Fungal β-D-Glucans: Versatile Agents in Immune Modulation, Tumor Suppression, and Nanomedicine Advances

Introduction/Objective: β-D-Glucans, natural polysaccharides abundant in fungal cell walls, have emerged as promising immunomodulatory and antitumor biomaterials due to their unique triple-helix structure and excellent biocompatibility. Their structural versatility—defined by β-1,3/1,6-glycosidic linkages, branching patterns, and conformational transitions—enables precise optimization for targeted cancer therapy, overcoming the limitations of conventional chemotherapeutics. This article provides a comprehensive review of the structural characteristics, preparation methodologies, pharmacological functions, and underlying mechanisms of fungal β-D-glucans. Methods: A systematic review of peer-reviewed literature was conducted to delineate the structure–activity relationships of fungal β-D-glucans, with a focus on extraction methodologies, antitumor mechanisms, and nanodrug delivery applications. Results: β-D-glucans exhibit dual antitumor efficacy: (1) Direct tumoricidal effects via induction of G1/S-phase cell cycle arrest, suppression of metastasis, and oxidative stress-mediated apoptosis; (2) Immunomodulatory effects by reprogramming Tumor-Associated Macrophages (TAMs) and exerting synergistic effects with Immune Checkpoint Inhibitors (ICIs). Nano-formulations based on β-D-glucans improve targeted delivery efficiency and overcome bioavailability barriers, achieving a 3-fold higher tumor accumulation than free drugs in murine models. Discussion: Fungal β-D-glucans represent a promising therapeutic platform that integrates direct tumor cytotoxicity and immune activation for next-generation cancer treatment. Although the safety and regulatory framework for glucan-based nanomedicines is still evolving, it is imperative to prioritize the clinical development of nanoparticle- based glucan delivery systems and explore optimized synergistic combination strategies to address the key challenges of tumor heterogeneity and drug resistance. Conclusion: The unique triple-helix structure renders them excellent nanocarriers to enhance targeted drug delivery and combination therapeutic efficacy. The current clinical translation of fungal β-D-glucans is limited by the lack of standardized extraction protocols, structural variation across different fungal sources, and insufficient safety evaluation. Future research should focus on optimizing the oral delivery system of β-D-glucans and developing novel combination strategies to overcome drug resistance and accelerate their clinical translation.