Macrophages are critical regulators of innate immunity and have emerged as a promising target in cancer immunotherapy. However, the tumor microenvironment often suppresses their antitumor functions, which include phagocytosis and pro-inflammatory cytokine release. Here, we present a bacteria-mimetic strategy to reactivate macrophages by engineering tumor cell membranes to display pathogen-associated molecular patterns (PAMPs). To generate this effect, we decorated cancer cell membranes with PAMP-carrying nanoparticles and co-cultured them with macrophages. We quantified phagocytic activity and cytokine secretion and performed transcriptomic profiling to evaluate innate immune activation. In vivo, PAMP-coated nanoparticles were injected into tumor-bearing mice alone or with doxorubicin to evaluate therapeutic efficacy. Macrophages exposed to PAMP-decorated cancer cells exhibited robust reprogramming. Phagocytosis nearly doubled, and secretion of TNF-α and IL-6 significantly increased compared to controls. Transcriptomic analysis revealed the upregulation of Toll-like receptor and NF-κB signaling pathways, which is consistent with the activation seen in bacterial infections. Intratumoral administration of PAMP-coated nanoparticles strongly suppressed tumor growth in vivo. Notably, co-treatment with doxorubicin further potentiated tumor regression, surpassing the effects of either therapy alone. Histological analysis demonstrated enhanced macrophage infiltration and apoptotic tumor cell death. This study establishes that mimicking a bacterial infection by using surface-engineered cancer cells can effectively overcome tumor-induced immunosuppression. By reactivating macrophages, this approach provides a powerful means to harness innate immunity against cancer. Furthermore, its synergy with chemotherapy highlights its potential for combinatorial therapeutic strategies in clinical applications. Our findings pave the way for a new approach to biophysically inspired immunotherapy, in which engineered membrane interfaces can reprogram innate immune cells to restore their natural tumor-clearing functions.
Song et al. (Sun,) studied this question.