Walking Dead Tumor Cells for Targeted Drug Delivery Against Lung Metastasis of Triple‐Negative Breast Cancer

Abstract

Lung metastasis is challenging in patients with triple-negative breast cancer (TNBC). Surgery is always not available due to the dissemination of metastatic foci and most drugs are powerless because of poor retention at metastatic sites. TNBC cells generate an inflamed microenvironment and overexpress adhesive molecules to promote invasion and colonization. Herein, "walking dead" TNBC cells are developed through conjugating anti-PD-1 (programmed death protein 1 inhibitor) and doxorubicin (DOX)-loaded liposomes onto cell corpses for temporal chemo-immunotherapy against lung metastasis. The walking dead TNBC cells maintain plenary tumor antigens to conduct vaccination effects. Anti-PD-1 antibodies are conjugated to cell corpses via reduction-activated linker, and DOX-loaded liposomes are attached by maleimide-thiol coupling. This anchor strategy enables rapid release of anti-PD-1 upon reduction conditions while long-lasting release of DOX at inflamed metastatic sites. The walking dead TNBC cells improve pulmonary accumulation and local retention of drugs, reprogram the lung microenvironment through damage-associated molecular patterns (DAMPs) and PD-1 blockade, and prolong overall survival of lung metastatic 4T1 and EMT6-bearing mice. Taking advantage of the walking dead TNBC cells for pulmonary preferred delivery of chemotherapeutics and checkpoint inhibitors, this study suggests an alternative treatment option of chemo-immunotherapy to augment the efficacy against lung metastasis.