Spatiotemporally Controlled Nanomicelles for Synergistic Phototherapy and Immune Reprogramming in Triple-Negative Breast Cancer

Immune reprogramming of the tumor microenvironment (TME) represents a promising strategy to overcome immunosuppressive barriers in triple-negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) are key contributors to immune evasion and tumor progression; however, existing strategies are limited by TAM heterogeneity, poor tumor-specific delivery, and transient immune activation. Here, we developed a self-assembled, reactive oxygen species (ROS)-responsive nanomicelle (IR825@HRG) for codelivery of the near-infrared photosensitizer IR825 and the immunomodulatory protein histidine-rich glycoprotein (HRG), which is capable of reprogramming TAMs. Upon laser irradiation, IR825 triggers ROS generation and localized hyperthermia, synergistically eradicating tumor cells via photothermal and photodynamic effects. Simultaneously, ROS cleave thioketal linkers to release HRG in a spatiotemporally controlled manner, achieving a 2.3-fold higher tumor accumulation than free HRG and effectively reprogramming TAMs from M2- to M1-like phenotypes. Moreover, ROS-mediated immunogenic cell death further enhances systemic antitumor immunity, suppressing both primary tumors and metastases. By transforming the TME from "cold" to "hot", laser-activated IR825@HRG nanomicelles achieved combinatorial photoimmunotherapy in TNBC. Together, this facile, highly responsive, and multifunctional nanoplatform offers a robust strategy to integrate phototherapy with immunotherapy to reprogram the TME in poorly immunogenic tumors.