MUSHROOMS

Chanterelle, shiitake and oyster mushrooms are edible fungii with the highest levels of glucan β 1,3/1,6. Common white button mushroom extracts at several grams daily showed significant response levels in 1/3 of relapsed prostate cancer patients, even 3 -5 year stable disease for about 10% of patients. Enough to justify moving to a phase II trial (Highlight 1). Researchers show the precence of mushroom compounds suppress so called MDSC immune cells, hijacked by many cancers to evade the immune system and fuel their spread. They also show that the mechanisms here would likely enhance immunotherapy response.

There is clinical evidence on the direct anti-cancer effects of mushroom beta glucans when used as extracts, several of which are derived from edible fungii (see Supplements Library). Shiitake is a good example, where active compound lentinan has been shown to improve outcomes particularly in gastric, colorectal and lung cancers. Even testing in otherwise healthy individuals has shown immune system enhancements (see References). Since even a kilogram of shiitake may only contain 150mg of lentinan, supplement forms are likely needed when clinical doses are often 500mg twice daily either orally or injected with similar effects.

There are refined branded products such as Active hexose correlated compound AHCC, which has positive clincial results in liver cancer. Lentinex is another brand likely to increase absorption and effects. The immune system binding of lentinan is linked to higher levels of a the Dectin 1 immune receptor. Dectin 1 levels may be increased with both dietary mushroom and oat glucans. Andosan is an interesting branded product from agaricus blazei, maitake and lions mane with successful trials against ulcerative colitis, and overall effects linked to reducing risk of cancer incidence (see References).

Studies in oyster mushroom extracts have shown increased natural immune system activation via the so called IL-12 – IFN-γ pathway. The researchers point to the anti-tumor activity linked to this natural immune reaction, and potential to improve immunotherapy response levels. Directly administering large dose IL-12 has failed in older trials, now advanced drug delivery approaches for IL-12 [interleukin-12] are emerging. IL-12 upregulation is also seen with lentinan extracts (see Supplements Library)

In prevention, evidence is mixed. Some recent meta-analysis of population and case controlled groups concluded showed a moderate protective effect, particularly for breast cancer, and tendencies to protective action in lung cancer.

Raw shiitake tend to contain significant amounts of copper, which is a concern for instance in breast cancer progression. And use of medicinal mushrooms is generally discouraged with existing autoimmune diseases. Always secure expert medical advice.

EXAMPLES OF IMPROVED OUTCOMES

YES

PRE-DIAGNOSIS OR PREVENTION

MIXED

Highlighted Studies

Thirty-six patients were treated…PSA response rate was 11%. Two patients receiving 8 and 14 g/d [white mushroom extract] demonstrated complete response (CR): their PSA declined to undetectable levels that continued for 49 and 30 months. Two patients who received 8 and 12 g/d experienced partial response (PR). After 3 months of therapy, 13 (36%) patients experienced some PSA decrease below baseline. Patients with CR and PR demonstrated higher levels of baseline interleukin-15 than nonres...

Thirty-six [liver cancer] patients were eligible among 40 enrolled patients. Median survival time of eligible patients was 13.6 months .. Survival times of patients who ingested test food for a mean period of 47 weeks (average) were significantly longer than that of patients who ingested for 7 to 12 weeks .. The rates of lentinan-binding cells in CD14+ monocytes showed individual variations (0.1-19.7%; Median, 1.6%). Survival times (median survival time, 16.3 months) of lentinan-high-binding ...

In our study, the 2-year recurrence-free survival rates [liver cancer] were 48.0% for complete two-year intake and 55.2% for all intakes. Hence, AHCC showed superior efficacy in preventing recurrence of HCC after curative hepatectomy…The 2-year recurrence-free survival rates in these 2 (comparable) reports were about 40% though the specific value of the 2-year recurrence-free survival rate was not given in these articles; hence, it was estimated from the survival curve…This study ...

Taken together, these facts suggest that Oyster mushrooms have the potential to enhance the immune system, through Th1 phenotype potentiation as the macrophage-IL-12 – IFN-γ pathway. This results in activation of the cell-mediated immune system as exemplified by up-regulation of NK cell activity. Oyster mushroom extract may be beneficial for the prevention of various diseases, including infectious diseases and cancer, due to its stimulation of the immune system.

