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.

Co-delivery of gemcitabine and paclitaxel plus NanoCpG empowers chemoimmunotherapy of postoperative “cold” triple-negative breast cancer

“…5 e). Lung metastasis frequently occurred in recurrent tumors and accounted for 36.9% for recurrent TNBC patients, leading to a low 5-year survival rate [ 44 , 45 ]. Of note, mG/P and ATN-mG/P drastically reduced tumor nodules in the lungs compared to PBS group that had massive tumor metastasis ( Fig.…”

A panel of seven immune-related genes can serve as a good predictive biomarker for cervical squamous cell carcinoma

“…In addition, ICI therapy has shown great clinical benefits since its introduction ( Tang et al, 2018 ; Sinha et al, 2022 ). The application of PD-1/PD-L1 and CTLA-4 have been shown good curative effect on improving patients’ prognosis in hepatocellular carcinoma, non-small cell lung carcinoma, breast cancer and so on ( Chae et al, 2018 ; Vaddepally et al, 2020 ; Lee et al, 2021 ; Chen Y. et al, 2022 ; Zhao et al, 2022 ). However, in terms of durable and effective response rate, a considerable number of patients fail to benefit from immune therapy, which accounts for 10%–40%.…”

Engineered tumor cell-derived vaccines against cancer: The art of combating poison with poison

“…(E) Inhibitory effect on subcutaneous 4T1 tumor mouse model. Copyright © 2022 Wiley-VCH GmbH [ 90 ]. …”

“…Numerous available reactive groups on the cell membrane surface have been used for surface chemical modification. Recently, Zhao et al [ 90 ] coupled DOX-loaded liposomes and anti-PD-1 antibodies to the surface of inactivated tumor cells (Cell-PD-1/Liposome) ( Fig. 1 C–E).…”

“… Vaccine type Modification strategy Feature Effect of vaccine Ref. Whole tumor cell vaccine Genetic engineering Expresses GM-CSF Increases DC antigen presentation ability, promotes DC survival [ 79 ] Expresses high levels of FAP Targets tumor cells and tumor-associated fibroblasts [ 83 ] Inhibits MYC expression Appropriate targets to induce and improve tumor cell immunogenicity [ 88 ] Knocks out Id2 gene in mouse neuroblastoma cells Imparts immunogenicity to tumor cells in hosts with normal immunity, acting synergistically with costimulatory CTLA-4 checkpoint inhibitors [ 89 ] Surface engineering Inactivates tumor cells surface couple with DOX-loaded liposomes and anti-PD-1 antibodies Delays tumor growth, reduces lung metastases, increases overall survival time [ 90 ] Cell hybridization H-2 b GL261 glioma cells fuse with H-2 d RAG-neo cells Increases cytokine production by immune cells, produces high levels of antitumor cytokines [ 85 ] Tumor cell-derived nanovaccines Genetic engineering Transduces FAP cDNA into tumor cells Targets tumor parenchyma and stroma, promotes tumor iron droop [ 101 ] Tumor cell lysate Genetic engineering Blocks STAT3 signaling pathway Inhibits tumor cell proliferation, promotes tumor cell apoptosis, promotes the generation of immune memory for HCC, prolongs the survival period of mice [ 106 ] Surface engineering Tumor cell lysates are covalently...…”