts cancer metabolism, and inhibits invasion and metastasis (2–5).

Alkalisation therapy can, however, not work in cases where a cancer tumour will directly express surface molecules or other signallers, which stop or slow immune response. Thus, advanced cancers use a variety of acquired genetic mutations, which enable them to express signallers, which inhibit cytotoxic immune response (a response, which kills defective and infected cells), such as PD-L1, IL-6, and TGF-beta (6–7). It's thus advisable to use pharmaceutical agents to directly stop this immune-suppressive signalling and thus allowing the maturation of an effective cytotoxic anticancer immune response. This approach of direct immune-modulation is known as immunotherapy and can be done with various agents with differing severity of side-effects.

Ganoderma mushrooms, their extracts, and some of their components show drastic promise in being able to be used as immunotherapeutic agents in cancer treatment, thus allowing for the further improvement of patient survival rates and durations.

I'll structure this digest in the same way as the original review paper and then add closing remarks at the end. Let's dig in.

'Introduction'

Ganoderma – also known as Lingzhi or Reishi – is used the world round for its medicinal properties and said to improve the body's resistance. In traditional Chinese medicine, it's linked to the heart, liver, and lungs. Multiple species of Ganoderma are cultivated and have been used for the treatment of chronic bronchitis, bronchial asthma, leukopenia, coronary heart disease, arrhythmia, and acute infectious hepatitis, usually as an adjunctive therapy.

Chemotherapeutics have multiple side effects, which can negatively influence patient quality of life. Taken together with the fact, that some cancer cells resist chemotherapeutic treatment, it opens up an unfilled therapeutic gap. Immunotherapy is a promising approach to fill this gap, because immune cells can already identify cancer cells and theoretically attack them. Treatment using Ganoderma has improved lymphocyte proliferation (a type of immune cell) in immunocompromised children. This shows promise in immunomodulation.

Ganoderma lucidum has been studied and reviewed for immunomodulation and anticancer effects as well as its potential mechanism of action. The specific bioactive compounds of Ganoderma and their immunoregulatory effects against cancer have yet to be reviewed.

'Literature Analysis'

Before this background, Cao et al. counted up the research done into Ganoderma in the English and Chinese languages between the years of 1987 and 2017. They found, that research into the immunomodulation and antitumour properties of Ganoderma was the most popular. This intersection in the available research indicated to Cao et al., that Ganoderma may prove to be a viable candidate in immunotherapy, thus inspiring the topic of their review.

Over the time period from 1987 to 2017, research publications made on the topic of Ganoderma increased drastically, especially in the English language. China, the USA, Malaysia, Japan, and South Korea were the principle countries of origin for these publications and also exhibited the most cooperation between countries.

The most abundant sub-topic of research were the pharmacological effects of Ganoderma and were studied in immunomodulation, cancer treatment, diabetic treatment, neuropharmacology, antioxidation, and liver protection, whereby immunomodulation occupied the largest space, followed by cancer treatment. There were about 200 publications made on cancer immunotherapy using Ganoderma specifically, which directly enabled this review by Cao et al.

'Immunomodulatory Effects of Ganoderma and Its Active Components on Cancer Treatment'

'Fungal Immunomodulative Proteins'

Four types of immunoregulatory proteins have been isolated from Ganoderma: Lz-8, Fip-gts, GMI, and Fip-gat.

Lz-8 was isolated from Ganoderma lucidum. It has a similar molecular structure to human antibodies (immunoglobulins) and shows significant effects against gastric cancer and some lung cancers. An experiment in a gastric cancer cell line showed, that recombinant Lz-8 (rLz-8) induces cell death through endoplasmatic stress.

Another team of researchers found, that rLz-8 targeted lung cancer cells, which were dependent on epithelial growth factor receptor (EGFR) activation. Lung cancers commonly use EGFR signalling to sustain growth.

Fip-gts was isolated from G. tsugae. A recombinant version of it (rFip-gts) was found to inhibit telomerase activity in lung cancer cells. In a mouse xenograft model (an animal model, where human tumour cells are transplanted into mice), the growth of the transplanted cancer cells was slower, when treated with rFip-gts than when treated with control. rFip-gts was also found to affect cervical cancer cells.

GMI was isolated from G. microsporum and its amino acid sequence has an overlap of 83% with Fip-gts and yet unfolds different effects. It was shown to inhibit the activation of EGFR and kinases in the downstream AKT pathway. The AKT pathway is involved in inhibiting apoptosis, which is important for cancer cells to survive normal quality control functions (1–2). GMI also led to accumulation of autophagosomes in one model. Autophagosomes are cell-internal recycling structures, where the cell will eat its own damaged structures, hence the name of 'auto-' (self), 'phago-' (eat), and '-some' (body). In a mouse model, GMI was found to slow the growth of xenograft tumour cells.

