A Nanodelivery Platform Harnessing Synthetic Lethality and Efferocytosis Inhibition for Synergistically Enhanced Immunotherapy of Triple‐Negative Breast Cancer

Triple-negative breast cancer (TNBC), defined by the absence of specific therapeutic targets, shows poor clinical benefit and readily develops chemoresistance, underscoring the need for therapies that couple precise tumor cell killing with robust antitumor immunity. Drug-induced immunogenic cell death (ICD) is a promising approach. However, its efficacy is curtailed by limited tumor-cell targeting with collateral immune-cell damage and by overactive efferocytosis that rapidly removes ICD-associated danger signals, thereby restricting antitumor immunity. Herein, we develop a microenvironment-responsive nanocarrier co-delivering both PLK1 inhibitor (BI6727) and TIM-3 inhibitor (ML-T7). It integrates dual-bioeffect of synthetic lethal selective ICD and whole-immuno system remodelling initiated by effective macrophage efferocytosis inhibition. In detail, the molecular hallmark differences between tumor and immune cells was utilized to provide high-quality antigens. Meanwhile, the nanotherapeutic enables serial phagocyte regulations, such as, suppressed macrophage phagocytosis, enhanced antigen recognition and phagocytosis by dendritic cells (DCs), and then alleviated T cell exhaustion. The underlying mechanism of nanotherapeutics-mediated overall immune system reprogramming was explored by transcriptional profile analyses. These findings indicate that precise molecularly targeted ICD combined with coordinated immune activation enables efficient primary tumor suppression and promotes T-cell phenotypes associated with antitumor immune memory, providing a novel paradigm for cancer immunotherapy.