Low dose radiotherapy-induced tumor-preferential antigens enhance antibody-drug conjugate efficacy in solid tumors

Antibody-drug conjugate (ADC) efficacy in solid tumors is often limited by low or heterogeneous antigen expression. Here, we investigated low-dose radiotherapy (LDRT) as a noninvasive sensitization strategy to enhance tumor surface antigen expression and improve ADC activity. Transcriptomic profiling and flow cytometry identified ICAM1 as the most strongly radiation-inducible antigen after 2 Gy irradiation, showing an approximately 4-fold increase and exceeding several established ADC targets. Mechanistic studies revealed that radiation-induced reactive oxygen species (ROS) and oxidative stress signaling upregulated ICAM1, enhanced antibody internalization, and improved ICAM1-targeted ADC delivery. In xenograft models, LDRT combined with ICAM1-targeted ADCs achieved >70% tumor growth inhibition with minimal toxicity. Transcriptomic and immunohistochemical (IHC) staining analyses further showed that LDRT induced recruitment of immunosuppressive CCL8^high M2-like tumor-associated macrophages, whereas ADC-mediated bystander killing attenuated this adaptive feedback and promoted a more immunoactive tumor microenvironment. Together, these findings support LDRT as a clinically translatable strategy to increase ICAM1 expression, overcome antigen-low barriers, and enhance ADC efficacy in refractory solid tumors.