Harnessing anti-tumor and tumor-tropism functions of macrophages via nanotechnology for tumor immunotherapy

Abstract

Reprogramming the immunosuppressive tumor microenvironment by modulating macrophages holds great promise in tumor immunotherapy. As a class of professional phagocytes and antigen-presenting cells in the innate immune system, macrophages can not only directly engulf and clear tumor cells, but also play roles in presenting tumor-specific antigen to initiate adaptive immunity. However, the tumor-associated macrophages (TAMs) usually display tumor-supportive M2 phenotype rather than anti-tumor M1 phenotype. They can support tumor cells to escape immunological surveillance, aggravate tumor progression, and impede tumor-specific T cell immunity. Although many TAMs-modulating agents have shown great success in therapy of multiple tumors, they face enormous challenges including poor tumor accumulation and off-target side effects. An alternative solution is the use of advanced nanostructures, which not only can deliver TAMs-modulating agents to augment therapeutic efficacy, but also can directly serve as modulators of TAMs. Another important strategy is the exploitation of macrophages and macrophage-derived components as tumor-targeting delivery vehicles. Herein, we summarize the recent advances in targeting and engineering macrophages for tumor immunotherapy, including (1) direct and indirect effects of macrophages on the augmentation of immunotherapy and (2) strategies for engineering macrophage-based drug carriers. The existing perspectives and challenges of macrophage-based tumor immunotherapies are also highlighted.

Keywords: immunotherapy; macrophage‐based drug carriers; nanostructures; tumor microenvironment; tumor‐associated macrophages.

FIGURE 1

Modulating macrophages for tumor immunotherapy and engineering macrophages as drug delivery vehicles. Inhibition of macrophage recruitment, depleting TAMs, repolarizing TAMs, and regulating macrophage‐mediated phagocytosis of tumor cells are the four major strategies for manipulating macrophage‐mediated tumor immunotherapy. Engineering macrophages as drug delivery carriers is very promising for tumor immunotherapy, including engineering macrophages as “Trojan Horses,” utilizing macrophage‐derived components, such as, macrophage membrane, macrophage‐derived extracellular vesicles (i.e., exosomes, microvesicles, or nanovesicles), for tumor‐targeting delivery of anti‐tumor payloads

FIGURE 2

Origins of macrophages and TAMs. Macrophages in the body's tissues are mainly originated from yolk sac, fetal liver, and bone marrow, of which the bone‐marrow‐derived circulating inflammatory Ly6c⁺ monocytes are the main source of tumor‐supportive M2‐like TAMs. Monocytes can differentiate into M1‐ or M2 like macrophages in response to different stimuli. LPS or IFN‐γ usually induces them differentiating into anti‐tumor M1 phenotype macrophages, which secrete IL‐6, IL‐12, IL‐23, TNF‐α, IFN‐γ, and NO, and overexpress MHC‐II, positive‐costimulatory molecules (e.g., CD40, CD80, and CD86) and iNOS. IL‐4, IL‐13, or CSF‐1 can promote them polarizing into M2 phenotype macrophages, which secrete IL‐10, TGF‐β, CCL17, Ym1, and IDO, and overexpress haemoglobin scavenger receptor CD163, C‐type lectin receptors (CD206, CD301, CD209, and detin‐1), as well as Arg1

FIGURE 3

Schematic illustration of preparing nano‐RBC‐based TAMs‐targeting system for reversing immunosuppressive TME to improve chemoimmunotherapy. (A) Preparation of the DOX‐encapsulated biomimetic nano‐RBC system (V(Hb)@DOX). (B) Inhibition of TAMs‐recruitment improved chemo‐immunotherapy. Reproduced with permission.^{[ 63 ]} Copyright 2021, John Wiley & Sons

FIGURE 4

Fabrication of Cowpea chlorotic mottle virus (CCMV)‐based VLPs for delivery of ODN1826 to reprogram M2‐like TAMs. (A) Schematic illustration of CCMV disassembly and reassembly. (B) CCMV‐ODN1826 facilitated the death of CT26‐luc cells cocultured with TAMs. (C) The iNOS/Arg1 ratio in the TAMs of ODN1826‐treated CT26 tumors. Reproduced with permission.^{[ 89 ]} Copyright 2020, John Wiley & Sons

FIGURE 5

Schematic illustration of LDH@155 remodeling the immunoenvironment to enhance tumor immunotherapy. Reproduced with permission.^{[ 113 ]} Copyright 2019, John Wiley & Sons

FIGURE 6

Schematic illustration of CINPs‐mediated M2‐like TAMs‐repolarization synergizing with photothermal therapy to suppress tumor growth. Reproduced with permission.^{[ 158 ]} Copyright 2019, American Chemical Society

