A lipid starvation strategy-synergized neutrophil activation for postoperative melanoma immunotherapy

Abstract

Abnormal metabolism of melanoma cells on lipids reveals that breaking their lipid addiction provides a starvation strategy to enhance immunotherapy effects and reduce resistance. Herein, we propose an extracellular matrix-inspired scaffold fabricated by multiple cross-linking of collagen and elastin encapsulated with fatty acid transporter proteins (FATP) inhibitor lipofermata (Lipo) to close the “valve” of lipid transported into both melanoma cells and pro-tumor neutrophils. Meanwhile, model TGF-β inhibitor loaded in scaffold synergized with Lipo to polarize postoperative locally enriched neutrophils towards cytotoxic N1 phenotypes after blocking their energy supply and modulate postsurgical immunosuppressive tumor microenvironment. These N1 neutrophils induced tumor pyroptosis through a reactive oxygen species (ROS)-dependent pathway under melanoma cells suffered starvation, and the intracellular contents released from dead melanoma cells stimulated macrophages into producing proinflammatory cytokines, which recruited a secondary wave of neutrophils to the tumor site. Benefiting from the N1 neutrophil induced tumor pyroptosis feedback loop in situ, adaptive and memory antitumor immunity is activated for suppressing aggressive melanoma recurrence and metastasis. Altogether, this lipid starvation strategy synergized with neutrophil activation for amplification of tumor-specific immunotherapy provides a new paradigm for pyroptosis-mediated postsurgical melanoma therapy.