Cancer remains a leading cause of mortality worldwide, with over 10 million deaths annually (WHO, 2023). Despite advancements, accessibility to affordable therapies remains challenging. Tumor microenvironment-driven cancers, such as lung and breast cancers, are particularly aggressive due to their reliance on hypoxia (low oxygen levels) and acidic pH for survival and progression. The tumor microenvironment, characterized by hypoxia and low pH, targeting these unique hallmarks of cancer through innovative therapeutic strategies offers a promising approach to overcoming these challenges. Specific enzymes, transporters, and pathways involved in this process, such as carbonic anhydrases, monocarboxylate transporters (MCTs), and sodium-hydrogen exchangers (NHEs), provide potential targets for disrupting tumor pH homeostasis. Such interventions could impair tumor growth and sensitize cancer cells to standard therapies. This research aims to develop benzopyrone-based therapeutics to disrupt the tumor’s ability to regulate intracellular pH under hypoxic conditions, leading to acidification of cancer cells, impaired cell proliferation, and increased sensitivity to conventional therapies such as chemotherapy and radiotherapy.