Small Molecules

Introduction

One of the critical factors that influence the efficacy of immunotherapy is the tumor microenvironment (TME). The TME provides rational targets for small molecule inhibition through which immunomodulation can occur. The foundation for the pursuit of small molecule immune therapies for cancer is the wide spectrum of cells and their molecular pathways that are used by the immune system to suppress or enhance cellular immunity. A lot of efforts have recently been made to generate small-molecule inhibitors that specifically target TME or the components of TME or develop special drug-delivery systems that release the cytotoxic drugs specifically in TME. Compared with macromolecule agents, small molecule targeted compounds are easily structurally modified to make it more applicable to clinical needs, and convenient to promote due to low cost.

Small Molecules as Immunotheranostics

Small molecules are designed to interrupt the specific features of TME, including the hypoxic, acidic, inflammatory milieu, as well as the abnormal ECM network in TME.

• Some hypoxia-activated prodrugs or hypoxia-targeting nanoparticle drug-delivery systems are developed to inhibit the growth of cancer cells. Drugs targeting angiogenesis also improve hypoxia TME and is an anticarcinomaous strategy. At present most of the angiogenesis inhibitors are developed targeting VEGFs or their receptors.
• As for the acidic TME, some small-molecule inhibitors are designed to target proton membrane transporters or exchangers (which transport the acid produced by tumor anaerobic glycolysis to the extracellular microenvironment) to suppress tumor progression.
• The small-molecule inhibitors that target immune cells or/and the inflammatory signaling are promising strategies to inhibit tumor progression. Among them, immune checkpoint inhibitors, mainly focused on PD-1, PD-L1 and CTLA-4, have achieved some exciting clinical applications.
• The major components of the ECM are fibronectin, fibrillar collagens, matricellular proteins and hyaluronan. Among them, the use of matrix metalloproteinases (MMPs) inhibitors as therapeutics in cancer has been explored but was shown to have limited clinical success. TGF-β signaling is another pathway that mediates communication between tumor cells and their ECM. Targeted drugs reduce the matrix overload by suppressing ECM via TGF expression blockade, which results in low matrix accumulation. Nonsteroidal anti-inflammatory drugs (NSAIDs) drugs inhibit cyclooxygenase-1 (COX-1), affect ECM components and exert their chemoprotective effects in many cancers.