Boosting Ferroptosis and immunotherapy for Colorectal Cancer by Lactate‐Related Metabolic Reprogramming

Abstract As the presence of anaerobic metabolism of glucose, solid tumors characteristically display higher levels of lactate production, which attenuate ferroptosis therapy and the subsequent anti‐tumor immune response. Herein, hyaluronic acid (HA)‐modified and lactate oxidase (LOX)‐loaded nanoscale metal organic frameworks (MOFs), termed as FCS@LOX@HA (FCSLH) is constructed, achieving tumor‐targeted metabolic combined chemo‐dynamic therapy (CDT). Notably, the high LOX‐loading capacity of MOFs is achieved by adjusting the Fe/Cu ratio. Upon internalization by cancer cells, the FCS MOFs reacted with local glutathione (GSH) to release Fe/Cu ions for CDT. Meanwhile, the LOX catalyzed endogenous lactate to pyruvate accompanied with a release of H₂O₂; while the latter can enhance the FCS MOFs‐mediated CDT effect. Additionally, lactate exhaustion can impair the antioxidant system by inhibiting the HIF‐1α/SLC1A1 pathway, resulting in the accumulation of lipid peroxidation, and ferroptosis occurs accompanied by immunogenic cell death. Furthermore, lactate exhaustion within tumor‐associated macrophages (TAMs) can inhibit M2 macrophage polarization by suppressing the NF‐κB/HIF‐1α pathway, thereby augmenting anti‐tumor immune response. The in vivo studies demonstrated that cooperating with PD‐L1 antibodies can achieve excellent anti‐tumor therapeutic efficacy. Taken together, FCSLH can amplify the ferroptosis‐mediated immune response through simultaneous dysfunction of cancer cells and TAMs, which provides novel insight for integrating metabolic programmed therapy and immunotherapy.