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TABLE OF REFERENCES

URL	Rating	Highlight	Highlight 2
https://ar.iiarjournals.org/content/29/7/2739	5	Lentinan significantly prolonged the overall survival (stratified log-rank p=0.011). The overall hazard ratio (HR) was 0.80 (95% confidence interval=0.68-0.95) and there was no heterogeneity between trials. Additionally, lentinan was possibly more effective in patients with lymph-node metastasis than in non-node metastasis patients (P for interaction=0.077). Conclusion: The addition of lentinan to standard chemotherapy offers a significant advantage over chemotherapy alone in terms of survival for patients with advanced gastric cancer	The combination of chemotherapy based on mainly fluorinated pyrimidines and lentinan statistically significantly prolonged the overall survival (stratified log-rank p-value=0.011). The overall HR was 0.80 (95% CI=0.68-0.95) and there was no heterogeneity between trials (heterogeneity p-value=0.466, Figure 3). The HR adjusted by trial and nine baseline characteristics (age, sex, performance status (≥2 or not), recurrent, prior therapy, surgery, peritoneal metastasis, hepatic metastasis, lymph-node metastasis) was 0.76
https://hibercell.com/wp-content/uploads/2020/12/uhlik-et-al-sabcs-poster-final-112719.pdf	5	Data presented here are from a primary analysis when all patients have been enrolled and through at least 12 weeks on therapy (2 CT scans/tumor assessments). In the intent-to-treat population (N=44; median duration of follow-up of 19.1 months..), confirmed ORR was 15.9% (1 CR, 6 PRs). Stable disease (SD) >12 wks as best response was observed in nearly 40% of pts (17/44). Four of these 17 were stable for≥24 wks. OS at 1 year are 57.6% with median OS currently at 16.4 months ... A majority of pts (62.5%) showed target lesion (TL) reduction or stabilization	he combination of Imprime and pembro showed promising response rates and overall survival in chemo- refractory metastatic TNBC. Biopsy analyses consistently revealed activation of both myeloid and T cells with extensive infiltration into tumor tissue. Examination of response patterns and clinical benefit revealed extended OS even in pts not classified as responders by RECIST. Indeed, extended OS was most evident in pts with any reduction in TL, regardless of NL/NTLs
https://jitc.bmj.com/content/8/Suppl_1/A10.1	4.5	Enhanced OS was observed in patients with >1.3 fold increase in CH50 (8/19; HR 0.385; p=0.1) or >1.5-fold reduction in the frequency of exhausted CD8 T cells (8/19; HR 0.102; p=0.001). The IPD responses observed in the ITT population included formation of circulating immune complexes (peak levels ranging from ~4.5-16.1-fold) and production of complement activation protein SC5b9 (~3.4-25.6-fold), and increase in the frequency of HLA-DR+ myeloid cells (~0.43-3.71-fold). Conclusions Overall, these data, albeit in a small population, demonstrate that Imprime/pembro combination can drive the innate/adaptive IPD responses that are critical for providing clinical benefit to the patients who have progressed through prior CPI treatments.	the disease control rate was 45% (1 CR and 8 SD), 6-month and 12-month OS rates were 65% and 45% respectively, and median OS (mOS) was 8.8 months. In the patients showing disease control, a significant increase in CH50, the classical pathway complement function (~0.7-2.6-fold), HLA-DR expression on classical monocytes (~0.61-1.94-fold) and reduction of frequency of PD-1+Tbet-EOMES+ exhausted CD8 T cells (~0.9-4-fold) was observed. Stimulation of peripheral blood mononuclear cells from a subset of patients by CD3/CD28 beads showed enhanced production of IL-2 and IFN-gamma in the CD8 T cells. Some of these IPD responses were also associated with 6-month landmark OS analyses. Additionally, whole blood gene expression analyses showed >2-fold upregulation of several myeloid and T cell activation genes
https://jeccr.biomedcentral.com/articles/10.1186/1756-9966-27-40	4	In this study, twenty patients with advanced malignancies receiving chemotherapy were given a β-(1,3)/(1,6) D-glucan preparation (MacroForce plus IP6, ImmuDyne, Inc.) and monitored for tolerability and effect on hematopoiesis. Our results lead us to conclude that β-glucan is well-tolerated in cancer patients receiving chemotherapy, may have a beneficial effect on hematopoiesis in these patients and should be studied further, especially in patients with chronic lymphocytic leukemia and lymphoma.	None of the twenty patients reported any new symptoms while taking the β-glucan. Sixty per cent of the patients reported a sense of well-being while taking the β-glucan and asked to remain on the treatment even after the completion of the study. Forty per cent of the patients who experienced fatigue during their chemotherapy treatments prior to entering the study reported feeling less fatigued while taking the β-glucan. In addition, one patient with lymphoma and significant cervical adenopathy who delayed his standard chemotherapy for 4 weeks during the study and only took the β-glucan, noted a marked reduction in the size of the nodes while taking the β-glucan alone.
https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-024-00651-x	4	β-glucan combined with Envafolimab and Endostar has considerable efficacy and safety for immune rechallenge in metastatic NSCLC patients who failed of anti-PD-1 treatment previously, especially for PD-L1 positive patients.	The overall response rate (ORR) was 21.7% and disease control rate (DCR) was 73.9%. Median progression-free survival (mPFS) and median overall survival (mOS) was 4.3 months [95% CI: 2.0–6.6] and 9.8 months, respectively. The mPFS between PD-L1 positive and negative subgroup has significant difference (6.3 months vs. 2.3 month
