Polysaccharide-mediated modulation of gut microbiota and lysine lactylation: implications for tumor microenvironment remodeling and cancer immunotherapy
- 1Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina , , ,
- 2Beijing Key Laboratory of New Drug Discovery based on Classic Chinese Medicine Prescription, Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College , ,
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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BibTeX
@article{yang2026polysaccharidemediated,
title = {{Polysaccharide-mediated modulation of gut microbiota and lysine lactylation: implications for tumor microenvironment remodeling and cancer immunotherapy}},
author = {Siwei Yang and Dongmei Long and Weixuan Qiu and Susan L. Morris‐Natschke and Guoxu Ma and Xudong Xu and Zijian Zhao and Yuanxiang Li and Qiongyu Zou and Haifeng Wu},
journal = {Frontiers in immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1924150},
url = {https://europepmc.org/article/PMC/PMC13670173},
note = {CC BY},
}
RIS
TY - JOUR
TI - Polysaccharide-mediated modulation of gut microbiota and lysine lactylation: implications for tumor microenvironment remodeling and cancer immunotherapy
AU - Siwei Yang
AU - Dongmei Long
AU - Weixuan Qiu
AU - Susan L. Morris‐Natschke
AU - Guoxu Ma
AU - Xudong Xu
AU - Zijian Zhao
AU - Yuanxiang Li
AU - Qiongyu Zou
AU - Haifeng Wu
PY - 2026
DA - 2026/10/01
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1924150
UR - https://europepmc.org/article/PMC/PMC13670173
AB - 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.
SN - 1664-3224
ER -