Advancing β-Glucan-Based Immunomodulation and Nanotherapeutic Strategies for Cancer Biotherapy.

β-glucans are structurally diverse polysaccharides from fungi, yeasts, bacteria, and cereals, exhibiting variable branching and molecular weights that shape their biological activity. Emerging preclinical and clinical evidence highlights their ability to modulate innate and adaptive immunity, exerting direct and adjunct antitumor effects via dectin-1, toll-like receptors, and complement receptor 3. Although well known as nutraceuticals, their integration into advanced cancer biotherapeutics, such as monoclonal antibody regimens, cytokine modulation, and nanoparticle delivery, remains in early translation. This review examines the molecular basis of β-glucan-induced immunostimulation, emphasizing how linkage type, branching frequency, triple-helical structure, and source influence receptor engagement and downstream immune responses. Emerging evidence is presented on β-glucan formulation engineering, including β-glucan-coated polymeric nanoparticles and micelles, β-glucan-complexed lipid nanoparticles for nucleic acid delivery, polymersomes with splenic/myeloid avidity, and β-glucan-stabilized nanosuspensions, several of which show enhanced lymphatic targeting, improved drug bioavailability, or reduced tumor growth in preclinical cancer models. Clinical translation is analyzed with attention to dosing protocols, administration routes (oral, intravenous, topical), and the impact of β-glucan adjuvancy in therapeutic antibodies, immunotoxins, and vascular disrupting agents. The review further addresses essential safety and toxicology data, regulatory compliance challenges, and the imperative for rigorous physicochemical standardization to ensure clinical reproducibility and patient safety. β-glucans have emerged as multifunctional immunomodulators and drug delivery enhancers, driving progress toward personalized cancer immunotherapy and innovative combinatorial regimens. Continued interdisciplinary research and harmonization of extraction, characterization, and delivery protocols are paramount for success in precision oncology.