https://link.springer.com/article/10.1007/s12325-008-0079-x	4	Combination therapy involving lentinan, RFA [radiation] and TACE [chem0] was beneficial in terms of increasing mean survival duration, tumour necrosis and reducing the recurrence rate. Lentinan may therefore be of benefit to HCC patients.	The tumour recurrence rate was significantly lower in the combination group (17.8%), compared to the TACE group (45.8%), the RFA group (34.7%) and the TACE/RFA group (29.0%; P<0.05). Finally, mean survival duration was significantly higher in the combination group (28.2 months; P<0.05).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10763102/	4	The existing clinical studies have revealed the application effect of LNT in colorectal cancer.Chen et al. randomized controlled experiments found that LNT combined with chemotherapy regimen can greatly improve the effective rate (chemotherapy regimen with 28% effective rate, LNT combined with effective rate 52%) in colorectal cancer [63]. Moreover, Tu et al. also found that LNT combined with pentafluorouracil can not only enhance the immune function of colorectal cancer patients (CD4/CD8 ratio is elevated), but also significantly improve the quality of life of patients	The clinical effect of LNT in gastric cancer has been widely reported. A randomized controlled study in Japan showed that LNT combined with pentafluorouracil improved survival time for advanced gastric cancer, which is consistent with the results of a meta-study of five randomized controlled trials [78, 79].
https://pmc.ncbi.nlm.nih.gov/articles/PMC2570358/	4	Lastly, because of the immunomodulatory properties of the glucans, these agents may have direct tumoricidal properties which deserve further investigation in a larger population in a controlled setting. Our anecdotal experience in one patient with lymphoma and enlarged cervical nodes who noted marked improvement on the β-glucan alone is extremely interesting at the very least. We conclude that β-(1,3)/(1,6) D-glucan can be safely administered to patients with advanced malignancies receiving chemotherapy and that this adjunctive therapy may have beneficial effects on the blood counts in these patients. Further studies are warranted in a larger patient population to confirm this latter finding and to determine if the β-glucans have tumoricidal effects in humans.	This trial demonstrates that β-(1,3)/(1,6) D-glucan is extremely well-tolerated in patients with advanced malignancies receiving chemotherapy. No adverse effects or toxicities were reported by any of the patients when compared to their symptom profile before entering the study. On the contrary, a significant number of patients reported a sense of well-being while taking the glucan, an effect which should be studied further in a larger, controlled trial. There clearly was some amelioration of the blood counts in patients taking the glucan as compared to the pretreatment mean counts. This effect supports the data from animal studies which demonstrates that the β-glucans improve hematopoiesis through a variety of mechanisms
https://pmc.ncbi.nlm.nih.gov/articles/PMC11381272/	4	Patients in the current our study demonstrated an mPFS of 10.4 (95% CI, 9.52-11.27) months, surpassing the mPFS of 7.7 reported in the CheckMate-649 study (24). Another phase III clinical study (the Orient-16 study) demonstrated that patients with a PD-L1 CPS >5 had an mPFS of 7.7 months, compared to only 7.1 months for the entire study population, with an ORR of 58.2% (25). These findings suggest potential advantages of the β-glucan plus immunotherapy plus chemotherapy over these other therapies for advanced GC	These preliminary results suggest that in patients with advanced GC, even those with poor ECOG performance, β-glucan combined with camrelizumab and SOX chemotherapy offers considerable clinical benefits and a manageable safety profile. Additional studies including control groups and larger patient populations are needed to further explore these initial findings.
https://pubmed.ncbi.nlm.nih.gov/10522061/	4	Median survival was significantly longer in the lentinan group than in the control group (297 days vs. 199 days, p = 0.028). One-year survival rate was greater in the lentinan group than in the control group (49.1% vs. 0%). Total QOL score, especially appetite and sleep quality, was significantly improved with the administration of lentinan.	Lentinan is considered to prolong survival and improved quality of life when gastric cancer patients with unresectable or recurrent diseases are treated in combination with other chemotherapeutic agents.
https://www.mdpi.com/2504-3900/79/1/1	4	8 meta-analyses met inclusion criteria. Retrieved evidence reported that lentinan may be useful to improve response rate, 1-year survival, performance status, quality of life and radio/chemotherapy toxicity when administered in adjunct to standard therapy, especially for some lung and gastrointestinal cancers.	In particular, lentinan integrative therapy was able to ameliorate performance status and radio/chemotherapy toxicity in patients with esophageal, gastric and colorectal cancer, whereas it was capable of improving response rate and adverse effects of standard therapy in subjects with lung malignancies. Individuals with advanced-stage solid tumors also benefited from lentinan integrative supplementation in terms of 1-year survival rate and health-related quality of life.
https://aacrjournals.org/cancerres/article/84/17_Supplement_2/PR-10/747743/Abstract-PR-10-Phase-1b-study-of-maintenance	4	Two patients remained on treatment for >100 days. The pharmacodynamic profile was consistent with the mode of action of odetiglucan and CDX-1140, including a reduction in peripheral Dectin-1 expressing monocytes and transient decreases in peripheral B cells. Patients with disease control (PR or SD, n=2) compared to patients with progression (PD, n=2) showed expansion of peripheral Ki67+ CD8+ T cells following treatment. Analysis of a paired tumor biopsy from 1 patient with PD confirmed penetration of odetiglucan into a liver metastasis with expansion of CD11b+ macrophages and a reduction of cytokeratin+ tumor content, but without significant changes in T cell infiltration	The combination of odetiglucan and CDX-1140 was feasible and safe when administered as maintenance therapy in patients with mPDAC whose disease had not progressed on 1L chemotherapy. Treatment produced encouraging activity with changes in immunological correlates associated with disease control. These early results support further investigation combining odetiglucan with a CD40 agonist in mPDAC.
https://pubmed.ncbi.nlm.nih.gov/19579616/	4	A superfine dispersed lentinan-containing supplementary food is effective for hepatocellular carcinoma patients' survival. Long-time ingestion is preferable. Assessment of lentinan-binding CD14+ monocytes is a promising prognostic predictor	Thirty-six patients were eligible among 40 enrolled patients. Median survival time of eligible patients was 13.6 months (95% confidence interval, 8.7-18.9 months). Survival times of patients who ingested test food for a mean period of 47 weeks (range, 26 to 145 weeks) were significantly longer than that of patients who ingested for 7 to 12 weeks
