From macrofungal polysaccharides to precision microbial immunotherapy: reprogramming the tumor microenvironment through immunometabolic and gene-regulatory pathways

Abstract

Engineered microbial immunotherapies can localize immune-modulating signals within solid tumors, where hypoxia, suppressive myeloid cells, deficient antigen presentation, and dysfunctional T-cell trafficking often limit immunotherapy. Macrofungal polysaccharides, especially structurally defined β-glucans, offer mechanistic templates rather than interchangeable drug substances for source-specific, structure-controlled immune engineering programs. Their activity depends on linkage, branching, molecular mass, conformation, solubility, aggregation, and physical presentation. Critically, the strongest Dectin-1 and trained-immunity evidence discussed here uses particulate β-glucans from Saccharomyces cerevisiae; those findings cannot be assigned directly to macrofungal β-glucans without material-specific comparison. We therefore distinguish four engineering architectures: de novo microbial biosynthesis of a defined β-glucan, microbial surface display, delivery of a pre-characterized β-glucan cargo, and delivery of non-glycan payloads that mimic the desired downstream immune program. Because therapeutic bacteria have not yet been shown to reproduce a macrofungal β-glucan with controlled linkage, branching, conformation, and presentation, near-term development should prioritize standardized cargo delivery or pathway mimicry. In pancreatic and colorectal cancer models, yeast whole-glucan particles have altered myeloid trafficking or generated epigenetically and metabolically trained macrophages linked to CXCL9/CXCL10 production, natural killer-cell recruitment, conventional type 1 dendritic-cell accumulation, and stronger CD8 T-cell responses. Human evidence remains preliminary and cannot establish β-glucan-specific efficacy in uncontrolled combination studies. This Perspective proposes source-resolved material characterization, receptor and cell-state testing, multidimensional pharmacodynamic biomarkers, and microbial safety controls as prerequisites for translating fungal-inspired immune programs into precision cancer therapeutics.