Fip-gat derives from G. atrum and was found to decrease cell viability in culture of a human breast cancer cell line dose-dependently. Fip-gat application led to significant cell cycle arrest (a stop of cell division and thus tumour growth) and a higher number of apoptotic cells (cells committing controlled suicide for the body's benefit).

'Polysaccharides and Other Active Components'

Beside proteins, polysaccharides (longer chains of multiple sugars) and other compounds – like terpenes, which are a complex class of secondary compounds with a plethora of different pharmacological properties – also play a role in the pharmacology of Ganoderma (8).

'Lung Cancer'

Specifically, a team of researchers looked at the effects of triterpenes (compounds formed of 3 terpene subunits) from G. lucidum on the growth of human lung cancer cells. They could significantly inhibit tumour growth in a mouse model, with increases in indicators of immune organ activity.

An in vitro study (petri-dish study, basically) found, that a polysaccharide fraction extracted from G. sichuanense with enrichment of the modified sugar L-fucose inhibited cancer cell growth through antibody-mediated cell-toxicity. It also decreased the production of tumour-associated inflammatory signallers. An in vivo study (complex organism study) showed an increase in the B1-cell population (a type of immune cell).

Another study showed, that plasma extracted from lung cancer patients was highly suppressive to growth and activity of lymphocytes (a group of immune cells). This effect of the plasma was reversed by polysaccharide fractions from G. lucidum. Purified Ganoderic acid Me from G. lucidum, however, had an immunosuppressive effect and created a tumour-tolerant environment. This seems to show, that the effects of Ganoderma extracts are modulating rather than directly forcing.

'Liver Cancer'

Lipid (fat) extracts from G. sinensis spores could kill tumour cells and exert anticancer effects through the stimulation of macrophage and monocyte (macrophage precursors) activation. Furthermore, G. lucidum polysaccharide fraction was able to change the miRNA (a type of gene expression regulator). This same polysaccharide fraction was found to slow tumour growth in mice with liver cancer. Slowing of tumour growth was hereby associated with a relative increase in effector T-cells over regulatory T-cells. This hints at improved cytotoxic T-cell activity against the cells of the tumour, as effector T-cells are responsible for killing defective and infected cells (9). This is also confirmed by the fact, that this polysaccharide fraction from G. lucidum eliminated the suppression of effector T-cell population growth, which was caused by increased interleukin 2 secretion from regulatory T-cells.

This means, that the polysaccharide fraction of G. lucidum was able to improve cancer cell–destructive immune activity by dampening the signalling, that usually stops the development and growth of effector T-cells. This is incredibly helpful in improving anticancer immune activity.

'Melanoma'

Other researchers found, that the same polysaccharide fraction stimulated lymphocyte growth (a class of immune cells), the expression of two immune supportive cell surface proteins, and the production of a signalling molecule, which stimulates cytotoxic immune activation.

Furthermore, the polysaccharide fraction enhanced the efficiency of cytotoxic immune activity against melanoma cells. Extracts from G. lucidum also inhibit the release of IL-6, IL-8, MMP-2, and MMP-9. IL-6 suppresses cytotoxic T-cell function (7). IL-8 improves the destruction of the extracellular matrix, as do both MMPs (10). Their inhibition improves anticancer T-cell activity, whilst simultaneously inhibiting cancer invasion and metastasis.

Constant administration of a specific polysaccharide from G. formosanum showed activation of anticancer immune function against ongoing tumour growth.

'Leukemia'

It was found, that G. lucidum polysaccharide fraction improved the cytotoxicity of T-cells. This polysaccharide fraction also improved differentiation of monocytes into dendritic cells, which stimulate immune function. A water extract of G. lucidum improved natural killer cell cytotoxicity (a type of innate immune cell) as well.

'Colon Cancer'

Polysaccharides from G. atrum improved macrophage activation and cancer immunity, and slowed tumour growth. Constant administration of a specific polysaccharide from G. formosanum also here showed activation of anticancer immune function against ongoing tumour growth.

'Major Pathways of Cancer Immunotherapy of Ganoderma in Immune Cells'

I quite honestly don't think that this part of the paper is of much interest to a laymen, as it simply explains the cell signalling pathways used by Ganoderma extracts to unfold their effect. I also think, that it's quite difficult, if not impossible, to follow without prior training in molecular biology, cell biology, and immunology. For that reason, I've elected to leave it out. You can naturally read through the original review article, if this interests you.

