Beta-Glucans and Checkpoint Inhibitors: Combo Research

Mushroom Immunotherapy

86.7% tumor suppression

A beta-glucan-conjugated anti-PD-L1 antibody achieved 86.7% tumor suppression in a preclinical mouse model of colorectal cancer.

Liu et al., Carbohydrate Polymers, 2024

PD-L1 Paradox

beta-glucans may upregulate immune checkpoints

Trained Immunity

oral beta-glucans reprogram bone marrow

TME Remodeling

shifts fatty acid composition in tumors

Liu et al., Carbohydrate Polymers, 2024

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Checkpoint inhibitors have transformed cancer treatment by releasing the brakes on immune cells that tumors suppress. Beta-glucans from mushrooms activate the same immune cells that checkpoint inhibitors unleash. The logic of combining them is straightforward: beta-glucans prime the anti-tumor immune response, and checkpoint inhibitors prevent tumors from shutting it down. Early preclinical and clinical data suggest this logic holds up in practice, with one study achieving 86.7% tumor suppression using a beta-glucan-conjugated anti-PD-L1 antibody in mice. But the picture is more complicated than simple addition. Beta-glucans themselves can upregulate PD-L1 expression on immune cells, creating a paradox that only the combination resolves.

For the foundational mechanisms of beta-glucan anti-tumor immunity, see beta-glucans and anti-tumor immunity. For how beta-glucans reach the immune system, see beta-glucan bioavailability.

Why Checkpoint Inhibitors Need an Immune Boost

Checkpoint inhibitors work by blocking proteins (PD-1, PD-L1, CTLA-4) that tumors use to suppress T cell activity. Anti-PD-1 drugs like pembrolizumab and nivolumab, and anti-PD-L1 drugs like atezolizumab, have produced remarkable responses in melanoma, lung cancer, and other malignancies. But response rates are often only 20-40%. Most patients do not respond, typically because their tumors have a "cold" immune microenvironment with insufficient immune cell infiltration.

This is where beta-glucans enter the picture. If checkpoint inhibitors remove the brakes, beta-glucans may step on the accelerator. Chan et al. (2009) documented how beta-glucans act on Dectin-1, complement receptor 3 (CR3), and TLR-2/6 to trigger macrophages, neutrophils, monocytes, NK cells, and dendritic cells, modulating both innate and adaptive immune responses.^[1] After oral administration, macrophages in Peyer's patches internalize and fragment beta-glucans, then transport the fragments to bone marrow and the reticular system, where they are released to activate other immune cells systemically.^[1]

Jin et al. (2018) reviewed beta-glucans specifically as immunoadjuvants, noting that they can connect innate and adaptive immunity and improve the immunogenicity of other treatments. The receptors involved include Dectin-1, CR3, CD5, and lactosylceramide.^[2]

The rationale for combination therapy: beta-glucans recruit and activate immune cells in the tumor microenvironment (turning a "cold" tumor "hot"), while checkpoint inhibitors prevent the tumor from suppressing those newly activated cells.

The PD-L1 Paradox: Beta-Glucans May Activate a Brake

Recent preclinical research has revealed a complication. When beta-glucans activate immune cells, some of those activated cells upregulate PD-1/PD-L1 expression. This creates a self-limiting loop: the very immune activation that beta-glucans trigger also engages the checkpoint pathway that tumors exploit for immune evasion.

In melanoma mouse models, researchers found that beta-glucan treatment converted tumor-recruited CD11b+ cells from an immunosuppressive to an immunopromotive phenotype. But the same treatment also enhanced PD-1/PD-L1 expression on those CD11b+ cells. The upregulated PD-L1 could then induce co-inhibitory signals in T cells, leading to T cell apoptosis and potentially counteracting the anti-tumor benefit.

This paradox is precisely why the combination with checkpoint inhibitors is logical rather than merely additive. PD-1/PD-L1 blockade removes the self-limiting brake that beta-glucan activation inadvertently engages, allowing the full anti-tumor potential of the beta-glucan-activated immune cells to persist.

