肿瘤相关巨噬细胞 (TAM) 经常被简单地归类为免疫抑制细胞，表面蛋白 CD206 是一种主要用于突出其所谓“M2”状态的分子。然而，由于缺乏足够的渗透性和特异性工具来在体内操纵巨噬细胞，因此巨噬细胞影响的直接证据仍然受到损害。因此，我们制作了一种新型条件性 CD206 敲入小鼠，以特异性地可视化和/或耗尽这些 TAM。 CD206 巨噬细胞和单核细胞（此处为“MonoMacs”）的早期消耗显着导致 NK 细胞、传统 I 型树突状细胞 (cDC1) 和 CD8 T 细胞的关键抗肿瘤网络的间接损失。在骨髓细胞中，我们发现 CD206 TAM 是 CXCL9 的主要产生者，CXCL9 是表达 CXCR3 的 NK 和 CD8 T 细胞的成熟趋化剂。相比之下，应激反应性 TAM（“缺氧”或 Spp1）和未成熟单核细胞（在耗尽后仍保留）的群体表达的 CXCL9 水平大大降低。我们证实缺失的 NK 和 CD8 T 细胞是 cDC1 吸引趋化因子 Xcl1 和 cDC1 生长因子 Flt3l 的主要产生者。与该关键网络的丧失一致，CD206 TAM 耗竭降低了小鼠的肿瘤控制。同样，在人类中，CD206 MonoMac 签名与刺激性 cDC1 签名基因密切相关。总之，这些发现否定了 CD206 巨噬细胞作为免疫抑制细胞的分类，而是阐明了大多数 TAM 在组织关键的肿瘤反应性免疫原型中的作用。

Tumor-associated macrophages (TAMs) are frequently and simplistically categorized as immunosuppressive, and one molecule prominently used to highlight their so-called 'M2' state is the surface protein CD206. However, direct evidence of the impact of macrophages remains impaired by the lack of sufficiently penetrant and specific tools to manipulate them in vivo. We thus made a novel conditional CD206 knock-in mouse to specifically visualize and/or deplete these TAMs. Early depletion of CD206+ macrophages and monocytes (here, 'MonoMacs') strikingly led to an indirect loss of a key anti-tumor network of NK cells, conventional type I dendritic cells (cDC1) and CD8 T cells. Among myeloid cells, we found that the CD206+ TAMs are the primary producers of CXCL9, the well-established chemoattractant for CXCR3-expressing NK and CD8 T cells. In contrast, a population of stress-responsive TAMs ("Hypoxic" or Spp1 +) and immature monocytes, which remain following depletion, expressed vastly diminished levels of CXCL9. We confirmed that the missing NK and CD8 T cells are the primary producers of the cDC1-attracting chemokine Xcl1 and cDC1 growth factor Flt3l . Consistent with the loss of this critical network, CD206+ TAM depletion decreased tumor control in mice. Likewise, in humans, the CD206+ MonoMac signature correlated robustly with stimulatory cDC1 signature genes. Together, these findings negate the classification of CD206+ macrophages as immunosuppressive and instead illuminate the role of this majority of TAMs in organizing a critical tumor-reactive archetype of immunity.