Acidic extracellular pH is a key feature of tumor tissues, primarily due to lactate production from anaerobic glycolysis. This acidic environment activates lysosomal enzymes and promotes the expression of pro-metastatic genes through intracellular signaling pathways distinct from hypoxia. Other sources of acidity include CO₂ from the pentose phosphate pathway, highlighting the complex relationship between hypoxia and extracellular acidity. The acidic microenvironment contributes to tumor progression by enhancing metastasis, promoting angiogenesis, and influencing immune responses. Lactate, a major contributor to acidity, inhibits T-cell function and enhances tumor cell motility. It also activates matrix metalloproteinases (MMPs), which facilitate tumor invasion and metastasis. The acidic environment is sensed by various proton-sensing receptors, such as OGR1 and TDAG8, which modulate cellular responses. The pH gradient formed by H⁺ pumps and exchangers is crucial for cell migration and tumor metastasis. Inhibiting these mechanisms or targeting proton-sensing pathways could be therapeutic strategies. Additionally, acidic pH affects drug efficacy and resistance, influencing treatment outcomes. Understanding the role of acidic pH in tumor progression is essential for developing effective cancer therapies.Acidic extracellular pH is a key feature of tumor tissues, primarily due to lactate production from anaerobic glycolysis. This acidic environment activates lysosomal enzymes and promotes the expression of pro-metastatic genes through intracellular signaling pathways distinct from hypoxia. Other sources of acidity include CO₂ from the pentose phosphate pathway, highlighting the complex relationship between hypoxia and extracellular acidity. The acidic microenvironment contributes to tumor progression by enhancing metastasis, promoting angiogenesis, and influencing immune responses. Lactate, a major contributor to acidity, inhibits T-cell function and enhances tumor cell motility. It also activates matrix metalloproteinases (MMPs), which facilitate tumor invasion and metastasis. The acidic environment is sensed by various proton-sensing receptors, such as OGR1 and TDAG8, which modulate cellular responses. The pH gradient formed by H⁺ pumps and exchangers is crucial for cell migration and tumor metastasis. Inhibiting these mechanisms or targeting proton-sensing pathways could be therapeutic strategies. Additionally, acidic pH affects drug efficacy and resistance, influencing treatment outcomes. Understanding the role of acidic pH in tumor progression is essential for developing effective cancer therapies.