https://acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.29421	4	Thirty-six patients were treated; no DLTs were encountered. The overall PSA response rate was 11%. Two patients receiving 8 and 14 g/d demonstrated complete response (CR): their PSA declined to undetectable levels that continued for 49 and 30 months. Two patients who received 8 and 12 g/d experienced partial response (PR). After 3 months of therapy, 13 (36%) patients experienced some PSA decrease below baseline. Patients with CR and PR demonstrated higher levels of baseline interleukin-15 than nonresponders; for this group, we observed therapy-associated declines in MDSCs.	Importantly, in 2 patients, PSA decreased to undetectable levels after WBM treatment. To the best of our knowledge, this has not been observed in other studies examining phytochemical compounds for biochemically recurrent prostate cancer. Almost all of the patients in our study (92%), including 2 patients with CR, had received prostatectomy and radiation therapy. As such, patients had exhausted a chance for a cure via traditional localized treatment. Compliance with the daily ingestion of up to 28 large mushroom powder tablets was excellent, reflecting a lack of significant, chronic toxicity. The most common adverse events were grade 1 abdominal bloating and grade 1 SGPT/SGOT elevation. One patient sustained asymptomatic grade 3 hyponatremia.
https://www.tandfonline.com/doi/full/10.1080/14712598.2018.1523392	3.5	Beta-glucans, when present in food and following uptake in the proximal gut, stimulate immune cells present in gut-associated lymphoid tissue and initiate highly conserved pro-inflammatory pathways. When tested in mouse cancer models, β-glucans result in better control of tumor growth and shift the TME toward a T cell-sensitive environment. Along these lines, we advocate that intake of β-glucans provides an accessible and immune-potentiating adjuvant when combined with adoptive T-cell treatments of cancer.	a study by Cosola and colleagues reported a decrease in p-cresyl sulfate levels in urine and an increase in short chain fatty acid levels in feces upon oral administration of a β-glucan derived from H. vulgare, suggesting a saccharolytic shift in gut microbiota metabolism [Citation82]. Zitvogel and colleagues demonstrated a dominance of distinct commensal species in patients who showed a clinical response toward PD-1 checkpoint inhibitors, making the observed effect of β-glucans on the microbiome highly relevant in the context of T cell therapies
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695648/	3.5	An extremely impactful aspect of β-glucan treatment is that it has been demonstrated to modulate the TME. Additionally, β-glucan is safe to use, non-immunogenic, and thus incites no other non-specific responses. It is well-tolerated even with a dose up to 10 mg/kg, induces specific responses through specific receptors and contains many side groups that allow further modification. These features establish β-glucan as a potent adjuvant [55]. Use of adjuvants not only with prophylactic vaccines, but also in therapeutic formulations or alone for immunomodulatory functions have been gaining popularity recently. Fungal β-glucan has been used as an adjuvant, along with other formulations, in both cancer prophylaxis and therapy, and as a single agent for immunomodulatory purposes, and are therefore referred to as immunoadjuvants	Modulation of the TME from an immune-suppressive to an inflammatory environment thus has a very promising potential as an anti-cancer therapy [55]. Fungal β-glucans have the potential to effectively manipulate the TME by influencing both innate and adaptive immune responses [56]. Once innate cells are activated through β-glucan binding to PRRs, as described above, they are recruited to further educate and activate adaptive immune cells. Fungal β-glucans thus have the ability to bridge the innate and adaptive immune responses
https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.887457/full	3.5	In summary, we found that the immune adjuvant WGP β-glucan improved the infiltration of both DCs and macrophages in the TME, while PD-1/PD-L1–blocking antibodies promoted the balance of T cells to antitumor effectors. Furthermore, combination therapy with WGP β-glucan plus PD-1/PD-L1–blocking antibodies was found to improve mPFS in ICB-resistant patients with advanced cancer. These results suggest that WGP β-glucan is a potentially useful adjuvant in combination with various ICB therapies in clinical practice.	ICB-resistant patients who were treated with β-glucan plus PD-1/PD-L1–blocking antibodies demonstrated a mPFS of 3.67 and a mOS of 8.0 months. These results suggest that β-glucan has promise in reversing resistance to immunotherapy in patients with advanced cancer. Furthermore, no significant toxicities were observed among study patients treated with β-glucan. Furthermore, compared with rechallenge of ICB therapy (Fujita et al., 2018; Niki et al., 2018), add or replace with different classes of ICB ...the combination therapy with WGP β-glucan is efficacy and practicability for patients.
https://www.mdpi.com/1422-0067/20/15/3618	3.5	Though fungal β-glucan’s have been studied and used as an immune-stimulant for centuries, there are many aspects of β-glucan biology that are only now being brought to light which are profoundly shaping immunological paradigms. Specifically, the ability of β-glucan to incite the metabolic reprograming and epigenetic regulation of myeloid cells and macrophages is a revelation in the fields of both infectious disease and cancer. As the concept of trained immunity in the context of metabolic reprograming is relatively novel and unstudied, we expect there to be a great deal of interest going forward in how innate memory responses may play a role in cancer immunoprevention and treatmen	An extremely impactful aspect of β-glucan treatment is that it has been demonstrated to modulate the TME. Additionally, β-glucan is safe to use, non-immunogenic, and thus incites no other non-specific responses. It is well-tolerated even with a dose up to 10 mg/kg, induces specific responses through specific receptors and contains many side groups that allow further modification. These features establish β-glucan as a potent adjuvant [55]. Use of adjuvants not only with prophylactic vaccines, but also in therapeutic formulations or alone for immunomodulatory functions have been gaining popularity recently. Fungal β-glucan has been used as an adjuvant, along with other formulations, in both cancer prophylaxis and therapy, and as a single agent for immunomodulatory purposes, and are therefore referred to as immunoadjuvants [
