We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid meta-bolic reprogramming. Fenofibrate was encapsulated in amphi-philic polygamma glutamic acid-based nanoparticles (F/ANs), and the surfaces of F/ANs were modified with an anti-CD3e f(ab′)2 fragment, yielding aCD3/F/ANs. An in vitro study reveals enhanced delivery of aCD3/F/ANs to T cells com-pared with plain F/ANs. aCD3/F/AN-treated T cells exhib-ited clear mitochondrial cristae, a higher membrane potential, and a greater mitochondrial oxygen consumption rate under glucose-deficient conditions compared with T cells treated with other nanoparticle preparations. Peroxisome proliferator-activated receptor-α and downstream fatty acid metabolism-related genes are expressed to a greater extent in aCD3/F/AN-treated T cells. Activation of fatty acid metabolism by aCD3/F/ANs supports the proliferation of T cells in a glucose-deficient environment mimicking the tumor microenvironment. Real-time video recordings show that aCD3/F/AN-treated T cells exerted an effector killing effect against B16F10 melanoma cells. In vivo administration of aCD3/F/ANs can increase infiltration of T cells into tumor tissues. The treatment of tumor-bearing mice with aCD3/F/ANs enhances production of vari-ous cytokines in tumor tissues and prevented tumor growth. Our findings suggest the potential of nanotechnology-enabled reprogramming of lipid metabolism in T cells as a new modality of immunometabolic therapy.