Advances in artificial metabzymes for macrophage polarization in tumor metabolic immunotherapy

Malignant tumor progression is driven by profound metabolic reprogramming, which not only fuels tumor growth but also impairs antitumor immune functions, particularly by inhibiting M1-type tumor-associated macrophages (TAMs) and thereby reinforcing an immunosuppressive microenvironment. Recent advances in nanotechnology have enabled the development of artificial nanozymes for metabolic regulation-also termed as metabzymes-which mimic natural metabolic enzymes to reprogram tumor and immune cell metabolism. Achieving precise control requires a systematic understanding of the chemical design, structure-activity relationships, and nano-bio interactions of metabzymes-insights that are critical for TAMs-targeted metabolic reprogramming and enhancing antitumor immunity. This review highlights the design and construction strategies of artificial metabzymes that mimic natural metabolic enzymes, as well as their application in modulating TAMs metabolism to promote M1 polarization, thereby advancing tumor metabolic immunotherapy. First, we discuss the rational structural design and atomic-level construction of artificial metabzymes, which mimic key natural metabolic enzymes through precisely engineered catalytic center architectures, spatial conformations, electron-transfer pathways, and intrinsic reaction mechanisms, thereby elucidating their structure-activity relationships and enabling the reprogramming of aberrant metabolic pathways. We further highlight the effects of these metabzymes on regulating both cellular metabolism (e.g., glucose, amino acid, purine, and redox metabolism) and intercellular metabolic crosstalk to reprogram TAM M1 polarization, thereby reversing immunosuppression and enhancing antitumor immunity. Finally, we discuss current challenges and delineate future directions for engineering intelligent metabzymes as next-generation immunomodulatory adjuvants to advance precision metabolic immunotherapy.