Compartmental pH regulation in cancer and antitumor immunity: therapeutic opportunities and challenges

Dysregulated pH homeostasis is a defining feature of tumor biology and a potential therapeutic vulnerability. Cancer cells maintain an alkaline intracellular pH, whereas the tumor microenvironment remains acidic and intracellular organelles preserve compartment-specific luminal acidity, together supporting tumor growth, metabolic adaptation, immune evasion, and therapeutic resistance. Recent studies show that modulation of pH regulation across the tumor microenvironment, cytoplasm, and intracellular organelles disrupts ionic balance, impairs organelle function, and triggers regulated cell death, including alkaliptosis and organelle stress-associated lethality. Beyond direct tumor killing, pH modulation also reshapes antitumor immunity by relieving extracellular acidosis, restoring immune-cell function, and inflammatory signaling. In this review, we summarize recent advances in compartmental pH regulation in cancer, with particular emphasis on the distinction between experimentally demonstrated mechanisms and emerging conceptual models. We discuss how alkalization-oriented interventions may suppress tumor growth in selected contexts, but may also produce neutral, adaptive, or even protumorigenic consequences depending on tumor type, buffering capacity, transporter activity, metabolic state, and immune composition. We further evaluate pH-dependent immune regulation, organelle alkalization, alkaliptosis, quantitative pH measurement, and monitoring technologies. Finally, we highlight major translational barriers. A more quantitative, compartment-resolved, and context-aware understanding of pH biology will be required before pH modulation can be reliably translated into clinically useful therapeutic strategies.