A Phase 2 clinical trial reversing standard breast cancer treatment order has revealed how radiotherapy alone impacts tumor biology. Delivering radiation before surgery allowed researchers at MD Anderson Cancer Center to observe increased genomic changes and immune cell population shifts within estrogen receptor-positive breast tumors. Single-cell RNA sequencing showed elevated macrophages and CD4 T cells with anti-tumor functions and altered expression of stress response genes in tumor cells post-radiation. These findings, published in Cell Reports, may inform better optimization of radiotherapy strategies in breast cancer treatment.