Mushrooms and Anti-PD-1 Therapy: The Preclinical Evidence

Mushrooms and Cancer Immunotherapy

HR 0.65 melanoma OS

Ameri Shah Reza's 2026 comprehensive review of beta-glucans in oncology documented a hazard ratio of 0.65 for melanoma and 0.72 for lung cancer when beta-glucan was combined with checkpoint inhibitor therapy, representing meaningful improvements in overall survival in clinical trial data.

Ameri Shah Reza et al., Naunyn Schmiedebergs Arch Pharmacol, 2026

HR 0.72

lung cancer overall survival with beta-glucan added to checkpoint inhibitor therapy

4

distinct mushroom compound classes shown to interact with the PD-L1/PD-1 checkpoint axis

2022

year of first clinical study showing beta-glucan improved outcomes after checkpoint inhibitor failure

Ameri Shah Reza et al., Naunyn Schmiedebergs Arch Pharmacol, 2026

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In 2020, a team of researchers reported something specific enough to stop you mid-sentence: Cordyceps militaris polysaccharide converts immunosuppressive tumor-associated macrophages into pro-immune cells AND specifically inhibits the same molecular signaling pathway that pembrolizumab and nivolumab target.^[1] These drugs, sold as Keytruda and Opdivo, are among the most successful cancer treatments developed in the last two decades. The idea that a mushroom polysaccharide targets the same molecular mechanism is, at minimum, worth examining carefully.

This article covers the mushroom compounds anti-PD-1 therapy preclinical evidence in detail: how the PD-1/PD-L1 checkpoint works, which mushroom compounds have been studied with checkpoint inhibitors, what the studies found, and where the evidence chain breaks before reaching clinical recommendation.

This is a companion article to the broader mushrooms and cancer immunotherapy overview. For background on the anti-cancer mechanisms of mushroom polysaccharides generally, see how mushroom sugars activate cancer-fighting immune cells and the cancer treatment pillar.

The Lock Cancer Puts on T Cells (And Why It Is So Hard to Break)

To understand why the mushroom-checkpoint inhibitor research matters, you need a working model of what PD-1/PD-L1 checkpoint therapy does.

T cells are the immune system's targeted killers. They can identify cells that don't belong in a healthy body, including cancer cells, and eliminate them. Cancer, however, has evolved a strategy for avoiding this surveillance. Cancer cells display a protein called PD-L1 on their surface. PD-L1 binds to a receptor called PD-1 on T cells. When this binding happens, it sends a "stand down" signal to the T cell, essentially convincing the immune system that the cancer cell is normal tissue that should not be attacked.

PD-1 and PD-L1 are "checkpoint proteins," part of the immune system's normal self-regulation system that prevents T cells from attacking the body's own healthy tissue. Cancer exploits this protective mechanism by displaying PD-L1 as camouflage.

Checkpoint inhibitor drugs like pembrolizumab (Keytruda) and nivolumab (Opdivo) work by blocking the PD-1/PD-L1 interaction. They act as molecular blockers that prevent the cancer's "stand down" signal from reaching the T cell. With the checkpoint blocked, T cells can recognize and attack the tumor again. This approach has produced remarkable results in certain cancers, particularly melanoma and some lung cancers, where it has extended lives in patients who had no good treatment options.

The problem is resistance. A substantial portion of patients either don't respond to checkpoint inhibitors initially, or respond at first and then stop responding as the tumor adapts. Finding approaches that can restore checkpoint inhibitor sensitivity is one of the most active areas of cancer research.

A 2026 review by Ameri Shah Reza and colleagues in Naunyn Schmiedebergs Archives of Pharmacology summarized the current state of beta-glucan research in oncology, including clinical trial data showing hazard ratios of 0.65 for melanoma and 0.72 for lung cancer when beta-glucan was combined with checkpoint inhibitor therapy.^[2] Hazard ratios below 1.0 indicate reduced risk of death during the study period. HR 0.65 means the beta-glucan group had 35% lower mortality risk than the checkpoint inhibitor-alone group.

