免疫检查点阻断（ICB）免疫疗法仍然受到免疫原性不足和高乳酸免疫抑制肿瘤微环境（TME）的阻碍。在此，构建了一种具有靶向代谢重编程能力的纳米抗体工程 NIR-II 纳米佐剂，用于增强 NIR-II 光热铁死亡免疫疗法。具体来说，纳米佐剂（2DG@FS-Nb）是通过金属铁离子介导的D-A-D型NIR-II分子的配位自组装和糖酵解抑制剂2-脱氧-D-葡萄糖（2DG）的负载，然后进行修饰而制备的。含有aPD-L1纳米抗体（Nb），可有效靶向免疫抑制性TME并触发原位免疫检查点封锁。纳米佐剂在酸性 TME 中响应性地释放治疗成分，通过 NIR-II 荧光/光声成像实现肿瘤的精确定位，同时启动 NIR-II 光热铁死亡治疗。显着的 NIR-II 光热效率和升高的谷胱甘肽 (GSH) 消耗进一步使铁死亡变得敏感，诱导严重的脂质过氧化，引发强烈的免疫原性细胞死亡 (ICD)，从而触发抗肿瘤免疫反应。重要的是，释放的 2DG 通过糖酵解障碍显着抑制乳酸生成。乳酸流出量的减少通过抑制 M2 巨噬细胞增殖和下调调节性 T 细胞水平来重塑免疫抑制性 TME。这项工作为将 NIR-II 光治疗和乳酸代谢调节整合到单个纳米平台中提供了新的范例，用于与 ICB 疗法相结合的放大抗肿瘤免疫疗法。© 2024 作者。 《Advanced Science》由 Wiley‐VCH GmbH 出版。

Immune checkpoint blockade (ICB) immunotherapy remains hampered by insufficient immunogenicity and a high-lactate immunosuppressive tumor microenvironment (TME). Herein, a nanobody-engineered NIR-II nanoadjuvant with targeting metabolic reprogramming capability is constructed for potentiating NIR-II photothermal-ferroptosis immunotherapy. Specifically, the nanoadjuvant (2DG@FS-Nb) is prepared by metallic iron ion-mediated coordination self-assembly of D-A-D type NIR-II molecules and loading of glycolysis inhibitor, 2-deoxy-D-glucose (2DG), followed by modification with aPD-L1 nanobody (Nb), which can effectively target the immunosuppressive TME and trigger in situ immune checkpoint blockade. The nanoadjuvants responsively release therapeutic components in the acidic TME, enabling the precise tumor location by NIR-II fluorescence/photoacoustic imaging while initiating NIR-II photothermal-ferroptosis therapy. The remarkable NIR-II photothermal efficiency and elevated glutathione (GSH) depletion further sensitize ferroptosis to induce severe lipid peroxidation, provoking robust immunogenic cell death (ICD) to trigger anti-tumor immune response. Importantly, the released 2DG markedly inhibits lactate generation through glycolysis obstruction. Decreased lactate efflux remodels the immunosuppressive TME by suppressing M2 macrophage proliferation and downregulating regulatory T cell levels. This work provides a new paradigm for the integration of NIR-II phototheranostics and lactate metabolism regulation into a single nanoplatform for amplified anti-tumor immunotherapy combined with ICB therapy.© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.