Preclinical Combination Results

The most striking preclinical result comes from a 2024 study that constructed beta-glucan-conjugated anti-PD-L1 antibody conjugates (AGC) using click chemistry. In an MC38 colorectal tumor-bearing mouse model, AGC achieved a tumor suppression rate of 86.7%. The conjugation strategy delivered beta-glucan directly into the tumor microenvironment while simultaneously blocking PD-L1, and the bridging effect promoted interaction between tumor cells and dendritic cells, enhancing immunotherapeutic benefit.

Additional preclinical evidence shows that whole glucan particle (WGP) beta-glucan combined with PD-1/PD-L1-blocking antibodies increased recruitment of immune cells, improved T cell activation balance, and delayed tumor progression in multiple mouse models.

A pancreatic cancer model demonstrated that beta-glucan combined with anti-PD-L1 reversed the immunosuppressive tumor microenvironment following ablation therapy, enhancing anti-tumor responses and prolonging survival in mice with orthotopic tumors.

These preclinical results are promising but come with standard caveats: mouse tumor models do not reliably predict human responses, and the doses, schedules, and beta-glucan preparations used vary across studies, making direct comparison difficult.

Trained Immunity: A Longer-Term Mechanism

Case et al. (2024) demonstrated a mechanism that may extend the value of beta-glucans beyond their immediate immune-activating effects. Mice given oral whole mushroom powder from Agaricus bisporus showed alterations in bone marrow hematopoietic stem and progenitor cell dynamics, shifting toward myeloid-committed multipotent progenitor cells.^[3]

Macrophages derived from the bone marrow of these mice displayed enhanced responses to restimulation, particularly to TLR2 ligands. This trained response was modest compared to yeast-derived beta-glucans but correlated with available beta-glucan content and was boosted by enrichment.^[3] Simulated digestion of the mushroom powder retained beta-glucans and preserved the ability to train human monocytes in culture.^[3]

For checkpoint inhibitor combinations, trained immunity is relevant because it creates a more reactive baseline immune state. Patients with trained immunity in their myeloid compartment may have innate immune cells that are already primed to respond when checkpoint blockade releases the brakes on adaptive immunity.

Tumor Microenvironment Remodeling

Beta-glucans do not just activate immune cells in circulation. They reshape the local tumor microenvironment. Xu et al. (2024) showed that Agaricus blazei murill polysaccharide (ABMP) promoted CD8+ T cell activity and enhanced cancer-killing function in co-culture systems (P < 0.05). In vivo, ABMP inhibited the growth of intraperitoneal colorectal tumors, though not subcutaneous ones.^[4]

Metabolic analysis revealed that ABMP reduced lipid-related signals in the peritoneal tumor microenvironment and increased omega-3 polyunsaturated fatty acid content.^[4] The researchers concluded that this fatty acid remodeling may promote T cell function and represent an important mechanism of anti-tumor action.^[4]

Guo et al. (2021) demonstrated a complementary pathway: Ganoderma lucidum polysaccharide modulated gut microbiota composition and immune cell function to inhibit inflammation and tumorigenesis in a colon cancer model, showing that beta-glucans can act on the tumor microenvironment indirectly through the gut-immune axis.^[5]

For checkpoint inhibitor therapy, tumor microenvironment remodeling is critical. A metabolically favorable, immune-infiltrated microenvironment is precisely what distinguishes "hot" tumors (which respond to checkpoint inhibitors) from "cold" tumors (which do not).

Macrophage Polarization as a Combination Target

Tumor-associated macrophages polarized toward the M2 phenotype promote tumor growth and immune evasion. Nilkhet et al. (2024) demonstrated that crude polysaccharides from Auricularia polytricha shifted macrophages from M0 toward M1 phenotype, with high CD86 expression, increased IL-6, IL-1beta, and TNF-alpha production, and NF-kB pathway activation that correlated with beta-glucan content.^[6]

These M1-polarized macrophages inhibited breast cancer cell invasion and induced apoptosis in MCF-7 and MDA-MB-231 cell lines.^[6] For combination therapy, this M2-to-M1 shift addresses one mechanism of checkpoint inhibitor resistance: when the tumor microenvironment is dominated by immunosuppressive M2 macrophages, even checkpoint blockade cannot generate an effective T cell response because the macrophages are actively sabotaging it.