Cordyceps Polysaccharide Directly Targets the PD-L1/PD-1 Axis

The Bi et al. 2020 study in International Journal of Biological Macromolecules is the most mechanistically specific piece of evidence for a mushroom compound directly engaging the checkpoint inhibitor pathway.^[1]

To understand what makes this finding significant, you need to know about one of cancer's key immune evasion strategies: recruiting macrophages to work for the tumor rather than against it.

Macrophages are the immune system's general-purpose surveillance cells. They come in two functional states. Macrophages in "attack mode" (called M1) identify pathogens and cancer cells and help destroy them; they recruit other immune cells and produce inflammatory signals that amplify the immune response. Macrophages in "protection mode" (called M2) suppress inflammation and help repair tissue; they are anti-inflammatory and immunosuppressive.

Tumors are very good at converting macrophages from M1 to M2. Once they have successfully converted the macrophages nearby, these tumor-associated macrophages (TAMs) become a protective shield: they suppress T cell activity, secrete growth factors that help the tumor expand, and critically, display PD-L1 on their own surface. This means the cancer is not only hiding directly (cancer cells displaying PD-L1) but has recruited immune cells to extend the camouflage.

Bi et al. showed that Cordyceps militaris polysaccharide does two things simultaneously in cell culture: it converts TAMs back from M2 to M1 mode (flipping the immunosuppressive cells back to attack mode), AND it specifically inhibits the PD-L1/PD-1 interaction between those macrophages and T lymphocytes. The T cells, no longer receiving the "stand down" signal, became activated.

This is a qualitatively different claim from "mushrooms boost immunity." This is a specific molecular mechanism showing a mushroom polysaccharide disrupting the exact molecular interaction that defines checkpoint inhibitor therapy. For reference, the PSK extract from turkey tail (Trametes versicolor) has been used as an approved cancer immunotherapy in Japan for decades, with Fisher and colleagues' 2002 review documenting its T cell activation, NK cell activation, and cytokine enhancement properties.^[3] The Bi 2020 finding adds a modern mechanistic explanation for why mushroom polysaccharides may be particularly relevant to contemporary immunotherapy approaches.

Ganoderma Polysaccharide + Anti-PD-1: Additive Effects in Colorectal Cancer

Li and colleagues published a 2024 study testing whether Ganoderma lucidum polysaccharide (GLP) and anti-PD-1 antibody, taken together, produce better results in colorectal cancer models than either agent alone.^[4]

Colorectal cancer has been one of the more difficult cancers for checkpoint inhibitor therapy. Only a subset of colorectal tumors respond well to anti-PD-1 drugs, specifically those with a particular genetic feature called microsatellite instability. The majority of colorectal cancers lack this feature and show limited response to checkpoint inhibitors alone.

Li's team found that GLP supplementation significantly inhibited tumor growth and activated antitumor immunity on its own. The combination of GLP with anti-PD-1 antibody produced further enhancement: increased CD8+ T cells (the killer T cells that directly destroy cancer cells) both in the spleen and within the tumor tissue itself, and decreased Tregs (regulatory T cells that suppress immune responses and protect tumors from attack). Tumor-infiltrating CD8+ T cells are a key indicator of effective antitumor immunity; Tregs in the tumor microenvironment are a key indicator of immune evasion.

The mechanism appeared to be GLP improving immune cell access to the tumor and activating the immune cells present there, while the anti-PD-1 antibody blocked the cancer's checkpoint signaling. The two approaches operated through complementary pathways, which is why the combination outperformed either agent alone.

For a broader overview of how mushroom polysaccharides fight tumors including non-immunotherapy mechanisms, see how mushroom polysaccharides fight cancer tumors.

The Resistance Reversal: When Patients Who Failed Checkpoint Therapy Were Re-Challenged With Beta-Glucan

The most clinically significant finding in this field (and the most carefully caveated) is from Wang and colleagues' 2022 study in Frontiers in Pharmacology.^[5]

The study enrolled patients with advanced cancer who had previously been treated with anti-PD-1/PD-L1 checkpoint inhibitors and had discontinued because their disease was progressing on those drugs. These are patients with established checkpoint inhibitor resistance, which is one of the hardest clinical problems in oncology.

These patients received beta-glucan (whole glucan particles derived from yeast, a close relative of mushroom beta-glucans in structure) combined with re-challenged PD-1/PD-L1 blockade. The study found improved progression-free survival compared to expected outcomes for this population.

