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