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661165/	3.5	We have shown that the combination of 3F8 [Chemo] and BG is safe. The encouraging responses observed in a heavily pretreated population support further (Phase II) studies of BG combined to other immunomodulatory agents for the therapy of NB and other tumors amenable to CR3-mediated immunotherapy. Given the low toxicity of BG and the absence of any evidence of dose-response correlations, we recommend a dose of 40–80 mg/Kg/day for future trials.	Objective responses were documented in 63% (15/24) of patients. All patients had previously received multiple chemotherapy regimens (median 3; range 2–6). Most patients had poor BM reserve (12/24 patients had platelet count < 100,000/μL at baseline) and would have been ineligible for most Phase I/II clinical studies involving conventional chemotherapeutics. Anti-NB responses were recorded for BM disease (histology, MIBG scans) and biochemical markers (urine catecholamines), but, as reported in other mAb-based clinical trials, responses in soft tissue disease were rare. In general, responses were transient and modest. Near-to-complete resolution of extensive MIBG-avid metastases after one cycle of 3F8 plus BG was observed in two chemorefractory patients
https://www.mdpi.com/1422-0067/20/15/3618	3.5	An extremely impactful aspect of β-glucan treatment is that it has been demonstrated to modulate the TME. Additionally, β-glucan is safe to use, non-immunogenic, and thus incites no other non-specific responses. It is well-tolerated even with a dose up to 10 mg/kg, induces specific responses through specific receptors and contains many side groups that allow further modification. These features establish β-glucan as a potent adjuvant [55]. Use of adjuvants not only with prophylactic vaccines, but also in therapeutic formulations or alone for immunomodulatory functions have been gaining popularity recently. Fungal β-glucan has been used as an adjuvant, along with other formulations, in both cancer prophylaxis and therapy, and as a single agent for immunomodulatory purposes, and are therefore referred to as immunoadjuvants	Though fungal β-glucan’s have been studied and used as an immune-stimulant for centuries, there are many aspects of β-glucan biology that are only now being brought to light which are profoundly shaping immunological paradigms. Specifically, the ability of β-glucan to incite the metabolic reprograming and epigenetic regulation of myeloid cells and macrophages is a revelation in the fields of both infectious disease and cancer. As the concept of trained immunity in the context of metabolic reprograming is relatively novel and unstudied, we expect there to be a great deal of interest going forward in how innate memory responses may play a role in cancer immunoprevention and treatment.
https://pmc.ncbi.nlm.nih.gov/articles/PMC11294916/	3.5	β-Glucan, as an immunomodulator, has demonstrated promising anti-tumor effects in preclinical studies of colorectal cancer, pancreatic cancer, and gastric cancer (14, 24, 25). Notably, the high stability of β-glucan renders it a crucial component for serving as a carrier for targeted drugs against gastric cancer (17). In clinical studies, β-glucan has been shown to improve the 5-year survival rate of hepatocellular carcinoma, gastric cancer, and colorectal cancer, while reducing the recurrence rate (26–28). Additionally, it can mitigate adverse reactions caused by chemotherapy, such as nausea, abdominal pain, mucositis, diarrhea, and leukopenia/thrombocytopenia	Lentinan, a β-glucan extracted from mushrooms, has been proven to possess antitumor activity (25, 85). Researchers have confirmed its preventive and therapeutic effects on gastric cancer, and the mechanisms of its action include: 1) inhibiting the G2/M phase of the gastric cancer cell division cycle to exert anti-proliferative effects; 2) Lentinan can attenuate the wound healing, colony formation, and migration abilities of AGS cells; 3) Lentinan can increase the expression of phospho-p38, while reducing the expression of phospho-ERK1/2 and Mu-2-related death-inducing gene (MuD) proteins; 4) Lentinan induces the generation of reactive oxygen species (ROS), directly participating in cell death (25). In the treatment of gastric cancer, β-glucan can be used as a main component of drug carriers to jointly exert anti-tumor effects
https://pubmed.ncbi.nlm.nih.gov/12076865/	3.5	Of the 269 patients, 113 received AHCC orally after undergoing curative surgery (AHCC group). The AHCC group had a significantly longer no recurrence period (hazard ratio (HR), 0.639) and an increased overall survival rate (HR, 0.421) when compared to the control group by Cox's multivariate analysis.	Active hexose correlated compound (AHCC) is a newly developed functional food. In vitro experiments have shown that AHCC enhances natural killer cell activity, and may be considered a potent biological response modifier in the treatment of cancer patients. However, the effects of AHCC in a clinical setting have not been reported. We seek to determine whether AHCC can improve the prognosis of hepatocellular carcinoma (HCC) patients following surgical treatment.
https://pmc.ncbi.nlm.nih.gov/articles/PMC8793419/	3.5	In this study, the 2-year recurrence-free survival rate for resected BCLC-B cases was 48% for those who completed 2 years of treatment and 55.2% for all patients with a history of treatment. These values are better than those previously reported.8,24 The inflammation-based prognostic scores of patients with AHCC, namely LNR, PNI, and SII, were maintained at favorable levels after hepatectomy. AHCC-related toxicity and adverse events were not observed in any patient treated with AHCC. In this study, AHCC has been found to be a promising adjuvant therapy for patients with advanced hepatocellular carcinoma after curative hepatectomy, and this should be verified in randomized trials.	AHCC has been reported to exert immune-protective effects against many types of cancer and the effect of AHCC on the components of the immune system, such as NK cells, dendritic cells (DCs), and T cells, including CD4 and CD8 positive T cells. 15 After AHCC treatment, NK cell activity, which was depressed by an anticancer drug, was reportedly restored and peritoneal macrophage cytotoxicity, nitric oxide production, and cytokine production were stimulated. 12 In patients with breast cancer, who were scheduled to receive postoperative adjuvant anthracycline-based chemotherapy, administration of L. edodes mycelia extract maintained patients’ quality of life and immune function by inhibiting the increase in the proportion of regulatory T cells to peripheral CD4+ cells. 33 Intake of AHCC increased CD8+ T cell lymphocyte levels after 6 cycles of chemotherapy.