This matters because it suggests beta-glucan may help restore sensitivity to checkpoint inhibitors in at least some patients who have lost it. The mechanism proposed involves beta-glucan resetting the tumor immune microenvironment: beta-glucan binds to complement receptor 3 (CR3) on immune cells, triggering a signaling cascade that activates macrophages and NK cells in the tumor vicinity, potentially disrupting the immunosuppressive state that was protecting the tumor from continued checkpoint inhibitor activity.

The caveat: this is not a large randomized controlled trial. It is a clinical study without a concurrent control group, and the patient population is heterogeneous. The result needs prospective validation in a properly powered RCT before it could inform clinical decision-making. What it does establish is that the hypothesis is worth testing rigorously, a meaningful advance over purely preclinical data.

Triterpenoids Join the Story: Ganoderic Acid T and Galectin-1

Most research on mushroom compounds and checkpoint inhibitors focuses on polysaccharides, specifically beta-glucans. A 2024 study published in Toxicology and Applied Pharmacology showed that a triterpenoid compound from reishi mushroom also has immunotherapy-enhancing properties, through a different mechanism entirely.^[6]

Ganoderic acid T (GAT) is one of the ganoderic acids found in Ganoderma lucidum (reishi). The 2024 study tested GAT in ovarian cancer models and found it downregulated a protein called galectin-1.

Galectin-1 is worth understanding because it represents a checkpoint mechanism separate from PD-L1/PD-1. Tumors and cancer-associated support cells (fibroblasts that form the structural scaffold of tumor tissue) secrete galectin-1 to suppress immune attack and promote tumor survival. High galectin-1 is associated with poor prognosis and resistance to immunotherapy in multiple cancer types.

Reducing galectin-1 levels in the tumor microenvironment produced several downstream effects: fewer cancer-associated fibroblasts (the support cells that help tumors resist immune infiltration), more tumor-infiltrating lymphocytes (immune cells reaching the tumor), and significantly enhanced anti-PD-L1 antibody efficacy compared to anti-PD-L1 treatment alone.

This finding extends the mushroom-immunotherapy story beyond polysaccharides and into the triterpenoid compound class. Reishi contains both polysaccharides (GLP, beta-glucans) that activate immune cells and triterpenoids (ganoderic acids) that modulate the tumor microenvironment through galectin-1 suppression. These operate through complementary mechanisms, which may explain why whole reishi extracts have been observed to have broader immunological effects than purified single-compound fractions.

Novel Direction: Physically Combining Beta-Glucan With a Checkpoint Antibody

The most forward-looking research in this cluster involves not just taking beta-glucan and a checkpoint inhibitor at the same time, but chemically conjugating them into a single molecule.

Wang and colleagues' 2024 study in a preclinical mouse model tested an anti-PD-L1 antibody that had been chemically linked to beta-glucan as a single molecular construct.^[7] The conjugated molecule outperformed anti-PD-L1 antibody alone on multiple measures: earlier initiation of the antitumor immune response, increased dendritic cell infiltration into the tumor, and activation of pre-existing T cells that were already in the tumor environment but had been suppressed.

Dendritic cells are the immune system's intelligence-gathering cells. They patrol tissue, identify foreign material (including cancer cell debris), and present it to T cells to initiate a targeted response. More dendritic cells infiltrating the tumor means better antigen presentation and a stronger, more specific T cell response. The beta-glucan portion of the conjugated molecule appeared to attract and activate dendritic cells through its normal dectin-1 receptor binding, bringing them into the tumor environment where the antibody portion was blocking checkpoint signaling.

This is drug development research, not a supplement study. The conjugated molecule is a novel engineered compound, not something found in a mushroom product. But it validates the mechanistic logic: beta-glucan activation and checkpoint inhibition are complementary pathways, and combining them in some form produces better antitumor effects than either pathway addressed alone.

Wu and colleagues extended the combination approach to pancreatic cancer in a 2025 preclinical study, testing beta-glucan with PD-1/PD-L1 blockade after tumor ablation therapy.^[8] Pancreatic cancer is among the most immunotherapy-resistant cancers, with very low response rates to checkpoint inhibitors alone. The combination suppressed tumor growth in mouse models, suggesting the additive mechanism may extend to cancer types where the checkpoint inhibitor approach has so far largely failed.

