Tumor metabolism is crucial in the continuous advancement and complex growth of cancer. The emerging field of nanotechnology has made significant strides in enhancing the understanding of the complex metabolic intricacies inherent to tumors, offering potential avenues for their strategic manipulation to achieve therapeutic goals. This comprehensive review delves into the interplay between tumor metabolism and various facets of cancer, encompassing its origins, progression, and the formidable challenges posed by metastasis. Simultaneously, it underscores the classification of programmable nanomodulators and their transformative impact on enhancing cancer treatment, particularly when integrated with modalities such as chemotherapy, radiotherapy, and immunotherapy. This review also encapsulates the mechanisms by which nanomodulators modulate tumor metabolism, including the delivery of metabolic inhibitors, regulation of oxidative stress, pH value modulation, nanoenzyme catalysis, nutrient deprivation, and RNA interference technology, among others. Additionally, the review delves into the prospects and challenges of nanomodulators in clinical applications. Finally, the innovative concept of using nanomodulators to reprogram metabolic pathways is introduced, aiming to transform cancer cells back into normal cells. This review underscores the profound impact that tailored nanomodulators can have on tumor metabolic, charting a path toward pioneering precision therapies for cancer.