Batbayar et al. (2012) noted that Dectin-1 on macrophages performs dual functions: internalizing beta-glucan particles and transmitting activation signals to the nucleus.^[7] This dual capacity means macrophage polarization and antigen processing happen through the same receptor engagement, making beta-glucans particularly efficient at converting the macrophage population within a tumor from immunosuppressive to immunoactive. For related species-specific research, see Agaricus blazei and NK cell activation.

Early Clinical Signals

A 2022 observational study examined 13 patients with advanced cancer who had previously discontinued anti-PD-1/PD-L1 therapy due to disease progression. When beta-glucan was added to retreatment with PD-1/PD-L1 inhibitors, the combination appeared to improve progression-free survival. The study proposed that beta-glucan could function as an immune adjuvant to reverse anti-PD-1/PD-L1 resistance by reactivating the suppressed immune system.

A 2024 case series using beta-glucan combined with the PD-L1 inhibitor envafolimab and the anti-angiogenic agent endostar showed efficacy and safety as an immune rechallenge strategy in metastatic non-small cell lung cancer patients who had previously failed anti-PD-1 therapy, particularly in PD-L1-positive patients.

Steimbach et al. (2021) systematically reviewed 16 clinical trials of fungal beta-glucans as cancer treatment adjuvants, involving 1,650 patients across 9 cancer types. Beta-glucan was safe and well-tolerated in all trials. Most showed reduced immune depression from chemotherapy and/or faster white blood cell recovery.^[8] The methodological diversity across trials prevented pooled statistical analysis, and some trials found no statistical difference between groups.^[8]

Timm et al. (2023) reviewed the broader immunotherapy applications of mushroom beta-glucans, noting their potential as adjuvants in both cancer treatment and vaccine enhancement, though they noted that studies on industry applications remain limited compared to the basic science literature.^[9]

Where This Research Stands

The combination of beta-glucans with checkpoint inhibitors is an active area of preclinical research with early-stage clinical signals. The mechanistic rationale is strong: beta-glucans activate the immune cells that checkpoint inhibitors protect. The PD-L1 paradox (beta-glucans upregulating the very checkpoint they are meant to overcome) makes the combination more logical than either approach alone. Preclinical results showing 86.7% tumor suppression with conjugated delivery are compelling.

But the evidence base has clear limits. Most data comes from mouse models. The clinical signals come from small, non-randomized studies. No large Phase III trial has tested mushroom beta-glucans combined with checkpoint inhibitors. The optimal beta-glucan source, dose, preparation, and schedule for combination therapy are unknown. And the difference between tumor types that respond to this combination and those that do not is still being defined.

For other approaches to mushroom-based cancer research, see can mushrooms make immunotherapy more effective and mushroom compounds and anti-PD-1 therapy.

The Bottom Line

Combining beta-glucans with checkpoint inhibitors addresses a biological paradox: beta-glucans activate anti-tumor immune cells but can also upregulate PD-L1, which tumors exploit for immune evasion. Checkpoint blockade removes this self-limiting brake. Preclinical studies show tumor suppression rates up to 86.7% with conjugated delivery, and early clinical data suggest the combination may help overcome anti-PD-1 resistance. Large randomized trials are needed before clinical conclusions can be drawn, but the mechanistic logic and preclinical evidence make this one of the more promising directions in mushroom immunotherapy research.

Frequently Asked Questions

Can beta-glucans improve checkpoint inhibitor therapy?

Preclinical evidence suggests yes. Beta-glucans recruit and activate immune cells in the tumor microenvironment, potentially converting "cold" tumors into "hot" tumors that respond to checkpoint blockade. A beta-glucan-conjugated anti-PD-L1 antibody achieved 86.7% tumor suppression in a mouse colorectal cancer model. Small human studies have shown early signals of improved progression-free survival.

What is the PD-L1 paradox with beta-glucans?

