Small molecules for immunomodulation in cancer: a review

Small-molecule cytotoxic agents are already in use for cancer immunotherapy in the form of antibody conjugates containing these molecules linked covalently to antibodies or their fragments with the goal of targeting specific surface components of tumor cells. However, there are also reports of small molecules that act as antagonists to surface enzyme-linked receptors and receptors that interact with the tumor microenvironment, or that even inhibit metabolic enzymes. Such molecules have been shown to directly inhibit the signaling initiated by the respective ligands binding to their receptors, to recruit antibodies and other immunomodulatory molecules, or to promote or inhibit the proliferation of different immune cells to target specific types of cancer cells. This review will discuss immune response modifiers such as imiquimod, antibody-recruiting molecules that target prostate cancer, integrin receptor antagonists, indoleamine-2,3-dioxygenase inhibitors, emodin, RORɣt antagonists, ephrin receptor antagonists, membrane-bound carbonic anhydrase IX (CAIX) inhibitors, and selected protein kinase inhibitors. These small molecules can open up new ways to treat many types of cancers and possibly even other diseases that arise from immune dysregulation. Finally, the review will briefly discuss some additional targets that are being pursued to modify immune system responses in the tumor microenvironment.