Synergistic Approach to Combat Triple-Negative Breast Cancer: B7-H4 Checkpoint-Based Photodynamic Nanodrug Coupled with Neutrophil Extracellular Trap Regulation

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, which often results in distant metastasis and dismal prognosis. Unfortunately, current treatments for TNBC are not effective due to its resistance to immunotherapy. Recent studies indicate that B7-H4 immune checkpoint overexpression and inflammation-initiated neutrophil extracellular traps (NETs) are closely associated with the poor immunotherapy outcome of TNBC. This study finds that a B7-H4 checkpoint-based photodynamic nanodrug combined with NETs regulation enables a potent therapeutic outcome of TNBC. The nanodrug induces antitumor immunity via photodynamic therapy, enabling a cascade reinforcement of B7-H4 target-based therapeutic outcomes. By combining DNase I with the B7-H4 checkpoint-based photodynamic nanodrug, the DNase I potentiates the immunotherapeutic efficacy by disrupting NETs barrier between tumor cells and T cells, cascade reinforcing the antitumor immune response and antimetastasis efficacy. This combination therapy demonstrates a powerful ability in suppressing TNBC growth and metastasis, offering a robust approach for treating immune-cold TNBC while addressing its resistance to immunotherapy. A B7-H4 checkpoint-based photodynamic nanodrug combined with neutrophil extracellular traps (NETs)-degrading enzyme DNase I is designed for treating immune-cold triple-negative breast cancer (TNBC). This synergistic approach enables cascade amplification of B7-H4 target-based outcomes and disrupts NETs-mediated metastasis, providing a potent strategy to reinvigorate the antitumor immune response and enhance the efficacy of TNBC immunotherapy.image