What This Evidence Does and Does Not Establish

The picture assembled by these studies is more specific than "mushrooms help with cancer." It is: several mushroom compound classes (Cordyceps polysaccharide, Ganoderma polysaccharide, beta-glucans broadly, ganoderic acid T) appear to interact with the PD-1/PD-L1 checkpoint pathway and other tumor immune evasion mechanisms in ways that are complementary to checkpoint inhibitor drugs.

Ameri Shah Reza's 2026 comprehensive review of beta-glucans in oncology synthesized the full clinical and preclinical picture, documenting the receptor pathways (Dectin-1, TLR, CR3), the macrophage polarization effects (M2 to M1 conversion), and the PD-L1 downregulation evidence, alongside the clinical trial data showing the hazard ratios described in the opening section.^[2]

What the evidence does NOT establish:

No standard clinical recommendation exists. No major oncology body currently recommends adding mushroom supplements to checkpoint inhibitor therapy. The clinical data is early-stage, comes from small studies without adequate controls, and has not been replicated in large prospective RCTs.

Drug interactions are unstudied at scale. Checkpoint inhibitors are immunologically powerful drugs; anything that modulates immune activity in ways that interact with them could theoretically alter their side effect profile. Immune-related adverse events (the autoimmune-like reactions that checkpoint inhibitors can cause) are the most serious safety concern, and whether mushroom polysaccharides might worsen, reduce, or neutrally interact with these adverse events has not been studied.

The doses and forms are different. The Bi 2020 study used purified Cordyceps militaris polysaccharide in cell culture. The Li 2024 study used a standardized GLP extract in animal models. The Wang 2022 clinical study used whole glucan particles from yeast, not mushrooms. These are not the same as the mushroom extract products in a health food store, and the doses used are not directly comparable to what any commercial product provides.

The honest summary: this is a biologically plausible and increasingly specific research direction that has produced some compelling preclinical findings and at least one clinical signal worth following. It is not yet established medicine, and cancer patients undergoing checkpoint inhibitor therapy should not modify their treatment plans based on this literature without discussing it with their oncology team. The research warrants attention; it does not warrant self-experimentation in a high-stakes treatment context.

For the broader mushroom cancer supplement evidence including quality-of-life data and chemotherapy adjunct research, see the evidence for mushroom-based cancer adjuncts and mushroom cancer quality of life research.

The Bottom Line

Multiple mushroom compound classes have been shown to interact with the PD-1/PD-L1 checkpoint pathway that modern cancer immunotherapy drugs target. Bi et al. (2020) demonstrated that Cordyceps militaris polysaccharide directly inhibits the PD-L1/PD-1 axis between tumor-associated macrophages and T cells. Li et al. (2024) found Ganoderma polysaccharide combined with anti-PD-1 antibody enhanced immunotherapy efficacy in colorectal cancer models. Wang et al. (2022) published clinical evidence that beta-glucan improved outcomes in patients who had already failed checkpoint inhibitor therapy. Ganoderic acid T, a reishi triterpenoid, enhanced anti-PD-L1 efficacy through galectin-1 downregulation. Ameri Shah Reza's 2026 review documented hazard ratios of 0.65 and 0.72 for melanoma and lung cancer respectively in clinical data combining beta-glucan with checkpoint inhibitor therapy. The research is biologically specific and increasingly detailed, but human clinical data remains early-stage without the prospective RCT evidence needed for clinical recommendation.

Frequently Asked Questions

How do mushroom beta-glucans interact with PD-1 inhibitors?

Beta-glucans and PD-1 inhibitors appear to work through complementary mechanisms. PD-1 inhibitors (like pembrolizumab) block the "stand down" signal that cancer cells send to T cells via the PD-1/PD-L1 interaction. Beta-glucans work upstream by activating macrophages and converting immunosuppressive tumor-associated macrophages back into pro-immune attack mode, reducing PD-L1 expression in the tumor environment. Bi et al. (2020) showed Cordyceps polysaccharide directly inhibits the PD-L1/PD-1 axis between macrophages and T cells. Wang et al.'s 2022 clinical study found beta-glucan combined with re-challenged PD-1/PD-L1 blockade improved outcomes in patients who had stopped responding to checkpoint inhibitor therapy.

