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The precise localization of metastatic tumors with subtle growth is crucial for timely intervention and improvement of tumor prognosis but remains a paramount challenging. To date, site-specific activation of fluorogenic probes for single-stimulus-based diagnosis typically targets an occult molecular event in a complex biosystem with limited specificity. Herein, we propose a highly specific site-specific cascade-activated strategy to enhance detection accuracy, aiming to achieve the accurate detection of breast cancer (BC) lung metastasis in a cascade manner. Specifically, cascade-activatable NIR fluorogenic nanomicelles HPNswere constructed using ultra-pH-sensitive (UPS) block copolymers as carriers and nitroreductase (NTR)-activated fluorogenic reporters. HPNsexhibit programmable cascade response characteristics by first instantaneous dissociating under in situtumor acidity, facilitating deep tumor penetration followed by selective fluorescence activation through NTR-mediated enzymatic reaction resulting in high fluorescence ON/OFF contrast. Notably, this unique feature of HPNsenables high-precision diagnosis of orthotopic BC as well as its lung metastases with a remarkable signal-to-background ratio (SBR). This proposed site-specific cascade activation strategy will offer opportunities for a specific diagnosis with high signal fidelity of various insidious metastatic lesions in situacross different diseases.