Lipid metabolic reprogramming has emerged as a hallmark in cancer research, especially that of fatty acids (FAs). It promotes the effective utilization of the limited nutrients in the tumor microenvironment (TME) by the cells and has considerably been associated with immune escape. Tumor cells exhibit enhanced FA uptake, synthesis, and oxidation for metabolic adaptation, and non-tumor cells also undergo FA metabolic remolding in the TME. Owing to the essential role of FA metabolism in TME, the associated critical enzymes may be targeted for developing novel therapeutic approaches. This review aims to comprehensively summarize the FA metabolic landscapes in various cancers and FA-related molecular changes, FA metabolic reprogramming in different cells in the TME to identify potential targets, and FA-related cell interactions and underlying mechanisms in the TME. The findings of this study may provide insights into exploring the intricate FA metabolism–TME adaptation interplay to uncover potential metabolic targets of therapeutic significance for combinatorial strategies and enhancing immunotherapy.