Activating Macrophage‐Mediated Cancer Immunotherapy by Genetically Edited Nanoparticles

Abstract

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.

Research trends in pharmacological modulation of tumor‐associated macrophages

“…For example, Rao et al . reported that the magnetic nanoparticles can be used to promote the repolarization of the M2‐like TAMs as well as the systemic circulation and tumor accumulation of the loaded drugs 397 . Notably, there are still some challenges for the effective targeting of TAMs with nanoparticles and their application in the clinic.…”

“…For example, Rao et al reported that the magnetic nanoparticles can be used to promote the repolarization of the M2-like TAMs as well as the systemic circulation and tumor accumulation of the loaded drugs. 397 Notably, there are still some challenges for the effective targeting of TAMs with nanoparticles and their application in the clinic. The major one can be attributed to the undesirable clearance of nanoparticles by the mononuclear phagocyte system (macrophages) in clearance organs (liver, lung, or spleen) upon their intra-venous injection.…”

Capturing Cytokines with Advanced Materials: A Potential Strategy to Tackle COVID‐19 Cytokine Storm

“…[ 12 ] For instance, various nanoparticles have been functionalized with high affinity to specific molecular targets, providing alternative options to the biological ligands, such as antibodies and proteins. [ 32,33 ] These engineered nanoparticles have been employed to detain and neutralize bacterial toxins, animal venoms, and inflammatory cytokines. [ 56,57,90 ] Other high‐affinity molecules, such as aptamers, have also been conjugated onto various biomaterials as potential alternatives to free antibodies for cytokine neutralization.…”

“…Macrophages are heterogeneous immune cells that link innate and adaptive immune responses, and are able to initiate rapid protection against pathogens. [31][32][33][34] In response to infection, monocyte-derived macrophages are recruited from blood circulation to the site of infection in order to orchestrate prompt immune response. [34,35] Equipped with pattern recognition receptors (PRRs), macrophages can identify pathogen-associated molecular patterns (PAMPs) and conduct phagocytosis and phagolysosome-mediated digestion of pathogens, therefore facilitate proinflammatory response.…”

CDK12 Promotes Cervical Cancer Progression through Enhancing Macrophage Infiltration

“…TAMs, as a kind of myeloid immune cell, have been reported to the important prognostic significances in human malignancies [ 16 ]. Current studies found that an increased infiltration in the TME is associated with a worse prognosis for lung and breast cancer patients [ 23 , 24 ]. Besides lung and breast cancer, increased accumulation of TAMs in gastric cancers and multiple myeloma is also associated with a poor prognosis [ 25 ].…”