Optically controllable nanoregulators enable tumor-specific pro-ferroptosis lipometabolic reprogramming for in-situ...

In-situ tumor vaccination remains challenging due to difficulties in the exposure and presentation of tumor-associated neoantigens (TANs). In view of the central role of lipid metabolism in cell fate determination and tumor-immune cell communication, here we report a photo-controlled lipid metabolism nanoregulator (PLMN) to achieve robust in-situ adjuvant-free vaccination, which is constructed through hierarchically integrating photothermal-inducible arachidonate 15-lipoxygenase (ALOX15)-expressing plasmids, cypate and FIN56 into cationic liposomes. Near-infrared light (NIR) stimulation triggers on-demand ALOX15 editing and causes excessive accumulation of downstream pro-ferroptosis lipid metabolites. PLMN treatment enables efficient TAN release through ferroptosis-dependent membrane perturbation and facilitates their capture and processing by antigen-presenting cells via cationic lipid-mediated TAN enrichment. Meanwhile, upregulation of ALOX15-associated lipid metabolites also enhances M2-to-M1 phenotypic transition of tumor-associated macrophages through regulating tumor-macrophage metabolic crosstalk. PLMN treatment significantly enhance the robustness and durability of adaptive antitumor immunity in vivo, offering an approach for in-situ tumor vaccination in the clinic.