Optimizing immunotherapy–radiotherapy synergy in triple-negative breast cancer: mechanisms, clinical evidence, and therapeutic windows

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer associated with a poor prognosis; conventional treatments provide limited durable benefit, and resistance commonly develops. The introduction of immune checkpoint inhibitors (ICIs) has expanded treatment options for TNBC; however, ICI monotherapy has demonstrated limited efficacy, particularly in patients with advanced disease. Radiotherapy (RT) has long played a pivotal role in the treatment of early-stage and locally advanced breast cancer, as it not only exerts direct tumoricidal effects but also remodels the tumor immune microenvironment. In recent years, increasing attention has been directed toward the potential synergistic effects of ICIs and RT. This article reviews the immunological characteristics of TNBC, the current status of ICI-based therapy, and the underlying mechanisms of resistance. It also summarizes the biological rationale for combining RT with ICIs in the treatment of TNBC and, in light of recent advances in clinical research, explores the impact of different RT dose-fractionation regimens, treatment sequencing, and patient selection on therapeutic efficacy. Although current research remains in an early exploratory stage and several small studies have demonstrated the potential of this combination strategy, maximizing efficacy while controlling toxicity remains a key challenge for future clinical translation.