Deciphering immunoregulatory mechanisms and structure-guided biosynthesis of β-glucans

As one of the most well-studied natural bioactive polysaccharides, β-glucans are widely applied in health foods, pharmaceuticals, skincare products, and animal feed. According to Future Market Insights, the β-glucan industry is growing rapidly, with its market size projected to reach $2.3 billion by 2033. Immunomodulation is one of the primary bioactivities of β-glucans, and their applications in tumor adjuvant therapy, infection prevention, and vaccine adjuvants are gaining increasing attention. This review provides a comprehensive synthesis of the current understanding of β-glucans, covering their sources, structural diversity, intestinal absorption, pharmacokinetics, multifaceted immunoregulatory mechanisms, and strategies of efficient biosynthesis. Moreover, we dissected their bidirectional immunomodulatory properties and significant role in inducing trained immunity, alongside the gut microbiota-dependent and -independent mechanisms underlying their actions. Furthermore, we examined the current advances in the structure-activity relationships of β-glucans and the cutting-edge strategies for structure-guided biosynthesis through genetic engineering and culture optimization. Finally, we identified key knowledge gaps in molecular mechanism research and efficient biosynthesis technologies, offering strategic insights and perspectives to advance the fundamental research of β-glucans and their industrial-scale production and applications.