Recent progress in small molecules targeting the acidic tumor microenvironment

Area of Science:

• Oncology
• Tumor Microenvironment
• Drug Development

Background:

• The acidic tumor microenvironment (pHe 6.5-6.9) promotes tumor invasion, immune evasion, and therapeutic resistance.
• Key pH regulators include monocarboxylate transporters, Na+/H+ exchanger 1, vacuolar ATPase, and carbonic anhydrases IX and XII.

Purpose of the Study:

• To review small molecule inhibitors targeting tumor-associated acid-base regulators.
• To highlight opportunities and challenges in developing novel anti-tumor drugs targeting tumor acidity.

Main Methods:

• Review of structural design, structure-activity relationships, and biological activity of small molecule inhibitors.
• Summary of acid-targeted delivery strategies, including pH-responsive prodrugs and pHLIP peptides.
• Analysis of clinical trial progress for relevant inhibitors.

Main Results:

• Small molecule inhibitors show potential in preclinical studies but face challenges like metabolic compensation and poor target selectivity.
• Acid-targeted delivery strategies offer a promising approach to enhance drug efficacy and reduce toxicity.
• Clinical translation remains a significant hurdle.

Conclusions:

• Developing highly selective and low-toxicity anti-tumor drugs targeting tumor acidity requires addressing current challenges.
• Further research into molecular design and advanced delivery systems is crucial for clinical success.