https://www.med.upenn.edu/ifi/assets/user-content/documents/sciimmunol.adj5097.pdf	3	Established pancreatic tumors that were resistant to T cell–targeted immunotherapy could be eradicated by systemic β-glucan in combination with CD40 agonist antibody therapy. The antitumor activity of Dectin-1/CD40 activation required T cells but was independent of classical T cell cytotoxicity and immune checkpoint pathways. Antitumor activity also required IFN-γ and intratumoral macrophages. These results demonstrate that combinatorial targeting of myeloid cell activation pathways can generate strong antitumor immune responses against tumors resistant to conventional immunotherapy	To define the mechanisms and clinical relevance of combinatory myeloid pathway activation, we focused on aCD40 plus BG therapy. At the cellular level, cDC1s, T cells, Ly6C+ monocytes, and CSF1R-dependent TAMs were necessary for maximal therapeutic activity triggered by coactivation of CD40 and Dectin-1, whereas B cells and granulocytes were dispensable. Thus, antitumor activity driven by BG and aCD40 treatment relies on distinct contributions from multiple adaptive and innate leukocyte subsets, which converge to establish a concerted immunological response to cancer
https://www.sciencedirect.com/science/article/pii/S2161831322004641	2.5	..the current meta-analysis showed a significant inverse association between higher mushroom consumption and lower risk of cancer. In particular, breast cancer appeared to be the most affected site because a significant association with mushroom intake was only observed for cancers at this site. A lack of significant association for site-specific cancers in this study could be due to the low numbers of studies specifically for these cancers. Our findings may have important public health implications in the prevention of chronic diseases and mortality. In addition, the results are useful for policy makers, contributing to increasing public awareness about the role of the diet on health, and potential protective effects of mushrooms	Higher mushroom consumption was associated with lower risk of total cancer in cohort studies (pooled RR for the highest compared with the lowest consumption groups: 0.89) and case-control studies (pooled RR for the highest compared with the lowest consumption groups: 0.52) . Higher mushroom consumption was also associated with lower risk of breast cancer (pooled RR for the highest compared with the lowest consumption groups: 0.65) and nonbreast cancer (pooled RR for the highest compared with the lowest consumption groups: 0.80)
https://pmc.ncbi.nlm.nih.gov/articles/PMC10073218/	2.5	A total of 3,900 gastric cancer cases and 7,792 controls from 11 studies were included in the StoP analysis. Mushroom consumption was measured using food frequency questionnaires (FFQ). Higher mushroom consumption was associated with a lower risk of gastric cancer (relative risk [RR] for the highest vs. lowest consumption categories: 0.82, 95% confidence interval [CI]: 0.71-0.95). The corresponding RRs were 0.59 (95% CI: 0.26-1.33) in a meta-analysis of 4 previously published studies, and 0.77 for all studies combined (95% CI: 0.63-0.9, n=15 studies). In geographic subgroup analysis, the pooled risk in Western Pacific countries was (RR=0.59, 95% CI: 0.40-0.87, n=6). The stronger effect in Asian countries may reflect high level of antioxidants in mushroom species consumed in Asia.	The adjusted RR from four previous studies are shown in Fig 1. The summary RR was 0.59. The adjusted RR from these studies and the StoP Project studies combined was 0.77 ...between-study heterogeneity was modest [i.e degree of certainty]. Combining both StoP and the previous studies, a meta-analyses of risk estimates by WHO geographic regions showed that higher mushroom consumption was associated with a lower adjusted risk of stomach cancer in the Western Pacific region (RR=0.59). The risk was (RR= 0.93) in the European region and (RR=0.88) in the American region.
https://thescipub.com/pdf/ajisp.2017.50.61.pdf	2.5	Most studies, with the exception of one (Yoshino et al., 2016), presented results that were concordant on one main point of interest, that is the advantage to introduce lentinan supplement in the treatment of cancer patients in association to the appropriate chemotherapy. Interestingly, the increased performance status and the reduction of the chemotherapy side effects by lentinan association allowed prolonged treatment to patients, favoring their survival.	It might be possible that the better-responding patients already had traits or characteristics for a higher tolerance to the therapy. However, two meta-analyses confirmed the advantage of lentinan use (Oba et al., 2009; Yin et al., 2015). Larger clinical studies, not only from the Asiatic countries, should be performed to confirm the described beneficial effects of lentinan. The problem must be addressed first, the availability of standard product of lentinan - with clearly known composition and quality - to permit full evaluation and replication of the results.
https://www.nature.com/articles/s41598-024-58742-z	2	The NK cell activity markedly increased in the male FCM [fermented cordyceps extract] group from baseline (p = 0.049) to 4 weeks after receiving FCM. Compared with those in the placebo group, the NK activity in women who received FCM for 8 weeks significantly increased (p = 0.023) from baseline. Within-group analysis revealed that the IL-1β levels were markedly reduced in the male FCM group (p = 0.049). Furthermore, the IL-6 levels decreased from baseline in the female FCM group (p = 0.047). The blood sugar, lipid, and safety indices were not different between the experimental groups. FCM can potentially be developed as an immune-boosting supplement without liver, kidney, or blood component toxicity.	FCM stimulates the human immune response by activating NK cells, increasing monocyte concentrations, and reducing inflammatory cytokine secretion in men and women without toxicity. This beneficial effect of FCM indicates its use as a new alternative approach as a natural immunostimulatory supplement. However, it should be noted that the mechanisms underlying the immune activator effects of FCM and its impact on immune-related disease in patients require further investigation.