Multiscale imaging on proton pump-driven acidity for assessing tumor progression and metastasis.

An acidic tumor microenvironment (TME), a hallmark of cancer progression, promotes tumor growth, invasion, and metastasis. Detecting and targeting tumor acidity have emerged as key frontiers in early cancer diagnosis and treatment. However, current approaches lack sensitive and specific methods to visualize and quantify tumor acidity in vivo across different stages of tumor development. Here we show that ATP6V0C, a subunit of the V-ATPase responsible for proton transmembrane transport, is a critical mediator of TME acidification. High ATP6V0C expression correlates with hepatocellular carcinoma (HCC) progression and metastasis. To enable real-time assessment of tumor acidity, we develop a pH-responsive ratiometric photoacoustic sensor (PPS) that dynamically monitors TME acidity throughout HCC initiation, progression, and metastasis. Using PPS-assisted photoacoustic molecular imaging, we visualize the spatiotemporal evolution of TME acidity from early tumor foci to solid tumors. PPS exhibits enhanced photothermal effects under acidic conditions, and its combination with the proton pump inhibitor esomeprazole synergistically suppresses tumor growth. Overall, PPS-assisted photoacoustic molecular imaging provides a sensitive and specific approach to characterize tumor initiation and progression, supporting its potential application in early diagnosis and therapeutic strategies that target the acidic TME.