Research Progress of Radiotherapy Combined With Immunotherapy for Breast Cancer: Mechanism Exploration and Clinical Translation.

Radiation therapy (RT) dynamically modulates the breast cancer immune microenvironment by inducing immunogenic cell death (ICD) and reshaping the tumor microenvironment. However, RT alone is often insufficient to achieve complete tumor eradication due to compensatory immunosuppressive mechanisms within the tumor microenvironment. The combination of RT with immune checkpoint inhibitors (ICIs) has thus emerged as a potent strategy to overcome these limitations, particularly in triple-negative breast cancer (TNBC).Preclinical studies confirm that radiotherapy fractionation regimens critically influence immune regulation: moderate hypo fractionated doses (eg, 8-12 Gy per fraction) optimally activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and promote CD8T cell infiltration, whereas single ablative doses exceeding 15 Gy may attenuate immunogenicity by upregulating the DNA exonuclease Trex1. Clinical trials such as PEARL demonstrate that this combination regimen, Stereotactic body radiotherapy (SBRT) with ICIs and neoadjuvant chemotherapy) achieves a pathological complete response (pCR) rate of 59.2% in TNBC patients. Key challenges remain, including optimizing RT-ICI sequencing, managing overlapping toxicities (eg, pneumonitis), and validating predictive biomarkers such as tumor-infiltrating lymphocytes (TILs) and circulating tumor DNA (ctDNA). Future research will focus on integrating AI-driven radiotherapy with multi-omics to address tumor heterogeneity. Targeting immunosuppressive pathways like indoleamine 2,3-dioxygenase1 (IDO1) and histone deacetylase (HDAC) may enhance treatment efficacy. This review synthesizes mechanistic, clinical, and translational advances in radiotherapy-ICI combinations, providing a theoretical foundation and strategic outlook for optimizing precision breast cancer therapy.