Saccharina japonica derived fucoidan potentiates immune checkpoint blockade therapy by modulating the survival and differentiation fate of myeloid-derived suppressor cells.

Immunotherapy has revolutionized cancer treatment paradigms due to its high specificity, favorable safety profile, and remarkable clinical efficacy. Immune checkpoint blockade (ICB) therapy has been widely adopted in clinical practice for various malignancies. Unfortunately, its limited response rates restrict broader application. Myeloid-derived suppressor cells (MDSCs) serve as key mediators of ICB resistance. In this study, we demonstrated that fucoidan extracted from Saccharina japonica LMWF modulated MDSCs activity to sensitize tumors to ICB therapy. Mechanistically, LMWF activated the TLR7-IRF7/STAT1 signaling axis to drive MDSCs differentiation into M1 macrophages while impairing MDSCs survival. LMWF treatment downregulated immunosuppressive mediators in MDSCs, promoted cancer cell apoptosis, and suppressed tumor cell migration and angiogenesis. In vivo studies revealed that LMWF- modulated MDSCs suppressed tumor progression through dual mechanisms: (i) immunological remodeling of the immunosuppressive tumor microenvironment (TME) and (ii) non-immunological inhibition of angiogenesis, collectively enhancing tumor sensitivity to PD-1 blockade therapy. Collectively, our work unveiled a novel strategy whereby LMWF, as a TLR7 agonist, synergizes with ICB therapy to overcome ICB resistance. These findings provide critical insights for overcoming the bottleneck of ICB refractoriness in cancer immunotherapy.