Targeting 4–1BB with fucoidan from Fucus vesiculosus: A strategy to activate macrophages and remodel the immunosuppressive microenvironment for pancreatic cancer therapy

Pancreatic ductal adenocarcinoma (PDAC) presents a significant clinical challenge due to its high mortality and resistance to chemotherapy. Over the past decade, fucoidan has been explored as a potential treatment for cancers of the lung, breast, bladder, colon, and pancreas. However, investigations into the efficacy of fucoidan within the tumor microenvironment (TME) of pancreatic cancer are scarce, and its governing mechanisms are not fully understood. Herein, fucoidan (Mfu) from Fucus vesiculosus significantly induced the mRNA expression of inflammatory cytokines (interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-ɑ) by real-time fluorescence quantitative PCR (qPCR) in macrophages. RNA spatial transcriptome sequencing and western blotting showed that Mfu specifically targeted the tumor necrosis factor receptor superfamily member 9 (4–1BB), thereby triggering the TNF signaling pathway in RAW 264.7 cells. Mfu-activated macrophages indirectly elicited the apoptosis and G1-phase arrest of PAN02 cells, as shown by apoptotic protein detection and flow cytometry, suggesting a regulatory effect on pancreatic cancer cell death. In a PDAC allograft model in mice, Mfu (100–400 mg/kg/day, oral gavage) exhibited robust anti-tumor efficacy. Besides, immunohistochemistry (IHC) revealed that Mfu targeted 4–1BB specifically to activate macrophages within the TME. By engaging with the 4–1BB receptor and activating macrophages, Mfu offers a promising strategy to advance the development of pancreatic cancer immunotherapy.