Acidic Tumor Microenvironments and Emerging Therapeutic Strategies for Cancer Therapy

Hypoxia and acidity represent two distinct properties of tumor microenvironments (TMEs). Tumor acidity was initially proposed to be a "by-product" of hypoxia, which results from abnormal vasculature and excessive oxygen demands. It is now recognized that acidity has its unique function in TMEs, as it can exacerbate abnormal cellular energy metabolism, inhibit cellular carcinogen metabolism, impede DNA damage repair mechanisms, and suppress immune cell activation, all of which play crucial roles during carcinogenesis. Acidic TMEs are also major contributors to the invasion and metastasis of tumor cells, and participate in the mechanisms underlying resistance to cancer treatments including immunotherapy. Therefore, the development of novel anti-cancer agents that target acidic TMEs may have considerable clinical benefits. This article reviews the updated information in this rapidly growing field, including the influence of acidic TMEs on cancer progression, resistance to current treatments and anti-cancer immunity, and their association with hypoxia and aerobic glycolysis. It also summarizes the key molecules that contribute to acidic TMEs and highlights the development of anti-cancer agents targeting tumor acidity, primarily inhibitors of carbonic anhydrases, monocarboxylic acid transporters, vacuolar-type adenosine triphosphatase (V-ATPase), and Na⁺/H⁺ exchangers. At present, none of the inhibitors targeting acidic TMEs have been approved for clinical use in cancer treatment, except for proton pump inhibitors that target V-ATPase. Development of highly specific agents and the discovery of more sensitive and precise biomarkers may help improve the effectiveness of these inhibitors for cancer therapy.