Programmable nanomicelles rewire myeloid immunity for durable control of primary and metastatic breast cancer.

Abstract

Immunosuppressive myeloid cells, including immature dendritic cells (DC) and tumor-promoting macrophages, drive tumor progression and immune evasion. Reprogramming these cells into immune effectors remains challenging. Here, we present a programmable nanomicelle platform that reconfigures myeloid immunity to combat both primary and metastatic breast cancer (BC). The nanomicelles co-deliver photosensitizers (IR825), anti-PD-L1 antibodies, and antagomiR-182 with spatiotemporal precision. Upon activation, they induce immunogenic cell death, promoting DC maturation to enhance antigen presentation. Concurrently, miR-182 inhibition repolarizes M2-like macrophages into M1-like phenotypes via the TLR4/MYD88/NF-κB pathway. This dual reprogramming enhances CD8⁺ T cell infiltration and functionality, driving durable anti-tumor responses. In multiple BC models, the platform suppresses tumor growth, prevents metastasis, and induces long-term immune memory. Its efficacy and immunomodulatory effects were further validated in a patient-derived tumor fragment assay and patient-derived xenograft models, highlighting translational potential. This work offers a clinically relevant strategy to rewire tumor-promoting myeloid cells for cancer immunotherapy.