Macrophages polarize into either pro-inflammatory (M1) and immunosuppressive (M2) phenotypes. M1-like macrophages are involved in the elimination of foreign body substances including tumor cells. In contrast, M2-like macrophages promotes angiogenesis, tissue regeneration, and tumor progression. As dynamics of macrophages during tumor progression, i.e., macrophage programing in the tumor microenvironment and functions of tumor-associated macrophages (TAMs), have been clarified, alternative immunotherapic approaches focused macrophages have been proposed. In this review, modification of mammalian cell surfaces by metabolic glycoengineering and surface functionalization of macrophages for cancer immunotherapy are described.

Since amphiphilic polymers has hydrophobic domain, the cellular membrane can be modified with the polymers, which enabled us to perform cell manipulation and cell fusion. Conjugation of single stranded DNA (ssDNA) or functional oligopeptide to poly(ethylene glycol)-conjugated phospholipid (PEG-lipid) made it possible to induce specific cell-cell attachment and cell-substrate attachment. Those PEG-lipid derivatives are very convenient for this purpose because they are not taken up into cells and are localized on the cell surface, which indicates that the functional domains are displayed on the cell surface. With the technique, new bioartificial pancreas will be made and also the improvement of cell fusion will be realistic.

In Japan, 10 cell products have already been approved, including cell sheets, mesenchymal stem cells, and CAR-expressing T cells. Therapies that use cells as drugs also need to control their pharmacokinetics in the body, such as delivery to the therapeutic target site and enhanced adhesion to target cells.

In therapies using CAR-expressing T cells, viral vectors are used to induce CAR expression on the T cell membrane. Specific cell adhesion of the T cells via the CAR allows them to attack the therapeutic target cells, resulting in a therapeutic effect. This is an example of the effective therapeutic use of regulation of pharmacokinetics by modification of cell membrane surfaces.

In this paper, we first give an overview of the three approved cell preparations and cell kinetics, then introduce each cell membrane modification technique, such as gene transfer, chemical modification, and use of lipophilic anchors, and then present studies in which the kinetics of therapeutic cells were controlled by cell membrane modification using these techniques. Finally, we will also introduce our work on orientation-aligned modification of cell membranes with a small antibody as a target-directed molecule.