Tumor-associated macrophages (TAMs) are a set of macrophages in the tumor microenvironment. They play an important role in mediating tumor angiogenesis, metastasis and immune evasion. Delivery of therapeutic agents to eliminate TAMs can be a promising strategy for cancer immunotherapy. In this study, we developed a bisphosphonate-glucomannan conjugate that could efficiently target and specifically eliminate TAMs in the tumor microenvironment. We employed the polysaccharide from Bletilla striata (BSP), a glucomannan affinitive for macrophages that express abundant mannose receptors, to conjugate alendronate (ALN), a bisphosphonate compound with in vitro macrophages-inhibiting activities. In both in vitro and in vivo tests, the ALN-BSP conjugate could preferentially accumulate in macrophages and induce apoptosis. In the subcutaneous S180 tumor-bearing mice model, the treatment using ALN-BSP effectively eliminated TAMs, remarkably inhibited angiogenesis, recovered local immune surveillance, eventually suppressed tumor weight and improved animal survival, without eliciting any side effects such as systematic immune response. Interestingly, ALN alone failed to exhibit any anti-TAMs activity in vivo, probably because this compound was susceptible to the mildly acidic tumor microenvironment, while when conjugated with BSP, ALN-BSP changed the results. Taken together, these results demonstrate the potential of ALN-BSP as a safe and efficient tool targeted at direct depletion of TAMs for cancer immunotherapy.

腫瘤相關巨噬細胞（TAMs)是腫瘤微環境中的巨噬細胞，它們在腫瘤血管生 成，轉移和免疫逃避中起到重要作用。輸送治療藥物去殺傷 TAMs,將會是一個 腫瘤免疫治療的新方向。 這裏我們合成了一個雙磷酸鹽-葡萄糖甘露聚糖複合物，可以有效並特異地殺傷 腫瘤微環境裏的 TAMs。我們利用與巨噬細胞表面上高表達的甘露糖受體有親 和性的白芨多糖去結合一種能夠有效殺傷體外巨噬細胞的雙磷酸鹽-阿侖膦酸 鈉。在體內，體外實驗中，阿侖膦酸鈉-白芨多糖都能夠有效地靶向巨噬細胞， 並引起細胞凋亡。在皮下註射 S180 的荷瘤小鼠模型中，阿侖膦酸鈉-白芨多糖 能夠在沒有引起副反應的情況下，顯著地殺傷 TAMs,抑制血管新生，恢復原位 免疫監督，最終抑制腫瘤生長，提高動物存活率。而阿侖膦酸鈉單體卻沒有在 體內實驗中表現出 TAMs 的殺傷作用，可能與其在腫瘤微環境中低 pH 失效有 關。綜上所述，結果表明阿侖膦酸鈉-白芨多糖能夠成為直接靶向殺傷 TAMs， 達到腫瘤免疫治療作用的一個安全、有效的工具。 關鍵詞：腫瘤相關巨噬細胞，巨噬細胞甘露糖受體，白芨多糖，雙磷酸鹽。