'Clinical Studies'

We now come to the make-or-break point of this paper. How useful is Ganoderma really in humans, and what results can it achieve in real patients?

A formulation of Ganoderma polysaccharides was found to enhance immune response in patients with advanced cancers. It was also found, that G. lucidum administration improved lymphocyte proliferation in immunocompromised children with cancer. Another study suggested, that G. lucidum lowered cancer-associated fatigue and improved wellbeing. Patients with gynecological cancer halted disease progression through ingestion of G. lucidum in the form of fruit body water extracts and spores.

'Toxicology'

One case is known, where ingestion of G. lucidum powder proved fatal through fulminant hepatitis. Another case is known of a patient having chronic watery diarrhoea during ingestion of G. lucidum. In rats, no difference in clinical symptoms, death, body weight, or food intake was observed during G. lucidum administration. No mutagenicity was observed.

'Discussion'

In this section, the authors summarise the results and give some indications as to what more research could be needed. They indicate, that Ganoderma is highly promising, due to its very low toxicity, but that patients should be monitored, when ingesting Ganoderma.

Closing Remarks

I think the given review clearly tells us, that Ganoderma extracts are an incredibly powerful tool against some immune-evasive cancers. I think them especially powerful in contexts, where alkalisation therapy isn't enough to destroy cancer immune evasion, as would be the case in some mesothelioma cells, which secrete high levels of IL-6, since the IL-6 inhibits the formation and extension of a cytotoxic anticancer immune response. There are certainly other contexts, where Ganoderma extracts can prove helpful in other immune evasive cancers, which may deploy other tools for immune evasion, such as the overexpression of PD-L1, as G. lucidum extracts have been found to lower levels of PD-1 (the receptor for PD-L1) in lymphocytes exposed to it (11).

As you may have noticed in the toxicology section above, there have been cases of adverse events. As you also may have noticed, the mentioned cases were single-patient cases. Furthermore, toxicity in mice is very low. In a human study with G. lucidum and Cordyceps sinensis extracts, G. lucidum 10:1 extract (10 parts of G. lucidum make one part of extract) showed a similar number of mild adverse events as the placebo group at 3 g/day (12). A group in the study, who was administered C. sinensis extract at 1 g/day in addition to G. lucidum extract showed the least reported adverse events. Furthermore, reporting on cases with liver toxicity is subpar (13).

Still, the issue of potential liver toxicity remains. I think it's telling, that the above fatal fulminant hepatitis was reported in patients, who took raw G. lucidum extracts for 1–2 months together with other therapeutic agents (14). This points toward a collective liver toxicity through overloading of the liver's detox systems by use of too many therapeutic agents at once. This is a common and known problem of using multiple agents that are all cleared through the liver or kidneys, where each agent alone is well-tolerated, but the combination of agents leads to toxicity. It's even more interesting, that the same patients, who experienced liver toxicity with raw G lucidum extract, didn't experience liver toxicity with boiled G. lucidum slices, which is the traditional preparation method of the medicinal mushroom.

Interestingly, heat treatment leaves the pharmacological potency of both Lz-8 and the polysaccharide fraction of G. lucidum untouched (15–6). It's thus probably smart to simply use Lingzhi or Reishi extracts, which have been won from hot water extraction. Tolerability in humans seems to go up to 3 g/day of 10:1 extract. 1g of 10:1 extract has the equivalent potency of 10 grams of raw Lingzhi. When using more highly concentrated extracts, like 20:1 or 60:1, you'd need to limit dosing to 1.5 g/day and 500 mg/day, respectively, to ensure tolerance. Another thing to mention here, is the potential, that a more highly concentrated extract doesn't provide as diverse of a chemical profile as the raw fungus. It could thus be sensible to stay around a 10:1 extraction level to balance the benefits of broader pharmacological profile and higher concentration. Data here, though, is very limited, and adaptations should probably be made to your specific situation and response to treatment.

I think this concludes our literature digest. If you've any feedback or questions, leave a comment.

I wish you swift healing and lasting health.

God bless,
Merlin L. Marquard.

On Ganoderma Mushrooms and Cancer Immunotherapy

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Primary Reference:
Cao, Y., Xu, X.-w., Liu, S., Huang, L., and Gu, J.X. (2018). Ganoderma: A Cancer Immunotherapy Review. Frontiers in Pharmacology 9.

