Enzyme‐Instructed Self‐Assembly Reprograms Fatty Acid Metabolism for Cancer Therapeutics

Abstract Enzyme‐instructed self‐assembly (EISA) is actively explored as a promising therapeutic approach for cancer treatment. However, the metabolic response of cancer cells to EISA remains under‐studied. Here, by stimulated Raman scattering (SRS) imaging in C─H, fingerprint, and silent windows, it is found that the formation of peptide assemblies within and around cancer cells significantly enhances both lipids catabolism and fatty acids (FAs) uptake. It is further found that the increased uptake of FAs aids the resistance of cancer cells under EISA treatment, likely to cope with the stress induced by the peptide assemblies. Combining EISA with FAs uptake inhibition leads to enhanced cancer suppression compared to EISA alone, while additional FAs supplementation rescue cancer cells from EISA treatment, both in vitro and in 3D‐culture spheroid models. These findings shed new light on the impact of EISA on the metabolic activities of cancer cells and suggest a new approach for improved cancer therapy.