Tumour‐associated macrophages (TAMs), which possess M2‐like characters and are derived from immature monocytes in the circulatory system, represent a predominant population of inflammatory cells in solid tumours. TAM infiltration in tumour microenvironment can be used as an important prognostic marker in many cancer types and is a potential target for cancer prevention or treatment. VEGI‐251 not only is involved in the inhibition of tumour angiogenesis, but also participates in the regulation of host immunity. This work aimed to investigate the involvement of VEGI‐251 in the regulation of specific antitumour immunity. We found that recombinant human VEGI‐251(rhVEGI‐251) efficiently mediated the elimination of TAMs in tumour tissue in mice, and induced apoptosis of purified TAMs in vitro. During this process, caspase‐8 and caspase‐3 were activated, leading to PARP cleavage and apoptosis. Most importantly, we further elucidated the mechanism underlying VEGI‐251‐triggered TAM apoptosis, which suggests that ASK1, an intermediate component of the VEGI‐251, activates the JNK pathway via TRAF2 in a potentially DR3‐dependent manner in the process of TAM apoptosis. Collectively, our findings provide new insights into the basic mechanisms underlying the actions of VEGI‐251 that might lead to future development of antitumour therapeutic strategies using VEGI‐251 to target TAMs.

中文翻译：

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肿瘤相关巨噬细胞作为 VEGI-251 在癌症治疗中的新靶点。

肿瘤相关巨噬细胞 (TAM) 具有 M2 样特征，来源于循环系统中的未成熟单核细胞，是实体瘤中炎症细胞的主要群体。肿瘤微环境中的 TAM 浸润可作为许多癌症类型的重要预后标志物，是癌症预防或治疗的潜在靶点。VEGI-251不仅参与抑制肿瘤血管生成，还参与调节宿主免疫。这项工作旨在调查 VEGI-251 在调节特异性抗肿瘤免疫中的作用。我们发现重组人 VEGI-251 (rhVEGI-251) 可有效介导小鼠肿瘤组织中 TAMs 的消除，并在体外诱导纯化的 TAMs 凋亡。在这个过程中，caspase-8 和 caspase-3 被激活，导致 PARP 裂解和凋亡。最重要的是，我们进一步阐明了 VEGI-251 触发 TAM 凋亡的机制，这表明 ASK1（VEGI-251 的中间成分）在 TAM 凋亡过程中以潜在的 DR3 依赖性方式通过 TRAF2 激活 JNK 通路. 总的来说，我们的研究结果为 VEGI-251 作用的基本机制提供了新的见解，这可能导致未来使用 VEGI-251 靶向 TAM 的抗肿瘤治疗策略的发展。