Dual targeting of lipid metabolic reprogramming and immunosuppressive sentinel lymph nodes potentiates anti-metastatic therapy for triple negative breast cancer

Inducing immunogenic cell death (ICD) in cancer cells provides a promising approach in immunotherapy, however, oxidative stress relief and metabolic plasticity enhancement limit the immune-stimulating effect of traditional ICD inducer in sentinel lymph nodes (SLN), owing to the metabolism of fatty acids. In this article, a biocompatible green liposome CL-Lip was designed to not only selectively induce ICD in primary and metastatic 4T1 cells, but also relieved the immunosuppression in invasive SLN. CL-Lip is composed of engineered liposomes modified with linoleic acid and catalase, which synergistically trigger ICD, stimulate lipid peroxidation, PD-L1 carbonylation and effectively promote the maturation of dendritic cells and T cell differentiation. Moreover, catalase also downregulated the hypoxia level in SLN. Through cellular experiments and transcriptome analysis, it is proved that the ICD induction via CL-Lip is mediated by ROS generation, resulting from the YAP-dependent fatty acid oxidation (FAO) interference. Transcriptome analysis revealed that engineered CL-Lip diminishes YAP-dependent FAO pathway and effectively antagonizes the metabolic flexibility, thereby selectively triggering the metabolic dead-associated ICD process in both primary and metastatic 4T1 cells. In animal experiments, this little reported metabolic-driven ICD route not only significantly reduces metastatic foci, but also induces a “cold-to-hot” remodeling of SLN, resulting in the formation of a in situ tumor vaccine. These findings hold great significance for the development of next-generation ICD inducers and immunotherapy approaches.