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Natural polysaccharides may synergize with anti-PD-1/PD-L1 immunotherapy through gut microbiota and TME remodelingNatural Polysaccharides May Help Improve Cancer Immunotherapy Results

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Key Takeaway
Note that natural polysaccharides may offer theoretical potential as adjuvants to overcome immune checkpoint inhibitor resistance.

This systematic review examines the role of natural polysaccharides in modulating the tumor microenvironment and potentially enhancing the efficacy of anti-PD-1/PD-L1 immunotherapies. The review focuses on a proposed triple regulatory axis involving gut microbiota composition, lactate homeostasis, and lysine lactylation (Kla) to influence immune-cell functional plasticity.

The authors synthesize findings suggesting that natural polysaccharides may provide synergistic benefits when combined with anti-PD-1/PD-L1 therapies. These findings are primarily supported by preclinical observations rather than clinical trials. The review highlights how these interactions may address current challenges in overcoming resistance to immune checkpoint inhibitors.

Significant limitations include the lack of direct experimental proof validating the complete causal chain between polysaccharide administration and the observed biological effects. Furthermore, the evidence for the conceptual cascade is described as fragmented. Clinical application is currently limited by the lack of large-scale human trials, and the findings are currently considered theoretical foundations for developing new adjuvant therapies.

How this fits prior evidence

This review addresses a gap in the management of cancer by exploring potential adjuvants to overcome resistance to immune checkpoint inhibitors. While prior coverage noted that pembrolizumab reduces death risk by 34% in early-stage triple-negative breast cancer, this review explores a different mechanism to enhance immunotherapy efficacy. The findings regarding polysaccharide-mediated synergy are currently based on preclinical observations and lack the clinical trial data required to confirm a definitive causal link.

Researchers looked into how natural polysaccharides might work alongside common cancer treatments like pembrolizumab and nivolumab. These substances are being studied for their potential to change the environment around tumors and improve how the immune system functions.

Early findings suggest these compounds might help the body better respond to immunotherapy. This is based on preclinical observations, which are studies done in labs rather than in human patients. The research highlights a potential way to help patients whose bodies do not respond well to standard treatments.

It is important to note that this research is still in the early stages. Because the evidence comes from lab studies and the data is currently fragmented, it is not yet clear how this would work in a clinical setting. More human trials are needed to confirm if these benefits are safe and effective for patients.

What this means for you:
Early lab studies suggest polysaccharides may help cancer treatments, but more human research is needed.

Common questions

What are the potential benefits of using polysaccharides in cancer treatment?

Polysaccharides may offer potential synergistic benefits when used with anti-PD-1 and anti-PD-L1 immunotherapies. These are common treatments for cancer. The goal is to help the body overcome resistance to these drugs by improving the immune environment and cell function.

Is this treatment currently available for patients?

No, this research is currently based on preclinical observations and theoretical foundations. Because the evidence is still early and the data is fragmented, it is not yet a standard medical practice. You should talk to your doctor about current treatment options.

What are the limitations of this current research?

The evidence for these benefits is primarily based on lab studies rather than human trials. There is currently a lack of direct experimental proof for the full chain of how these substances work. More research is needed to confirm these findings.

Study Details

Study typeSystematic review
EvidenceLevel 1
PublishedOct 2026
View Original Abstract ↓
Despite the revolutionary clinical benefits of immune checkpoint inhibitors (ICIs), their therapeutic efficacy is largely hampered by the immunosuppressive tumor microenvironment (TME) as well as primary and acquired drug resistance. Natural polysaccharides serve as promising immunomodulators to boost anti-tumor immunity, yet their systematic regulatory network remains poorly characterized. Accumulating evidence demonstrates that gut microbiota and its fermentative metabolites, including short-chain fatty acids and lactate, govern systemic immune surveillance and determine patient responsiveness to ICIs. Meanwhile, lysine lactylation (Kla), a lactate-dependent epigenetic modification, drives glycolytic reprogramming and facilitates tumor immune evasion. This mechanistic review systematically synthesizes current literature and proposes a hypothetical triple regulatory axis: natural polysaccharides act as prebiotics to reshape gut microbial composition and modulate lactate homeostasis, thereby connecting polysaccharide effects, gut microbiota metabolism and lysine lactylation signaling. We comprehensively elaborate how this axis may mediate epigenetic remodeling and immune-cell functional plasticity to reverse TME-derived immunosuppression and confer potential synergistic benefits with anti-PD-1/PD-L1 immunotherapy, benefits so far largely supported by preclinical observations. Notably, although fragmented observational evidence supports this conceptual cascade, direct experimental proof validating the complete causal chain is still lacking. By constructing an integrated metabolic-epigenetic-immune crosstalk framework, this review provides theoretical foundations for developing polysaccharide-based microbiota-targeting adjuvants to overcome ICI resistance. We further summarize major translational bottlenecks and discuss preclinical as well as clinical strategies targeting this cascade to advance tumor immunotherapy.
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