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0093437	2	Eight case-control studies and two cohort studies with a total of 6890 cases were ultimately included. For dose-response analysis, there was no evidence of non-linear association between mushroom consumption and breast cancer risk (P = 0.337) and a 1 g/d increment in mushroom intake conferred an RR of 0.97 (95% CI: 0.96–0.98) for breast cancer risk, with moderate heterogeneity (I2 = 56.3%, P = 0.015). Besides, available menopause data extracted from included studies were used to evaluate the influence of menopausal statues. The summary RRs of mushroom consumption on breast cancer were 0.96 (95% CI: 0.91–1.00) for premenopausal women and 0.94 (95% CI: 0.91–0.97) for postmenopausal women, respectively. Our findings demonstrated that mushroom intake may be inversely associated with risk of breast cancer,	The meta-analysis including 10 eligible studies indicated a linear dose-response association between mushroom intake and risk of breast cancer, with the summary RR being 0.97 (95% CI: 0.96–0.98) for per 1 g/d increment in mushroom consumption. Besides, the protective effects of mushroom intake on risk of breast cancer were consistently exhibited in premenopausal women and in postmenopausal women. Potential benefits to breast cancer patients taking high dosage of the extract of specific medicinal mushrooms over long term have been well-studied with positive results [35]. While benefits of oral administration of mushrooms on breast cancer risk were still unclear. In the present meta-analysis, the summary RRs of breast cancer presented a steady linear decrease with the increasing intake of edible mushroom
https://www.spandidos-publications.com/10.3892/etm.2010.121/	2	After CM-G [beta glucan preparation] administration, the total leukocyte count increased significantly (p≤0.02), with no associated changes in the lifestyle habits of the patients. A significant increase (p≤0.001) was also observed for red blood cell, hematocrit, hemoglobin and platelet counts. No changes were observed in hepatic or renal function after CM-G administration, and no side effects associated with its use were recorded. These results suggest that using CM-G as an adjuvant to cancer treatment may improve the health parameters of prostate cancer patients	low white blood cell counts were observed prior to CM-G treatment in patients who had received radiation therapy. CM-G has proven effective in stimulating hematopoiesis after repeated doses of radiation, and in increasing granulocytes and other hematopoietic indices (18). Several experimental models have demonstrated the ability of β-glucans and derivatives administered by different routes to raise blood cell counts after leukopenia caused by cancer treatments
https://link.springer.com/article/10.1007/s00262-014-1628-6	2	Maitake was well tolerated. Enhanced in vitro neutrophil and monocyte function following treatment demonstrate that Maitake has beneficial immunomodulatory potential in MDS... Maitake increased endogenous (basal) neutrophil (p = 0.005) and monocyte function (p = 0.021). Pre-treatment monocyte response to E. coli was reduced in MDS patients compared with HC (p = 0.002) and increased (p = 0.0004) after treatment. fMLP-stimulated ROS production response also increased (p = 0.03). Asymptomatic eosinophilia occurred in 4 patients (p = 0.014). Other changes in albumin, hemoglobin, and total protein were not clinically relevant.	Both neutrophils and monocytes showed increased basal production of ROS after Maitake treatment. Recent studies show that LPS from E. coli activates neutrophils to prime monocyte ROS production, leading to release of proinflammatory cytokines and further priming of neutrophils [37, 38]. Our data therefore suggest that monocyte ROS dysfunction may be an early marker of impaired microbicidal activity due to defective monocyte–neutrophil interaction. Maitake has been shown to stimulate human neutrophil phagocytosis in vitro
https://pubmed.ncbi.nlm.nih.gov/25866155/	2	Eating L. edodes for 4 weeks resulted in increased ex vivo proliferation of γδ-T (60% more, p < 0.0001) and NK-T (2-fold more, p < 0.0001) cells. Both cell types also demonstrated a greater ability to express activation receptors, suggesting that consuming mushrooms improved cell effector function. The increase in sIgA implied improved gut immunity. The reduction in CRP suggested lower inflammation.	Regular L. edodes consumption resulted in improved immunity, as seen by improved cell proliferation and activation and increased sIgA production. The changes observed in cytokine and serum CRP levels suggest that these improvements occurred under conditions that were less inflammatory than those that existed before consumption.
https://ascopubs.org/doi/10.1200/jco.2011.29.15_suppl.1582	1.5	AA measurements were able to detect a consistent post-prandial peak in activity in the 5g and 8g dose groups (p==.003 and <.001, respectively), which diminished in the 10g group and disappeared in the 13g group. Among patients with detectable baseline cytokine levels, IL-1β, IL-2, and IL-6 decreased on treatment, but there was no clear dose effect.	High doses of WBM extract are well tolerated. An ex vivo assay of aromatase activity developed in our lab is sensitive to short-term changes and demonstrated suppression of post-prandial fluctuations with a 10g or 13g daily dose of WBM extract. These results suggest that anti-aromatase phytochemicals are present in plasma with daily consumption of 100-130g whole WBM, but not at high enough concentrations to significantly reduce estrogen levels
https://onlinelibrary.wiley.com/doi/10.1111/sji.12476	1.5	In conclusion, in this placebo-controlled clinical study consumption of AndoSan™ influenced cytokine levels, marginally for UC and moderately for CD, supporting a weak systemic anti-inflammatory effect. Therefore, the reported beneficiary clinical effects mediated by AndoSan™ for these patients probably also involve other anti-inflammatory compounds, not examined.	Only IL-2 was significantly reduced at visit 3 in the Andosan™ compared with the placebo group. However, when combining IL-1ß, IL-6 and G-CSF in the patients with CD, the cytokine levels were significantly lower in the AndoSanTM - versus the placebo group, visit 3. In UC, levels of IL-2, IL-5 and MIP-1ß were reduced within the AndoSan™ group. IL-5 was also reduced at visit 3 compared with placebo. Generally, the effect on reduction in systemic cytokine levels by consumption of AndoSan™ was limited
