Abstract: Metabolic reprogramming represents one of the core hallmarks of cancer, and the underlying regulatory mechanisms are attributable not only to alterations in the activities of metabolic enzymes, but also to the participation of elaborate protein-protein interaction networks. As a key intracellular molecular chaperone system, the heat shock protein (HSP) family is extensively involved in the regulation of tumor metabolic reprogramming. This review systematically summarizes the latest research progress of HSP-driven tumor metabolic reprogramming and malignant tumor progression, and proposes an integrated regulatory framework termed the“HSPmetabolism axis”: 1) directly binding to and stabilizing key metabolic enzymes involved in glycolysis, tricarboxylic acid cycle, lipid metabolism and other metabolic pathways; 2) regulating signaling molecules such as mammalian target of rapamycin and hypoxiainducible factor-1α, to systematically reshape tumor metabolic profiles; and 3) assembling metabolic enzyme-signaling protein complexes as scaffold proteins, thereby coupling metabolic processes and signal transduction in a spatiotemporal manner. On this basis, this paper compares the metabolic regulatory features of distinct HSP members and reviews the research status of their representative HSP inhibitors. Relevant studies have clarified the novel function of HSPs in modulating tumor metabolic networks, providing a theoretical basis for the development of anti-tumor strategies targeting HSPs.