Polysaccharide-mediated modulation of gut microbiota and lysine lactylation: implications for tumor microenvironment remodeling and cancer immunotherapy.

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.