Natural polysaccharides as immune adjuvants to overcome immune checkpoint inhibitor resistance: mechanistic insights, clinical evidence, and translational challenges.

Immune checkpoint inhibitors (ICIs) have redefined the treatment landscape of advanced malignancies, yet primary and acquired resistance severely limits their therapeutic efficacy across most solid tumors. Even in biomarker-stratified patient cohorts, objective response rates frequently fall below 25%. Natural polysaccharides have emerged as a unique category of immune adjuvants. Beyond activating innate immune receptors including Toll-like receptor 4 and downstream MyD88 signaling, such macromolecules remodel the gut microbiota-metabolite axis and partially reverse immunosuppressive tumor microenvironments. Cumulative preclinical findings and early-phase clinical observations suggest synergistic therapeutic benefits for polysaccharide plus ICI combinations. Still, robust evidence from large-scale randomized Phase III trials remains absent, and polysaccharides cannot yet be validated as standard adjuvants to resolve ICI resistance. In this review, we systematically dissect the structural basis governing polysaccharide immunomodulation and elaborate four core mechanisms for overcoming immunotherapy resistance: repolarizing tumor-associated macrophages toward anti-tumor phenotypes, alleviating CD8+ T cell exhaustion, regulating bidirectional gut microbiota-immune crosstalk, and inhibiting tumor-intrinsic immune escape cascades. We further summarize persistent translational bottlenecks: structural heterogeneity, nonstandard quality control, low oral bioavailability, and inconsistent clinical trial protocols, and conduct a head-to-head comparison between polysaccharides and mainstream immunostimulants (CpG oligodeoxynucleotides, STING agonists, fecal microbiota transplantation). Advanced technical tools including AI-assisted glycomics and graph neural networks, alongside synthetic biology platforms, provide new solutions to resolve structural identification and mass-production limitations. Integrating polysaccharide production with Industry 6.0 intelligent manufacturing and circular bioeconomy models can balance therapeutic development and global sustainable development targets. Finally, we propose a precision medicine workflow incorporating multi-layer biomarkers (gut microbial profiles, intratumoral immune signatures, glycomic fingerprints) to optimize patient stratification and individualized dosing. Rather than presenting rigid standardized treatment schemes, this review constructs a realistic, mechanism-guided roadmap to accelerate the clinical translation of natural polysaccharide ICI adjuvants.