Radiotherapy in combination with PD-1 and TIGIT blockade mediate antitumor abscopal effects and immune memory via CD8+ T cells
Chunsheng Wang, Linzhi Han, Jianguo Zhang, Ji Qian, Xiuli Guo, Yangyi Li, Siqi Li, Jingyi He, Fajian He, Weijing Dai, Minghuan Li, Jinming Yu, Dawei Chen, Yan Gong, Conghua Xie
Abstract
This study investigated the synergistic antitumor effects of radiotherapy combined with anti-PD-1 and anti-TIGIT antibodies (aPD-1/aTIGIT), focusing on primary and abscopal tumor control, immune mechanisms, and long-term immune memory. Using bilateral subcutaneous tumor models (LLC, CMT-167, B16-F10, MC38) in C57/BL6 mice, we demonstrated that triple therapy (radiotherapy + aPD-1 + aTIGIT) significantly enhanced tumor regression and systemic antitumor responses. Flow cytometry, multicolor immunofluorescence, and single-cell transcriptomics revealed that triple therapy amplified CD8 + T cell activation, reversed exhaustion, and increased tumor infiltration. M1 macrophages exhibited robust immune activation and enhanced interactions with CD8 + T cells, driven by upregulated NF-κB, STAT1, and chemokine pathways. Longitudinal Luminex cytokine profiling identified sustained increases in TNF-α, CXCL10, and CCL5 post-treatment, supporting macrophage-T cell crosstalk. Rechallenge experiments and adoptive CD8 + T cell transfers confirmed that triple therapy generated durable central memory CD8 + T cells, which mediated antigen-specific immune memory and prevented tumor recurrence. These findings establish CD8 + T cells as central mediators of abscopal effects and long-term immunity, highlighting the critical role of M1 macrophage polarization in amplifying therapeutic synergy. By elucidating the mechanisms underlying resistance to PD-1 monotherapy, this study provides a translatable strategy to enhance clinical outcomes through radiotherapy-immunotherapy combinations.