Aspects of the present disclosure include methods and compositions related to therapeutic immune cells having enhanced metabolic fitness. In certain aspects, polynucleotides encoding one or more viral, bacterial, and / or fungal genes capable of manipulating
cell metabolism and, optionally, one or more
antigen-specific receptors, are disclosed. In some aspects, disclosed are methods for enhancing the metabolic fitness of an immune
cell comprising introducing into the immune
cell a
polynucleotide encoding one or more viral, bacterial, and / or fungal genes capable of manipulating
cell metabolism. Cells (e.g., NK cells, T cells) expressing polynucleotides encoding one or more viral, bacterial, and / or fungal genes capable of manipulating
cell metabolism and, optionally, one or more
antigen-specific receptors are described. Also described are therapeutic methods using polynucleotides of the disclosure.