Severely polarized extracellular acidity around tumour cells

Area of Science:

• Oncology
• Biochemistry
• Nanotechnology

Background:

• Extracellular pH is critical for cellular functions and tightly regulated.
• Tumor microenvironments often become acidic due to cancer cell metabolism and poor perfusion.
• Understanding tumor acidity is key for developing new cancer therapies.

Purpose of the Study:

• To investigate the spatial distribution and cause of acidity in the tumor microenvironment.
• To utilize novel fluorescent pH nanoprobes for detecting localized acidic regions.
• To explore the potential of targeting tumor acidity for cancer diagnosis and treatment.

Main Methods:

• Development and application of fluorescent pH nanoprobes with a specific activation profile (pH 5.3).
• Genetic manipulation (knockout) and pharmacological inhibition of monocarboxylate transporters (MCTs).
• In vivo studies using mouse tumor models and ex vivo analysis of human squamous cell carcinoma tissue.

Main Results:

• Cancer cells excrete hydronium ions into small extracellular regions, creating severely polarized acidity (pH <5.3).
• This localized acidity is primarily driven by the co-export of protons and lactate via MCTs.
• Ex vivo analysis showed a correlation between spot acidification, MCT expression, and exclusion of cytotoxic T cells in human tumors.

Conclusions:

• Severely polarized tumor acidity is a distinct feature of the tumor microenvironment.
• Monocarboxylate transporters play a crucial role in generating this localized acidity.
• Targeting or leveraging this spatial acidity presents a promising avenue for cancer diagnosis and therapy.