肿瘤进展和治疗反应受到肿瘤微环境（TME）中癌细胞与周围环境相互作用的严重影响。许多与此相互作用有关的可溶性因子和信号受体由脱粘蛋白和金属蛋白酶（ADAMs）进行抑制。ADAM15的上调与癌症患者的较差生存率和体外以及小鼠癌模型中的肿瘤促进功能有关。尽管ADAM15参与细胞间和细胞与细胞外基质间的相互作用，但其在体内癌细胞与TME之间的相互作用的作用尚未被探究。因此，我们的目标是了解ADAM15如何调节TME的细胞组成以及其对肿瘤进展的影响。我们在直肠癌患者的肿瘤组织中显示了ADAM15的上调。在同种移植模型的小鼠中，皮下注射野生型和ADAM15敲除CT26结肠癌细胞证实了ADAM15的促肿瘤作用。肿瘤的分析显示了ADAM15缺失肿瘤中更高的免疫细胞浸润和癌细胞凋亡。具体来说，ADAM15缺失导致颗粒细胞数量减少，抗原呈递细胞包括树突状细胞和巨噬细胞的浸润增加，以及更多的T细胞。通过体外实验，我们证实了ADAM15对巨噬细胞迁移的调节作用，并确定了ADAM15衍生的CYR61可能是其调节作用的分子介导物。根据这些发现，我们推测靶向ADAM15可能会增加结直肠肿瘤中免疫细胞的浸润，这是有效免疫疗法的前提条件。© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Tumor progression and response to treatment are highly affected by interactions between cancer cells and the tumor microenvironment (TME). Many of the soluble factors and signaling receptors involved in this crosstalk are shed by a disintegrin and metalloproteinases (ADAMs). Upregulation of ADAM15 has been linked to worse survival in cancer patients and a tumor-promoting function both in vitro and in murine cancer models. Although ADAM15 has been involved in cell-cell and cell-extracellular matrix interactions, its role in the crosstalk between cancer cells and the TME in vivo remains unexplored. Therefore, we aimed to understand how ADAM15 regulates the cell composition of the TME and how it affects tumor progression. Here, we showed an upregulation of ADAM15 in tumor tissues from rectal cancer patients. Subcutaneous injection of wildtype and ADAM15-knockout CT26 colon cancer cells in syngeneic mice confirmed the protumorigenic role of ADAM15. Profiling of tumors revealed higher immune cell infiltration and cancer cell apoptosis in the ADAM15-deficient tumors. Specifically, loss of ADAM15 led to a reduced number of granulocytes and higher infiltration of antigen-presenting cells, including dendritic cells and macrophages, as well as more T cells. Using in vitro assays, we confirmed the regulatory effect of ADAM15 on macrophage migration and identified ADAM15-derived CYR61 as a potential molecular mediator of this effect. Based on these findings, we speculate that targeting ADAM15 could increase the infiltration of immune cells in colorectal tumors, which is a prerequisite for effective immunotherapy.© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.