Secondary References:

1. Hamaguchi, R., Isowa, M., Narui, R., Morikawa, H., and Wada, H. (2022). Clinical review of alkalization therapy in cancer treatment. Frontiers in Oncology Volume 12 - 2022. 10.3389/fonc.2022.1003588.
2. Ying, C., Jin, C., Zeng, S., Chao, M., and Hu, X. (2022). Alkalization of cellular pH leads to cancer cell death by disrupting autophagy and mitochondrial function. Oncogene 41, 3886-3897. 10.1038/s41388-022-02396-6.
3. Rastogi, S., Mishra, S.S., Arora, M.K., Kaithwas, G., Banerjee, S., Ravichandiran, V., Roy, S., and Singh, L. (2023). Lactate acidosis and simultaneous recruitment of TGF-β leads to alter plasticity of hypoxic cancer cells in tumor microenvironment. Pharmacology & Therapeutics 250, 108519. https://doi.org/10.1016/j.pharmthera.2023.108519.
4. Rolver, M.G., Holland, L.K.K., Ponniah, M., Prasad, N.S., Yao, J., Schnipper, J., Kramer, S., Elingaard-Larsen, L., Pedraz-Cuesta, E., Liu, B., et al. (2023). Chronic acidosis rewires cancer cell metabolism through PPARα signaling. International Journal of Cancer 152, 1668-1684. https://doi.org/10.1002/ijc.34404.
5. Kim, S.K., and Cho, S.W. (2022). The Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment. Frontiers in Pharmacology Volume 13 - 2022. 10.3389/fphar.2022.868695.
6. Alberts, B., Johnson, A., Lewis, J., Morgan, D., Raff, M., Roberts, K., and Walter, P. (2015). Cancer. In Molecular Biology of the Cell, (Garland Science, Taylor & Francis Group, LLC), pp. 1091-1144.
7. Abdul Rahim, S.N., Ho, G.Y., and Coward, J.I. (2015). The role of interleukin-6 in malignant mesothelioma. Transl Lung Cancer Res 4, 55-66. 10.3978/j.issn.2218-6751.2014.07.01.
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9. Alberts, B., Johnson, A., Lewis, J., Morgan, D., Raff, M., Roberts, K., and Walter, P. (2015). Cell Death. In Molecular Biology of the Cell, (Garland Science, Taylor & Francis Group, LLC), pp. 1021-1034.
10. Radulescu, R., Totan, A.R., Imre, M.M., Miricescu, D., Didilescu, A., and Greabu, M. (2021). Mediators of extracellular matrix degradation and inflammation: A new team of possible biomarkers for oral squamous cell carcinoma stage. Exp Ther Med 22, 877. 10.3892/etm.2021.10309.
11. Wang, G., Wang, L., Zhou, J., and Xu, X. (2019). The Possible Role of PD-1 Protein in Ganoderma lucidum-Mediated Immunomodulation and Cancer Treatment. Integr Cancer Ther 18, 1534735419880275. 10.1177/1534735419880275.
12. Klupp, N.L., Kiat, H., Bensoussan, A., Steiner, G.Z., and Chang, D.H. (2016). A double-blind, randomised, placebo-controlled trial of Ganoderma lucidum for the treatment of cardiovascular risk factors of metabolic syndrome. Scientific Reports 6, 29540. 10.1038/srep29540.
13. Lingzhi, Reishi.  (2012). In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda, MD, USA: National Institute of Diabetes and Digestive and Kidney Diseases. 2024-10-5. https://www.ncbi.nlm.nih.gov/books/NBK609014/.
14. Wanmuang, H., Leopairut, J., Kositchaiwat, C., Wananukul, W., and Bunyaratvej, S. (2007). Fatal fulminant hepatitis associated with Ganoderma lucidum (Lingzhi) mushroom powder. J Med Assoc Thai 90, 179-181.
15. Tong, M.-H., Chien, P.-J., Chang, H.-H., Tsai, M.-J., and Sheu, F. (2008). High Processing Tolerances of Immunomodulatory Proteins in Enoki and Reishi Mushrooms. Journal of Agricultural and Food Chemistry 56, 3160-3166. 10.1021/jf800205g.
16. Kiss, A., Grünvald, P., Ladányi, M., Papp, V., Papp, I., Némedi, E., and Mirmazloum, I. (2021). Heat Treatment of Reishi Medicinal Mushroom (Ganoderma lingzhi) Basidiocarp Enhanced Its β-glucan Solubility, Antioxidant Capacity and Lactogenic Properties. Foods 10. 10.3390/foods10092015.