traditional treatment modalities in the clinic. [1,2] Macrophages are a significant constituent of innate immune system and have an indispensable impact in activating body's first-line defense against infection and cancer. [3] Effectively activating macrophage-mediated immunity holds great potential in cancer immunotherapy. [4] However, cancer cells are masters of immunomodulation and express "don't eat me" signal CD47 on the cellular surface, protecting them from the phagocytosis via binding to signal regulatory protein alpha (SIRPα) receptor on macrophages. [5,6] Blockade of CD47-SIRPα signaling pathway has been widely studied and dozens of CD47 antagonists are being actively tested in clinical trials. [7,8] CD47 checkpoint inhibitors have been demonstrated to not only promote macrophages to directly "eat" cancer cells but also trigger potent T-cell immune responses. [9] Although promising, systemic infusion of these CD47 inhibitors can cause significant side effects, such as thrombocytopenia and anemia. [2,10] Meanwhile, similar to other checkpoint inhibitors, the clinical benefit rate and objective response rate of these antagonists need to be further improved. [10] Thus, addressing these concerns are Immunomodulation of macrophages against cancer has emerged as an encouraging therapeutic strategy. However, there exist two major challenges in effectively activating macrophages for antitumor immunotherapy. First, ligation of signal regulatory protein alpha (SIRPα) on macrophages to CD47, a "don't eat me" signal on cancer cells, prevents macrophage phagocytosis of cancer cells. Second, colony stimulating factors, secreted by cancer cells, polarize tumor-associated macrophages (TAMs) to a tumorigenic M2 phenotype. Here, it is reported that genetically engineered cell-membrane-coated magnetic nanoparticles (gCM-MNs) can disable both mechanisms. The gCM shell genetically overexpressing SIRPα variants with remarkable affinity efficiently blocks the CD47-SIRPα pathway while the MN core promotes M2 TAM repolarization, synergistically triggering potent macrophage immune responses. Moreover, the gCM shell protects the MNs from immune clearance; and in turn, the MN core delivers the gCMs into tumor tissues under magnetic navigation, effectively promoting their systemic circulation and tumor accumulation. In melanoma and breast cancer models, it is shown that gCM-MNs significantly prolong overall mouse survival by controlling both local tumor growth and distant tumor metastasis. The combination of cell-membrane-coating nanotechnology and genetic editing technique offers a safe and robust strategy in activating the body's immune responses for cancer immunotherapy.

Multicellular aggregates in three-dimensional (3D) environments provide novel solid tumor models that can provide insight into in vivo drug resistance.