Lung cancer remains the most prevalent and deadliest malignant tumor worldwide, and there is an urgent need to develop novel antitumor therapies to achieve satisfactory treatment outcomes. Traditional Chinese Medicine (TCM) is a traditional therapeutic approach in China, and extensive clinical and basic research has shown its excellent antitumor efficacy. Dysregulation of lipid metabolism is one of the significant characteristics of malignant tumors, with mitochondria playing a crucial role. Inducers of the cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes (cGAS/STING) pathway can influence the lipid metabolism of tumor cells. Here, we designed a polydopamine-based nanomaterial targeting mitochondria and encapsulated Cryptotanshinone to enhance cGAS/STING-mediated lipid metabolism and mitochondrial apoptosis, thereby exerting a targeted inhibitory effect on primary tumor lesions and ex vivo tumor cells. Consequently, our engineered nanosystem represents a novel strategy for promoting tumor lipid metabolism reprogramming and mitochondrial apoptosis through the modulation of the cGAS/STING pathway, thus addressing the significant challenge associated with regulating mitochondrial function to suppress Non-Small Cell Lung Cancer (NSCLC).