Natural polysaccharides in pancreatic cancer therapy: From immunomodulation and gut microbiota regulation to metabolic intervention.

Natural polysaccharides derived from plants, fungi, macroalgae, cyanobacteria, and other marine microorganisms have attracted increasing interest as adjuvant candidates for pancreatic cancer management due to their biocompatibility, structural diversity, and multi-target activities. This review consolidates current knowledge on their anti-pancreatic cancer activities, integrating findings from in vitro, in vivo, and mechanistic studies. We delineate the multi-level regulatory networks through which polysaccharides exert anti-tumor effects via four interconnected mechanisms: direct actions on cancer cells including proliferation inhibition, apoptosis and ferroptosis induction, cell cycle arrest, metastasis suppression, and autophagy modulation; immunomodulation via M1 macrophage polarization, natural killer cell activation, and cytotoxic T lymphocyte mediated killing; restoration of gut microbial homeostasis through beneficial taxa enrichment, intestinal barrier integrity enhancement, short-chain fatty acid elevation, and lipopolysaccharide driven inflammation reduction; and indirect tumor suppression by ameliorating obesity and type 2 diabetes mellitus. The polysaccharide gut microbiota axis emerges as a critical hub integrating these pathways. Structure-activity relationship analysis indicates that low molecular weight, high galacturonic acid content, arabinose and galactose richness, and sulfation may influence activity, although robust attribution requires structurally defined polysaccharides. More than twenty well characterized polysaccharides are documented, with several showing synergistic effects with chemotherapeutics. Despite encouraging preclinical evidence, challenges remain in structural characterization, bioavailability, and clinical validation.