Bacteria-mimicking cancer cells reprogram macrophages via multiple pattern recognition receptor pathways for cancer immunotherapy.

Although macrophages are a powerful cell-based platform for cancer immunotherapy, their antitumor functions, such as phagocytosis and inflammatory responses, are limited by the immunosuppressive tumor microenvironment. Here, we show that decorating cancer cell membranes with bacteria-derived pathogen-associated molecular patterns (PAMPs) initiates phagocytosis and inflammatory responses of macrophages toward cancer cells involving various pattern-recognition receptor signaling pathways. Bacteria-derived PAMPs were formulated into membrane-decorating nanoparticles, and these nanoparticles reprogrammed immunosuppressive macrophages into inflammatory phenotypes. Cancer cell membrane-attached PAMP nanoparticles maintained their immunostimulatory responses, stimulating macrophages' antitumor functions. The fraction of phagocytic macrophages significantly increased when coincubated with membrane-decorated cancer cells, along with an increased secretion of inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Transcriptomic gene ontology analysis revealed that the response of macrophages to PAMP-decorated cancer cells resembled their response to bacteria, involving signaling pathways including inflammatory response and innate immune response. In a mouse model, locally injected membrane-decorating PAMP nanoparticles suppressed tumor growth. The therapeutic effect was more pronounced in combination with the chemotherapeutic drug doxorubicin. Median survival days significantly increased in both the PAMP nanoparticle and the PAMP nanoparticle plus doxorubicin combination group with complete remission cases, compared to the doxorubicin group. Our findings provide insights into the use of macrophages as a cancer immunotherapy modality.