树突状细胞（DCs）是先天和适应性抗肿瘤免疫的关键媒介者，而外源性和内源性驱动的脂质堆积导致免疫耐受性的肿瘤关联DCs（TADCs），因此降低了肿瘤对各种治疗的反应性。在这里，我们设计了一种多级脂质重构纳米粒子（NPs）用于TADC的振兴。这些自组装的NPs特异性地结合到TADC表面的脂质转运受体Msr1，并编排限制细胞外脂质摄取、细胞质内的新生脂质生物合成和核内脂肪生成基因的转录。我们发现，通过三合一脂质代谢重编程使TADC瘦身，显著促进它们的成熟并恢复其在炎性细胞因子产生、细胞毒性T细胞招募和抑制肿瘤的功能。更重要的是，它还克服了肿瘤对免疫检查点阻断治疗的抵抗力。我们的研究提出了一种非常规的策略来重塑肿瘤浸润的免疫细胞，并为提高癌症免疫治疗效果开辟了一条新路。本文章受版权保护，版权所有。

Dendritic cells (DCs) are crucial mediators of innate and adaptive anti-tumor immunity, whereas exogenously- and endogenously-driven lipid accumulation causes immune tolerance of tumor-associated DCs (TADCs) and thereby diminishes tumor responsiveness to various therapies. Herein, we design a type of multilevel lipid rewiring nanoparticles (NPs) for TADC revitalization. These self-assembled NPs specifically bind to the lipid transport receptor Msr1 on the TADC surface and orchestrate the restriction of extracellular lipid uptake, cytoplasmic de novo lipid biosynthesis and nuclear lipogenic gene transcription. We find that the slimming of TADCs via the three-in-one lipid metabolic reprogramming substantially promotes their maturation and rehabilitate their functions in inflammatory cytokine production, cytotoxic T cell recruitment and tumor inhibition. Significantly, it further overcomes tumor resistance to immune checkpoint blockade therapy. Our study presents a non-canonical strategy to remodel tumor-infiltrating immune cells and paves a new path for improving the efficacy of cancer immunotherapy. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.