FIGURE 7

Schematic illustration of engineering PMLR nanoplatform to exhaust intra/extracellular lactic acid for alleviating immunosuppressive TME. (A) Synthesis of PMLR nanoplatform. (B) The inhibition of macrophage‐mediated engulfment by mRBC‐camouflaged nanoplatform mimicking the CD47‐mediated “don't eat me” signal. (C) The release of 3PO by PLMR system to block glycolysis of tumor. (D) The Cascade catalytic reaction of PLMR nanoplatform. PLMR initiated LOX‐mediated oxidation of lactic acid by O₂ to generate H₂O₂ and pyruvate, in which H₂O₂ could react with HMnO₂ to sustainably generate O₂ for lactic acid oxidation. Reproduced with permission.^{[ 172 ]} Copyright 2019, John Wiley & Sons

FIGURE 8

Schematic illustration of adoptive transfer CuS NPs‐repolarized macrophages to treat solid tumor. CuS NPs could polarize BMDMs to M1 phenotype via induce mitochondrial fission‐mediated generation of ROS. The adoptively transferred CuS‐MΦ could not only promote M2‐to‐M1 repolarization, but also enhance tumor‐phagocytosis of macrophages through blocking anti‐phagocytic PD‐1‐PD‐L1 checkpoint, which decreased immunosuppressive tumor‐infiltrating MDSC and Tregs, and enhanced tumor specific CD8⁺ T cell immunity. Reproduced with permission.^{[ 187 ]} Copyright 2021, John Wiley & Sons

FIGURE 9

The schematic illustration of CS NPs repolarizing tumor‐associated macrophages (TAMs) toward M1 phenotype to enhance anti‐tumor immunity. CS NPs enhance intracellular ROS level of macrophages to promote TRAF6 auto‐ubiquitination that activates the transcription factor IRF5 to reprogram TAMs toward M1 phenotype. Reproduced with permission.^{[ 189 ]} Copyright 2021, John Wiley & Sons

FIGURE 10

Schematic illustration of genetically engineered cell‐membrane‐coated magnetic nanoparticles (gCM‐MNs) blocking CD‐47‐SIRPα anti‐phagocytic checkpoint for tumor immunotherapy. (A) The fabrication of gCM‐MNs, including the gene edition of cells to overexpress SIRPα variants on the membrane, the isolation of cell membrane, and the coating of magnetic nanoparticles (MNs) with membrane. (B) The resultant gCM‐MNs could efficiently accumulate into tumor site upon the external magnetic field guidance, and inhibit CD47‐ SIRPα “don't eat me” signaling, leading to effective M2‐to‐M1 repolarization, enhanced tumor‐phagocytosis of macrophages and potent tumor‐specific T cell immunity. Reproduced with permission.^{[ 220 ]} Copyright 2020, John Wiley & Sons

FIGURE 11

Schematic illustration of engineering living macrophages for drug delivery to treat solid tumor. (A) The synthesis of Oxa(IV)@ZnPc@M. (B) Oxa(IV)@ZnPc@M displayed an pro‐inflammatory M1 phenotype polarization and could efficiently target primary and bone metastatic tumor. The combined chemo‐photodynamic therapy induced ICD to release tumor‐associated antigens and elicit DCs maturation and effective anti‐tumor immunity, which could significantly suppress primary and bone metastatic tumor progression by combining with anti‐PD‐L1 immunotherapy. Reproduced with permission.^{[ 233 ]} Copyright 2021, Springer Nature

FIGURE 12

Schematic illustration of RAW‐4T1 hybrid membrane‐based drug delivery system applied for treating lung metastases of breast tumor. The synthetic RAW‐4T1 hybrid membrane coated (DOX‐loaded PLGA nanoparticles (DPLGA@[RAW‐4T1] NPs) enhanced tumor‐targeted delivery of DOX due to their multi‐target capability, thereby elicited significant inhibition of lung metastases in breast tumor. Reproduced with permission.^{[ 241 ]} Copyright 2020, Springer Nature

FIGURE 13

Schematic illustration of utilizing the M1CCD for trimodal anti‐tumor therapy. (A) Fabrication of M1CCD. (B) Mechanism of chemically triggered luminescence and the singlet oxygen generation. (C) The mechanism of synergistic tumor inhibition of M1CCD. Reproduced with permission.^{[ 247 ]} Copyright 2021, John Wiley & Sons

FIGURE 14

Schematic illustration of isolating SαV‐C‐NVs, M1‐NVs, and P‐NVs for producing the hNVs to inhibit tumor metastasis and recurrence. The hNVs could target the post‐surgical tumor site, recognize and interact with CTCs, and block CD47‐SIRPα anti‐phagocytic checkpoint, thereby enhancing tumor phagocytosis of macrophages, promoting M2‐to‐M1 repolarization, and potentiating tumor‐specific T cell immunity to result in robust suppression of tumor metastasis and recurrence. Reproduced with permission.^{[ 252 ]} Copyright 2020, Springer Nature