Fig. 4.
Strategies for targeting macrophages for tumor immunotherapy. These strategies are categorized into six types based on their objectives. Agents or drugs are listed as examples in the subcategory for one of their main effects. This may not be the only effective because of their complex mechanisms. (1) Suppression of macrophage recruitment;81,82,205 molecules on monocytes/macrophages, such as CCR2, CCR5, VEGFR, CSF1R, ITGA4, and C5a, contribute to the infiltration of macrophages into tumors. Inhibitors or antibodies against them or some of their ligands (such as CCL2, CCL5, VEGF, and CSF1) could suppress the recruitment of macrophages. Reduced angiogenesis caused by targeting Nrp1 and ANG2 could also result in a decrease in macrophage recruitment. (2) Reduction of macrophage survival.205–208 As CSF1 is a crucial signal for the differentiation of macrophages, CSF1 inhibitors restrain the formation of macrophages. Trabectedin could also be used to reduce the survival of macrophages by inducing apoptosis. Immunotoxins targeting scavenger receptor-A or folate receptor β (FRβ) can deplete TAMs, and bisphosphonates are metabolic analogs that reduce macrophages. (3) Inhibition of tumor-promoting functions;205,209–211 Tim-3 blocking antibody is reported to regulate the activation of TAMs. By inhibiting angiogenesis, anti-VEGF, anti-VEGFR, and tyrosine kinase inhibitors could weaken the protumoral function of TAMs. TAMs contribute to an immunosuppressive microenvironment by expressing indoleamine-pyrrole 2,3-dioxygenase (IDO), heme oxygenase, arginase, TGFβ, IL-10, prostaglandins, and so on. Aspirin reduces the generation of prostaglandins. Blocking immune checkpoints (PD-L1, PD-L2, B7-H4, VISTA, B7-1, and B7-2) on macrophages could relieve the function of other immune cells. (4) Removal of the macrophage blockade;207,212,213 interactions between CD47 on tumors and SIRPα on macrophages help tumor cells evade macrophage phagocytosis. Antibodies against CD47 or SIRPα could remove the blockage. In addition, antibodies against MUC1 and EGFR inhibit SIRPα. (5) Induction of repolarization;43,113,193,207,210,214–222 M1 polarization of TAMs is associated with antitumor responses, while M2 polarization is associated with protumor activities. Several factors can induce M1 polarization, including IFNγ, CD40 agonists, inhibitors of PI3Kγ/mTOR/DICER, agonists of TLR4/7/8/9, methionine sulfoximine, histone deacetylase (HDAC) inhibitors, and antibodies against macrophage receptors with collagenous structures (MARCOs). In contrast, factors inhibiting M2 polarization, such as CSF1R inhibitors, corosolic acid, omeprazole, Gpr132 inhibitors, MEK/STAT3 inhibitors, fast-mimicking diets, and antibodies against IL-4, IL-4Rα, and IL-13, can also reduce the tumor burden. (6) Modification of effector cells.177 Chimeric antigen receptor macrophages (CAR-Ms) similar to CAR-T cells have been used to enhance tumoricidal functions. Targets, such as CD19, HER2, and mesothelin, have been explored