Background <p>Metastatic lung carcinoma poses considerable treatment difficulties. It exhibits cellular characteristics that differ from those of early-stage cancer. Immunotherapy demonstrates enhanced hope for patients with advanced and metastatic lung cancer. Tumor-associated macrophages (TAMs) may be a contributing factor that diminishes the effectiveness of immunotherapy. Secreted phosphoprotein 1 (SPP1)⁺TAMs are considered to possess immunosuppressive characteristics, as their interaction with CD8⁺ T lymphocytes results in the exhaustion of these cells.</p> Methods <p>We analyzed single-cell RNA sequencing datasets of lung cancer metastases in order to examine the development of brain metastatic tumors. Furthermore, the cell–cell interactions between SPP1⁺ TAM cells and CD8⁺ T cells within primary and brain metastatic cancers were systematically compared. Additionally, we utilized a flow cytometer and immunofluorescence to demonstrate how SPP1 affects the function of CD8⁺ T cells. In vitro, we generated SPP1-overexpressing macrophages and performed qPCR, Western blot, and co-culture assays with or without anti-SPP1 or anti-A2AR treatment to evaluate immunosuppressive effects.</p> Results <p>The results demonstrated that the proportions of immune cells in metastatic brain tissues are lower, while the infiltration of macrophages is higher. SPP1⁺ TAMs contribute to immune suppression in lung cancer by limiting the activation of CD8⁺ T cells and cytokine production. Anti-SPP1 treatment positively impacts CD8⁺ T cell function, counteracting SPP1-induced dysfunction and facilitating the production of cytokines. SPP1 overexpression in macrophages enhanced their immunosuppressive phenotype by upregulating CD73 and cytokines such as IL-10 and TGF-β, leading to impaired CD8⁺ T cell function via A2AR signaling; notably, neutralization of SPP1 or A2AR successfully restored CD8⁺ T cell activity.</p> Conclusions <p>Our findings characterize the immunological environment of both primary and metastatic lung cancer, highlighting SPP1-mediated immune suppression as a potential therapeutic target to restore T cell responses. Preclinical data demonstrate that Anti-SPP1 antibodies can reverse T cell exhaustion and enhance immune responses in lung cancer.</p>