https://www.sciencedirect.com/science/article/pii/S2225411015001169	2	we examined the effect of Oyster mushroom extract in the human diet, focusing on the activation of immune reactions by evaluating cytokine profiles, particularly the Th1/Th2 balance. For example, IL-4 inhibits IFN-γ-dependent activation of macrophage effector function. Conversely, IFN-γ antagonizes the IL-4 dependent induction of IgE receptors.13, 14, 15 In this study, we demonstrated that 8-week ingestion of Oyster mushroom extract enhanced IFN-γ production in a randomized, double-blind, placebo-controlled, parallel-group clinical study. A strong IFN-γ producer, IL-12 was also increased, but to a lesser extent. On the other hand, Th2-type cytokines such as IL-10 and IL-13 were minimally changed, and IL-4 was undetected because of low production	In addition, we measured plasma levels of IL-4, IL-5 and TNF-α to better understand the cytokine profile, and found some increase in the level of Th1-type cytokine TNF-α (P = 0.115) and minimal change in that of Th2-type IL-5 (P = 0.265) at week 8 (Fig. 4). IL-4 plasma levels were too low to be measured in almost subjects (data not shown). Increase of TNF-α is compatible with Th1-type increase and would be functional for suppression of tumor growth. In fact, TNF-α participates in the induction of IFN-γ in an additive fashion in the presence of cofactors such as IFN-α, resulting in NK cell activation. Overall, it was strongly suggested that Oyster mushroom extract stimulates the release of Th1-type cytokines, and minimally affects that of Th2-type cytokines
https://pmc.ncbi.nlm.nih.gov/articles/PMC8542389/	1	Our PDX showed that oral intake of WBM extract (200 mg/kg/day) suppressed tumor growth and decreased PSA levels in both tumors and serum. In the present study, we also identified a conjugated linoleic acid isomer (CLA-9Z11E) as a strong AR antagonist by performing LanthaScreen™ TR-FRET AR Coactivator Interaction Assays. The inhibitory effect of CLA-9Z11E (IC50: 350 nM) was nearly two times stronger than the known AR antagonist, cyproterone acetate (IC50: 672 nM). The information gained from this study improves the overall understanding of how WBM may contribute to the prevention and treatment of PCa.	For the in vivo study, we fed 6X WBM extract at a dose of the extract originating from 200 mg WBM powder/kg/day (average body weight of mice is 30 g, equal to 6 mg/mice/day). The 6X WBM extract was originated from 6 g freeze-dried WBM powder in 1mL water (6mg/μL). Oral intake of WBM extract (200 mg/kg/day) significantly suppressed the growth of the PDX tumor, with declined levels of serum and tissue PSA. The expression of Ki67 and DNA topoisomerase 2α (TOP2A) was also strongly suppressed by WBM (Figure 5). For adult men with an average body weight of 80 kg, the estimated daily WBM powder intake would be 16 g/day. In our clinical phase I trial, we examined 6 dosages of WBM powder pellet, beginning with 4 g/d to 14 g/d
https://pmc.ncbi.nlm.nih.gov/articles/PMC4312620/	3.5	The study showed evidence of a number of immunomodulating effects of AndoSan, used as adjuvant therapy to high dose of melphalan with autologous stem cell support in patients with multiple myeloma, which possibly may have a clinical significance. However, the results must be interpreted with caution because of the restricted sample size of the study. No statistically significant clinical impact of AndoSan was detected, although trends for a longer median time to next treatment (37.5 months versus 31.2 months) and a shorter period of i.v. antibiotics (8.6 days versus 10.0 days) were noted in the Agaricus group	Forty patients with multiple myeloma scheduled to undergo high dose chemotherapy with autologous stem cell support were randomized in a double blinded fashion to receive adjuvant treatment with the mushroom extract AndoSan, containing 82% of Agaricus blazei Murrill (19 patients) or placebo (21 patients). Intake of the study product started on the day of stem cell mobilizing chemotherapy and continued until the end of aplasia after high dose chemotherapy, a period of about seven weeks. Thirty-three patients were evaluable for all study endpoints, while all 40 included patients were evaluable for survival endpoints. In the leukapheresis product harvested after stem cell mobilisation, increased percentages of Treg cells and plasmacytoid dendritic cells were found in patients receiving AndoSan. Also, in this group, a significant increase of serum levels of IL-1ra, IL-5, and IL-7 at the end of treatment was found.
https://onlinelibrary.wiley.com/doi/10.1002/ctm2.70048	2.5	In summary, our study involving both animal models and PCa patients elucidates the cellular and molecular mechanisms by which WBM consumption modulates the immune response in prostate cancer. It highlights the significant reduction of PMN-MDSCs as a key biological response to WBM treatment, thereby enhancing anti-cancer immunity through the activation of cytotoxic T and NK cells. Methodologically, our study established a representative model of a full-circle translational study in developing botanical drugs by following the US FDA regulatory guidelines.60-63 Further research and clinical investigations are needed to assess the optimal route of administration and dosage of WBM, along with other health impacts, such as effects on the human microbiota. Future studies should focus on uncovering the molecular mechanisms of the various mushroom constituents, their interactions with cancer immunotherapy, and their potential applications in clinical practice	These results were confirmed by nonbiased single cell analysis of PCa patient circulating immune cells and flow cytometry, which provide complementary evidence to our animal model studies. There was a decrease in MDSCs, accompanied by a concomitant increase in T and NK cell numbers and functions in the WBM treated patients, as there were no significant MDSC changes in the control patients (Figures 4 and S5). Single-cell analyses of patients’ specimens, including clustering and annotation, revealed that a subset of MDSCs, notably PMN-MDSCs, were particularly reduced in WBM-treated patients (Figure 5). Functional enrichment analyses of these cells showed that gene clusters involved in the response to fungal infection (e.g., WBM) and regulation of the immune response were induced by WBM treatment