SBRT embedded in low-dose RT plus αPD-1 (immuno-EclipseRT, iERT) elicits CD8⁺ T cell immunity against bulky tumors...

Bulky tumors remain challenging to treat, and immune checkpoint inhibitors (ICIs), alone or combined with conventional radiotherapy (RT), yield limited efficacy. We present EclipseRT (ERT), an RT technique that delivers low-dose RT (LDRT) to the gross tumor volume (GTV) and stereotactic body RT (SBRT) to selected subvolume(s) within the GTV. Combined with ICIs (iERT), this approach achieves marked control of bulky tumors through the coordinated activity of NK and CD8⁺ T cells. Single-cell RNA sequencing and validation experiments show that the SBRT component robustly induces type I interferon (IFN-I), which activates NK cells to secrete XCL1, thereby recruiting cross-presenting XCR1⁺ dendritic cells (DCs). SBRT also promotes the release of extracellular vesicles carrying neoantigens, enhancing DC cross-presentation and CD8⁺ T-cell responses. The LDRT component further promotes NK and CD8⁺ T-cell recruitment. iERT also induces precursor exhausted CD8⁺ T cells in tumors and tumor-draining lymph nodes. Collectively, iERT activates the IFN-I/NK/DC/CD8⁺ T-cell axis, driving potent antitumor immunity against bulky tumors.