Tolerance to extracellular acidic pH facilitates tumor plasticity

Cancer cells sustain glycolysis despite oxygen availability, creating an acidic microenvironment via proton and lactate export, but how they survive acid stress is unclear. We show that severe acidification (pH 5.6) induces necroptosis, whereas moderate acidity (pH 6.8) prevents death and enables anchorage-independent survival and tumor initiation. RNA sequencing of suspended cells at pH 6.8 revealed activation of respiratory chain complex and complement pathways, consistent with adaptation to this pH. A genome-wide CRISPR- Cas9 knockout screen in PANC1 cells under chronic acidity identified FAM129C as a regulator of acid tolerance and survival. In xenografts, FAM129C overexpression reduced PIGR expression, implicating this axis in tumor growth and immune infiltration. Anti-PD-L1 plus a complement inhibitor showed synergistic anti-tumor activity in PIGR-overexpressing tumors. Thus, acidic stress engages a pathway that allows cancer cells to evade necroptosis and promote tumor plasticity, providing potential avenues for therapeutic intervention targeting pH-dependent cell-death pathways.