Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment^1,2. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis^3,4,5, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions¹. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial–mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8⁺ T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions.

巨噬细胞在塑造肿瘤微环境 (TME)、肿瘤免疫和对免疫治疗的反应方面发挥着关键作用，这使它们成为癌症治疗的重要目标^1,2。然而，调节巨噬细胞已被证明极其困难，因为我们仍然缺乏对肿瘤巨噬细胞区室的分子和功能多样性的完整了解。巨噬细胞来自两个不同的谱系。组织驻留巨噬细胞在局部自我更新，独立于成人造血^3,4,5，而短寿命的单核细胞衍生巨噬细胞来自成人造血干细胞，主要积聚在发炎的病变中¹. 这些巨噬细胞谱系如何促进 TME 和癌症进展仍不清楚。为了探索人类非小细胞肺癌 (NSCLC) 病变中巨噬细胞区室的多样性，我们在这里对肿瘤相关白细胞进行了单细胞 RNA 测序。我们确定了富含人类和小鼠肺肿瘤的不同巨噬细胞群。使用谱系追踪，我们发现这些巨噬细胞种群的起源不同，并且在 TME 中具有明显的时间和空间分布。在肿瘤形成的早期，组织驻留巨噬细胞在肿瘤细胞附近积累，以促进肿瘤细胞的上皮-间质转化和侵袭，它们还诱导有效的调节性 T 细胞反应，保护肿瘤细胞免受适应性免疫。⁺ T 细胞和减少肿瘤的侵袭性和生长。在肿瘤生长期间，组织驻留的巨噬细胞在 TME 的外围重新分布，在小鼠和人类 NSCLC 中，TME 以单核细胞衍生的巨噬细胞为主。本研究确定了组织驻留巨噬细胞对早期肺癌的贡献，并将其确立为预防和治疗早期肺癌病变的靶点。