Polysaccharides-mediated mitochondrial remodeling: role in chemotherapy resistance of gastrointestinal tumors.

BACKGROUND: Chemotherapy resistance remains a major clinical challenge in the treatment of gastrointestinal (GI) cancers. Mitochondrial remodeling contributes to chemoresistance through several interconnected functional modules, including metabolic reprogramming, elevation of the apoptotic threshold, adjustment of the reactive oxygen species setpoint, and mitophagy-mediated mitochondrial quality control. Polysaccharides and polysaccharide-based systems may represent promising candidates for modulating mitochondria-associated dysfunctions because of their structural diversity, biological activity, and generally favorable biocompatibility in specific experimental settings.

PURPOSE: This review aimed to systematically summarize the molecular mechanisms by which mitochondrial remodeling contributes to chemotherapy resistance in GI tumors and to evaluate the potential of polysaccharides and polysaccharide-based systems as therapeutic candidates for modulating these mitochondrial abnormalities.

METHODS: This PRISMA-guided systematic review with qualitative evidence synthesis searched PubMed and Web of Science from database inception to July 4, 2026. The search strategy covered terms related to polysaccharides and polysaccharide-based delivery systems, GI tumors, chemoresistance or chemosensitization, and mitochondria-related mechanisms. Records were deduplicated and screened according to predefined eligibility criteria. Core eligible studies were original experimental studies that investigated polysaccharide or polysaccharide-based interventions in GI tumor models, reported chemotherapy-related outcomes, and included endpoints related to mitochondria, redox regulation, apoptosis, autophagy, metabolism, or the tumor microenvironment. Because of substantial heterogeneity in polysaccharide sources, tumor models, chemotherapeutic agents, intervention formats, and mechanistic endpoints, the evidence was synthesized qualitatively rather than by meta-analysis.

RESULTS: The search identified 652 records, including 322 from PubMed and 330 from Web of Science. After removal of 174 duplicate records, 478 records were screened. Full texts were sought for 75 reports, of which 20 could not be retrieved. Ultimately, 55 reports were assessed for eligibility; one retracted article and 34 reports that did not meet the core eligibility criteria were excluded. In total, 20 studies were included in the core evidence synthesis. These studies supported the involvement of polysaccharides or polysaccharide-based systems in modulating chemotherapy responses in GI tumors through several mitochondria-related mechanisms, including metabolic remodeling, regulation of the apoptotic threshold, modulation of redox status, and autophagy/mitophagy-associated adaptation. Additional mechanistic and contextual evidence suggested that polysaccharide-based delivery platforms and gut microenvironment modulation may influence drug accumulation, chemotherapy-related toxicity, and therapeutic sensitivity.

CONCLUSIONS: Current evidence, mainly from preclinical studies, suggests that polysaccharides and polysaccharide-based systems may help modulate chemotherapy resistance in GI cancers by targeting mitochondria-related pathways. However, clinical translation remains limited by heterogeneity in polysaccharide structure, incomplete pharmacokinetic characterization, limited human evidence, and insufficient standardization of intervention models. Future studies should prioritize structural characterization, mechanism-guided validation, pharmacokinetic evaluation, and well-designed clinical studies to clarify their therapeutic value.