SPP1⁺ TAM: CD8⁺ T Cell Crosstalk Associates with Blocking Radiotherapy Efficacy in Lung Cancer

Radiotherapy (RT) is a cornerstone treatment for non-small cell lung cancer (NSCLC), but its efficacy is often limited by immune suppression in the tumor microenvironment. In this study, we identified SPP1 as a key factor up-regulated after RT, mainly expressed by immunosuppressive macrophages. Single-cell RNA sequencing and in vivo models showed that SPP1⁺ macrophages inhibit CD8⁺ T cell infiltration and correlate with poor prognosis. Targeting SPP1 in macrophages enhanced RT efficacy, reduced tumor burden, and restored antitumor immunity. In summary, combining RT with SPP1⁺ macrophage-targeted intervention may serve as a promising strategy to overcome immune-mediated radioresistance and enhance therapeutic efficacy in NSCLC.