在资源有限和高炎症条件下生存和发展的能力是肿瘤恶性肿瘤的主要驱动因素。在这里，我们鉴定了在黑色素瘤、胰腺癌和前列腺癌小鼠模型的肿瘤边缘诱导的慢周期 ADAM12 PDGFRα 间充质基质细胞 (MSC)。使用诱导谱系追踪和转录组学，我们证明代谢改变的 ADAM12 MSC 通过 Gas6、Lgals3 和 Csf1 等基因的过度表达促进巨噬细胞胞吞作用和极化，从而诱导病理性血管生成和免疫抑制。 ADAM12 细胞的基因耗竭恢复了功能性肿瘤脉管系统，减少了缺氧和酸中毒，并使 CAF 正常化，诱导效应 T 细胞浸润并抑制黑色素瘤和胰腺神经内分泌癌的生长，这一过程依赖于 TGF-β。在人类癌症中，ADAM12 对具有高水平缺氧和先天抵抗机制以及与不良预后和耐药性（例如 AXL）相关的因素的患者进行分层。总而言之，我们的数据表明，通过 ADAM12 消耗肿瘤诱导的慢周期 PDGFRα MSC 可恢复抗肿瘤免疫力。© 2023。作者。

The capacity to survive and thrive in conditions of limited resources and high inflammation is a major driver of tumor malignancy. Here we identified slow-cycling ADAM12+PDGFRα+ mesenchymal stromal cells (MSCs) induced at the tumor margins in mouse models of melanoma, pancreatic cancer and prostate cancer. Using inducible lineage tracing and transcriptomics, we demonstrated that metabolically altered ADAM12+ MSCs induced pathological angiogenesis and immunosuppression by promoting macrophage efferocytosis and polarization through overexpression of genes such as Gas6, Lgals3 and Csf1. Genetic depletion of ADAM12+ cells restored a functional tumor vasculature, reduced hypoxia and acidosis and normalized CAFs, inducing infiltration of effector T cells and growth inhibition of melanomas and pancreatic neuroendocrine cancer, in a process dependent on TGF-β. In human cancer, ADAM12 stratifies patients with high levels of hypoxia and innate resistance mechanisms, as well as factors associated with a poor prognosis and drug resistance such as AXL. Altogether, our data show that depletion of tumor-induced slow-cycling PDGFRα+ MSCs through ADAM12 restores antitumor immunity.© 2023. The Author(s).