传统上被称为“代谢垃圾”的乳酸现在已被认为是重要的“能量货币”和有助于肿瘤进化、免疫抑制等的重要“信使”，从而为抗肿瘤干预提供了一种有前景的策略。同样，犬尿氨酸（Kyn）也发挥免疫抑制功能，从而显着损害免疫疗法的有效性。这项研究提出并验证了一种通过类循环 O2 供应维持的光热辅助消耗乳酸来增强免疫治疗的策略，同时阻断色氨酸 (Trp)/Kyn 代谢途径。简而言之，构建了一种纳米酶治疗剂（PNDPL），其主要由PtBi纳米酶、乳酸氧化酶（LOX）和吲哚胺2,3-双加氧酶（IDO）抑制剂NLG919组成。 PtBi 纳米酶表现出类似过氧化氢酶 (CAT) 的活性，与 LOX 形成正反馈回路，消耗乳酸，同时自我供应 O2。此外，PtBi纳米酶即使在微酸性肿瘤微环境中也能保持酶样性能。在 1064 nm 照射下，光热疗法 (PTT) 不仅会诱导肿瘤细胞死亡，还会加速乳酸消耗。因此，乳酸消耗诱导的饥饿疗法与PTT相结合，加上阻断IDO介导的免疫逃逸，可以有效抑制肿瘤生长并逆转免疫抑制微环境，从而防止肿瘤转移。这项研究首次研究了乳酸代谢调节和 IDO 相关免疫疗法的协同抗肿瘤作用。© 2023 Wiley-VCH GmbH。

Traditionally referred to as "metabolic junk", lactate has now been recognized as essential "energy currency" and crucial "messenger" that contributes to tumor evolution, immunosuppression, etc., thus presenting a promising strategy for antitumor interventions. Similarly, kynurenine (Kyn) also exerts an immunosuppressive function, thereby significantly compromising the effectiveness of immunotherapy. This study proposes and validates a strategy for enhancing immunotherapy through photothermal-assisted depletion of lactate sustained by cycle-like O2 supply, with blocking the tryptophan (Trp)/Kyn metabolic pathway. In brief, a nanozyme therapeutic agent (PNDPL) is constructed, which mainly consists of PtBi nanozymes, lactate oxidase (LOX) and the indoleamine 2,3-dioxygenase (IDO) inhibitor NLG919. The PtBi nanozymes, which exhibit a catalase (CAT)-like activity, form a positive feedback loop with LOX to consume lactate while self-supplying O2 . Moreover, PtBi nanozymes retain enzyme-like performance even in a slightly acidic tumor microenvironment. Under 1064 nm irradiation, photothermal therapy (PTT) not only induces tumor cell death but also accelerates lactate exhaustion. Therefore, the combination of lactate depletion-induced starvation therapy and PTT, along with the blocking of IDO-mediated immune escape, effectively inhibits tumor growth and reverses immunosuppressive microenvironment, thus preventing tumor metastasis. This study represents the first investigation into the synergistic antitumor effects by lactate metabolism regulation and IDO-related immunotherapy.© 2023 Wiley-VCH GmbH.