What research shows mushroom compounds enhance anti-PD-1 therapy?

Four compounds have been specifically studied: Cordyceps militaris polysaccharide (Bi 2020, directly inhibits PD-L1/PD-1 axis in tumor-associated macrophages); Ganoderma lucidum polysaccharide (Li 2024, additive effects with anti-PD-1 in colorectal cancer, increased CD8+ killer T cells); beta-glucan whole glucan particles (Wang 2022, clinical study showing improved outcomes after checkpoint inhibitor failure); and ganoderic acid T (2024, reishi triterpenoid enhancing anti-PD-L1 via galectin-1 downregulation in ovarian cancer models). Ameri Shah Reza's 2026 review synthesized clinical trial data showing hazard ratios of 0.65 for melanoma and 0.72 for lung cancer when beta-glucan was added to checkpoint inhibitor therapy.

Can polysaccharides from mushrooms overcome PD-1 resistance?

Wang et al.'s 2022 clinical study specifically addressed checkpoint inhibitor resistance: patients with advanced cancer who had already discontinued PD-1/PD-L1 therapy due to disease progression received beta-glucan combined with re-challenged checkpoint inhibitor therapy and showed improved progression-free survival. This is the most clinically significant finding in the field and suggests beta-glucan may help reset tumor immune microenvironments that have become resistant. However, the study lacked a concurrent control group, and the findings need prospective RCT confirmation before they can inform clinical recommendations.

Which mushroom compounds have been tested with checkpoint inhibitor therapy?

The most studied compounds are: beta-glucans broadly (from Trametes versicolor/turkey tail as PSK, from Ganoderma, from Cordyceps militaris, and from yeast as whole glucan particles); Ganoderma lucidum polysaccharide (GLP) specifically; and Cordyceps militaris polysaccharide. More recently, ganoderic acid T, a triterpenoid from reishi, has been studied. A 2024 study also tested a novel compound that physically conjugated beta-glucan to an anti-PD-L1 antibody as a single molecule, finding enhanced antitumor efficacy over the antibody alone. PSK from turkey tail has the longest clinical history, approved in Japan as a cancer immunotherapy since the 1980s.

What is the evidence for combining mushrooms with cancer immunotherapy?

The evidence ranges from preclinical to early clinical: strong cell culture data (Bi 2020 Cordyceps mechanism), animal model data for multiple cancer types (Li 2024 colorectal, Wu 2025 pancreatic), one clinical study showing efficacy after checkpoint inhibitor resistance (Wang 2022), and a 2026 review summarizing clinical trial hazard ratios. The biological mechanisms are well-defined and specific. The human clinical evidence is early-stage, comes from small studies, and has not been validated in large prospective trials. No major oncology organization currently recommends adding mushroom supplements to checkpoint inhibitor therapy, and cancer patients should discuss any supplement use with their oncologist given the potential for immune modulation interactions.

Sources & References

1. 1RTHM-01171·Bi, Sixue et al. (2020). “Cordyceps militaris polysaccharide converts immunosuppressive macrophages into M1-like phenotype and activates T lymphocytes by inhibiting the PD-L1/PD-1 axis between TAMs and T lymphocytes..” International journal of biological macromolecules.Study breakdown →PubMed →↩
2. 2RTHM-02222·Ameri Shah Reza, Mahdieh et al. (2026). “Beta-glucans in oncology: revolutionizing treatment with immune power & tumor targeting..” Naunyn-Schmiedeberg's archives of pharmacology.Study breakdown →PubMed →↩
3. 3RTHM-00089·Fisher, Monte et al. (2002). “Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy..” Anticancer research.Study breakdown →PubMed →↩
4. 4RTHM-01930·Li, Wenshuai et al. (2024). “Ganoderma lucidum Polysaccharide Supplementation Significantly Activates T-Cell-Mediated Antitumor Immunity and Enhances Anti-PD-1 Immunotherapy Efficacy in Colorectal Cancer..” Journal of agricultural and food chemistry.Study breakdown →PubMed →↩
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