Targeting Tumor Microenvironment by Small-Molecule Inhibitors

Abstract

The tumor microenvironment (TME) is a hypoxic, acidic, and immune/inflammatory cell-enriched milieu that plays crucial roles in tumor development, growth, progression, and therapy resistance. Targeting TME is an attractive strategy for the treatment of solid tumors. Conventional cancer chemotherapies are mostly designed to directly kill cancer cells, and the effectiveness is always compromised by their penetration and accessibility to cancer cells. Small-molecule inhibitors, which exhibit good penetration and accessibility, are widely studied, and many of them have been successfully applied in clinics for cancer treatment. As TME is more penetrable and accessible than tumor cells, 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. In this review, we briefly summarize the recent advances of small-molecule inhibitors that target TME for the tumor treatment.

Figure 1

Hypoxia-targeted therapy. The hypoxia in TME is resulted from several factors. Some hypoxia-activated prodrugs or hypoxia-targeting nanoparticle drug-delivery system are developed to inhibit the growth of cancer cells. TME, tumor microenvironment; ECM, extracellular matrix; EPR, enhanced permeability and retention effect.

Figure 2

Schematic diagram for the acidic-targeted therapy. When acid is produced due to the anaerobic glycolysis in tumor cells, several membrane transporters or exchangers, including NHE1, MCTs, V–H⁺-ATPase, AEs, and NBCs, transport the acid to extracellular microenvironment. In addition, the oxidative stress from tumor cells impairs the mitochondrial function of CAFs, resulting in the production and secretion of lactate. Some small-molecule inhibitors are designed to target these proton membrane transporters or exchangers to suppress tumor progression. And some pH-responsive prodrugs or pH-sensitive drug delivery systems are developed to specifically release drug in acidic TME. Abbreviation: pHi: intracellular pH; pHe: extracellular pH; NHE1: Na⁺/H⁺ exchanger 1; MCTs: monocarboxylate-H⁺ efflux cotransporters; V–H⁺-ATPase: vacuolar-type H-ATPase; AEs: anion exchangers; NBCs: Na⁺-HCO₃^- co-transporters; CAIX: carbonic anhydrase IX; CAXII: carbonic anhydrase XII; ROS: reactive oxygen species; TME, tumor microenvironment; CAFs, cancer-associated fibroblasts; EPR, enhanced permeability and retention effect.