Yi Wang,Yabin Ding,Xiaomei Wei,Wenxiu Tian,Wenxiang Zheng,Yongliang Liu,Chuanqin Shi,Xinxin Xiang
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.
Ye Qian-Ni,Zhu Long,Liang Jie,Zhao Dong-Kun,Tian Tai-Yu,Fan Ya-Nan,Ye Si-Yi,Liu Hua,Huang Xiao-Yi,Cao Zhi-Ting,Shen Song,Wang Jun
The functions of natural killer (NK) and T cells in innate and adaptive immunity, as well as their functions in tumor eradication, are complementary and intertwined. Here we show that utilization of multi-specific antibodies or nano-antibodies capable of simultaneously targeting both NK and T cells could be a valuable approach in cancer immunotherapy. Here, we introduce a tri-specific Nano-Antibody (Tri-NAb), generated by immobilizing three types of monoclonal antibodies (mAbs), using an optimized albumin/polyester composite nanoparticle conjugated with anti-Fc antibody. This Tri-NAb, targeting PDL1, 4-1BB, and NKG2A (or TIGIT) simultaneously, effectively binds to NK and CD8 + T cells, triggering their activation and proliferation, while facilitating their interaction with tumor cells, thereby inducing efficient tumor killing. Importantly, the antitumor efficacy of Tri-NAb is validated in multiple models, including patient-derived tumor organoids and humanized mice, highlighting the translational potential of NK and T cell co-targeting.
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