Non-genetically reprogrammed meta-neutrophils potentiate chemo-immunotherapy against lung metastatic triple-negative breast cancer.

Neutrophils (NEs) exhibit significant therapeutic potential in tumor therapy owing to their distinct advantages. In clinical trials, however, adoptive transfer of NEs shows limited efficacy against advanced solid tumor, partially owing to the unsatisfactory antitumor potency. Besides, the phenotype plasticity of NEs in tumor environment restricts their direct application. Here, we report a non-genetic reprogramming strategy via sequential interferon gamma (IFNγ) training and Abraxane arming to obtain meta-NEs, which hold persisted antitumor phenotype of NEs and potentiated chemo-immunotherapy effect. We find that meta-NEs demonstrate enhanced accumulation in lung metastases and thus harness the strengthened tumoricidal and immunostimulatory potency of NEs and the cytotoxicity of Abraxane to achieve safe and potentiated chemo-immunotherapy against lung metastatic triple-negative breast cancer. In short, we provide a non-genetic reprogramming strategy for NEs to generally improve their antitumor efficacy regardless of donors, which puts forward rationale for the clinical development of NEs in metastatic breast cancer therapy.