Lysosomal adaptation to extracellular acidity compromises CD8+ T cell cytotoxicity

Chronic exposure of human CD8+ T cells to pH 6.5 drives lysosomal remodeling that hyper-acidifies lysosomes and impairs cytotoxic killing by depleting the granzyme B reservoir.

• Why it matters: Extracellular acidosis is a hallmark of aggressive tumors and suppresses CTL killing, but the sustained acid-driven changes to T cell cytotoxicity are poorly understood.
• What they did: Quantitative proteomics of CD8+ T cells cultured at pH 6.5 showed lysosomes as the dominant target, with V1 vacuolar H+-ATPase upregulation, increased lysosomal proteolytic activity, and Ca2+-dependent constitutive LAMP1+ vesicle release.
• The result: The remodeled lysosome acts as a proton sink and drains intracellular granzyme B via constitutive vesicle release, reducing CTL activity and suggesting lysosomal hydrolase activity as a target to improve function in acidic tumors.