Cancer lactate metabolic reprogramming induces an elevated level of extracellular lactate and H, leading to an acidic immunosuppressive tumor microenvironment (TEM). High lactic acid level may affect the metabolic programs of various cells that comprise an antitumor immune response, therefore, restricting immune-mediated tumor destruction, and leading to therapeutic resistance and unsatisfactory prognosis. Here, we report a metal-phenolic coordination-based nanocomplex loaded with a natural polyphenol galloflavin, which inhibits the function of lactate dehydrogenase, reducing the production of lactic acid, and alleviating the acidic immunosuppressive TME. Besides, the co-entrapped natural polyphenol carnosic acid and the synthetic PEG-Ce6 polyphenol derivative (serving as a photosensitizer) could induce immunogenic cancer cell death upon laser irradiation, which further activates immune system and promotes immune cell recruitment and infiltration in tumor tissues. We demonstrated that this nanocomplex-based combinational therapy could reshape the TME and elicit immune responses in a murine breast cancer model, which provides a promising strategy to enhance the therapeutic efficiency of drug-resistant breast cancer.

中文翻译：

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多酚纳米复合物调节乳酸代谢重编程并引发免疫反应以增强癌症治疗效果

癌症乳酸代谢重编程会诱导细胞外乳酸和 H 水平升高，从而导致酸性免疫抑制肿瘤微环境 (TEM)。高乳酸水平可能会影响构成抗肿瘤免疫反应的各种细胞的代谢程序，从而限制免疫介导的肿瘤破坏，并导致治疗耐药和预后不良。在这里，我们报道了一种负载天然多酚没食子黄素的金属酚配位纳米复合物，它可以抑制乳酸脱氢酶的功能，减少乳酸的产生，并减轻酸性免疫抑制性TME。此外，共包埋的天然多酚鼠尾草酸和合成的PEG-Ce6多酚衍生物（作为光敏剂）可以在激光照射下诱导免疫原性癌细胞死亡，从而进一步激活免疫系统并促进免疫细胞在肿瘤组织中的募集和浸润。我们证明，这种基于纳米复合物的联合疗法可以重塑小鼠乳腺癌模型中的 TME 并引发免疫反应，这为提高耐药乳腺癌的治疗效率提供了一种有前途的策略。