Abstract

Neoadjuvant radiotherapy (NRT) is widely applied to reduce tumor burden and improve surgical outcomes. However, accumulating evidence indicates that radiation, at certain dose levels, paradoxically promotes the infiltration and polarization of tumor-associated macrophages (TAMs), especially the immunosuppressive M2-like subtype, thereby fostering an immunosuppressive tumor microenvironment (TME) and compromising long-term therapeutic efficacy. To overcome this limitation, we developed a biomineralized nanoghost platform (SBC@CaP) derived from senescent erythrocyte vesicles and coated with a pH-responsive calcium phosphate (CaP) shell. In the acidic TME, the CaP layer gradually dissolves, exposing the senescent erythrocyte membrane for selective recognition and uptake by TAMs, particularly those enriched after radiotherapy. Functioning as a universal TAM-targeting carrier, SBC@CaP can be modularly loaded with agents, such as disodium clodronate to induce apoptosis or ferrous ions to trigger ferroptosis in TAMs. In addition, released CaP buffers intratumoral acidity and enhance radiosensitization. This modular strategy enables precise TAMs clearance, TME remodeling, and immune activation. In multiple tumor models, SBC@CaP effectively reprograms the immune landscape and suppresses tumor progression, offering a versatile platform to mitigate the drawbacks of NRT and potentiate macrophage-targeted cancer therapy.