Lung adenocarcinoma is the most common subtype of lung cancer, which has the second highest incidence among cancers. Immunotherapy has revolutionized lung cancer treatment, yet the checkpoint blockade response rate is less than 20% in patients with lung adenocarcinoma. As lung adenocarcinoma consists of heterogeneous histologic subsets with diverse tumor invasion phenotypes and clinical outcomes, understanding the mechanisms of resistance based on the histology subset is essential. In the current issue, Jang and colleagues demonstrated that PD-1-expressing macrophages are the dominant immune cell population in the tumor-immune microenvironment (TiME) of invasive lung adenocarcinoma and are responsible for driving tumor progression from preinvasive to invasive subtypes. PD-1-expressing macrophages are protumorigenic and highly plastic, potentially promoting invasive solid tumor development. Ablation of macrophages remodels the TiME and leads to a favorable anti-PD-1 blockade response, suggesting a potential combination therapy in patients with lung adenocarcinoma resistant to monotherapy. This current work highlights the spatiotemporal dynamics of the TiME during lung adenocarcinoma progression and the critical role of PD-1-expressing macrophages in driving tumorigenesis as well as resistance to immunotherapy. See related article by Jang et al., p. 2593.