Anti-Tumor Strategies by Harnessing the Phagocytosis of Macrophages

Abstract

Macrophages are essential for the human body in both physiological and pathological conditions, engulfing undesirable substances and participating in several processes, such as organism growth, immune regulation, and maintenance of homeostasis. Macrophages play an important role in anti-bacterial and anti-tumoral responses. Aberrance in the phagocytosis of macrophages may lead to the development of several diseases, including tumors. Tumor cells can evade the phagocytosis of macrophages, and “educate” macrophages to become pro-tumoral, resulting in the reduced phagocytosis of macrophages. Hence, harnessing the phagocytosis of macrophages is an important approach to bolster the efficacy of anti-tumor treatment. In this review, we elucidated the underlying phagocytosis mechanisms, such as the equilibrium among phagocytic signals, receptors and their respective signaling pathways, macrophage activation, as well as mitochondrial fission. We also reviewed the recent progress in the area of application strategies on the basis of the phagocytosis mechanism, including strategies targeting the phagocytic signals, antibody-dependent cellular phagocytosis (ADCP), and macrophage activators. We also covered recent studies of Chimeric Antigen Receptor Macrophage (CAR-M)-based anti-tumor therapy. Furthermore, we summarized the shortcomings and future applications of each strategy and look into their prospects with the hope of providing future research directions for developing the application of macrophage phagocytosis-promoting therapy.

Unraveling the Multifaceted Roles of Extracellular Vesicles: Insights into Biology, Pharmacology, and Pharmaceutical Applications for Drug Delivery

“…Similarly, EVs engineered with CD47 inhibit their uptake by monocytes and prolong their half-life in circulation [ 411 ]. Similar observations have been made in other studies that have utilized CD47 overexpression [ 412 , 413 ], as well as expression of CD47-resembling molecules such as CD55 and CD59 on the surface of EVs [ 330 ]. The relatively long in vivo half-life of 3 weeks of albumin, the most abundant human plasma protein, has brought much interest for its use in drug delivery for a range of biotherapeutics, either by direct incorporation or via a binding domain on the surface of the carrier [ 414 ].…”

The cell stress and immunity cycle in cancer: Toward next generation of cancer immunotherapy

“…Furthermore, CD47 blockade facilitates phagocytosis of cancer cells by DCs, thereby increasing antigen presentation by DCs to T cells. 185,190,191 The first antibody targeting CD47, Hu5F9-G4, was used in children with brain tumors and had a curative effect in five different cases. 190,192 Although CD47 targeting antibodies have shown great preclinical success, there are some important clinical challenges associated with it.…”

“…[196][197][198] CD24 on the other hand is a more novel "don't eat me signal" expressed on cancer cells that binds to the inhibitory receptor sialic acid-binding Ig-like lectin 10 (Siglec-10) and targeting the CD24-Siglec-10 axis increases phagocytic abilities of macrophages. 185,191 CD24 is a promising target for cancer immunotherapy, due to its expression on immune cells however therapies targeting it might also be susceptible to adverse effects owing to its ubiquitous expression patterns. 190 Finally, MHC-I targeting can also enhance phagocytosis of cancer cells.…”

“…MHC-I, which is expressed on cancer cells, binds via its subunit β2M, to its receptor leukocyte immunoglobulin-like receptor B1 (LILRB1). 190,191 The MHC-I-LILRB1 axis plays a crucial role in inhibiting phagocytosis and therefore, blocking either MHC-I or LILRB1 can promote phagocytosis. However, as MHC-I is important in antigen presentation, targeting MHC-I may also cause loss of T-cell recognition of antigens.…”

Therapeutic In Situ Cancer Vaccine Using Pulsed Stereotactic Body Radiotherapy—A Translational Model

“…Being a step ahead in the immunity cycle, RT promotes more expression of MHC-1 molecules in murine models, playing a role in cross-presentation and T-cell priming [ 38 ]. The use of drugs facilitating macrophage-mediated professional phagocytosis, e.g., oligonucleotide cytosine phosphate guanine (CpG), will reduce the interstitial pressure [ 39 ]. If the programmed cell death ligand (PD-L)1 is a “don’t find me signal”, CD47 is a “don’t eat me signal”, and drugs like metformin and small-molecule gefitinib are CD47 suppressants.…”