Beta-glucans activate immune cells, but that activation can also upregulate PD-1/PD-L1 expression on the activated cells. This creates a self-limiting loop where the immune response beta-glucans trigger is partially suppressed by the very checkpoint pathway tumors exploit. Combining beta-glucans with PD-1/PD-L1 inhibitors addresses this by blocking the self-limiting brake while maintaining the immune activation.

Are mushroom supplements used alongside immunotherapy?

No mushroom beta-glucan supplement is approved as an immunotherapy adjuvant in Western medicine. A systematic review of 16 clinical trials found fungal beta-glucan adjuvant therapy was safe and well-tolerated alongside chemotherapy, but evidence for checkpoint inhibitor combinations remains at the preclinical and early clinical stage. Patients should discuss any supplement use with their oncology team.

How do beta-glucans change the tumor microenvironment?

Beta-glucans remodel the tumor microenvironment through multiple mechanisms: polarizing macrophages from immunosuppressive M2 to anti-tumor M1 phenotype, enhancing CD8+ T cell function, shifting fatty acid composition to favor immune activity, and recruiting immune cells into the tumor. These changes may help convert "cold" tumors that resist immunotherapy into "hot" tumors that respond to checkpoint blockade.

What is trained immunity from beta-glucans?

Trained immunity is long-term reprogramming of innate immune cells. A 2024 study found that oral mushroom powder from Agaricus bisporus shifted bone marrow progenitor cells toward myeloid production in mice. Macrophages from these mice responded more strongly to immune challenges. This baseline immune priming could make checkpoint inhibitor therapy more effective by ensuring a more reactive myeloid compartment.

Which beta-glucan form works best with checkpoint inhibitors?

Preclinical data suggests structured, particulate beta-glucans produce stronger immune activation than soluble fragments. The highest tumor suppression (86.7%) used a chemically conjugated beta-glucan-antibody construct delivered directly to the tumor. No human trial has compared beta-glucan preparations head-to-head in the checkpoint inhibitor context. Source, molecular weight, and delivery method all remain variables under investigation.

Sources & References

1. 1RTHM-00151·Chan, Godfrey Chi-Fung et al. (2009). “The effects of beta-glucan on human immune and cancer cells..” Journal of hematology & oncology.Study breakdown →PubMed →↩
2. 2RTHM-00513·Jin, Yiming et al. (2018). “β-glucans as potential immunoadjuvants: A review on the adjuvanticity, structure-activity relationship and receptor recognition properties..” Vaccine.Study breakdown →PubMed →↩
3. 3RTHM-00867·Case, Sarah et al. (2024). “β-glucans from Agaricus bisporus mushroom products drive Trained Immunity..” Frontiers in nutrition.Study breakdown →PubMed →↩
4. 4RTHM-00916·Xu, Yongzhao et al. (2024). “Preventive intervention with Agaricus blazei murill polysaccharide exerts anti-tumor immune effect on intraperitoneal metastasis colorectal cancer..” International journal of biological macromolecules.Study breakdown →PubMed →↩
5. 5RTHM-00690·Guo, Cuiling et al. (2021). “Ganoderma lucidum polysaccharide modulates gut microbiota and immune cell function to inhibit inflammation and tumorigenesis in colon..” Carbohydrate polymers.Study breakdown →PubMed →↩
6. 6RTHM-00897·Nilkhet, Sunita et al. (2024). “M1 macrophages polarized by crude polysaccharides isolated from Auricularia polytricha exhibit anti-tumor effect on human breast cancer cells..” Scientific reports.Study breakdown →PubMed →↩
7. 7RTHM-00244·Batbayar, Sainkhuu et al. (2012). “Immunomodulation of Fungal β-Glucan in Host Defense Signaling by Dectin-1..” Biomolecules & therapeutics.Study breakdown →PubMed →↩
8. 8RTHM-00719·Steimbach, Laiza et al. (2021). “Fungal beta-glucans as adjuvants for treating cancer patients - A systematic review of clinical trials..” Clinical nutrition (Edinburgh.Study breakdown →PubMed →↩
9. 9RTHM-00854·Timm, Thaynã Gonçalves et al. (2023). “Mushroom β-glucans: application and innovation for food industry and immunotherapy..” Applied microbiology and biotechnology.Study breakdown →PubMed →↩