化疗药物可以通过触发自噬诱导免疫原性细胞死亡（ICD）并介导抗肿瘤免疫疗法。然而，仅使用化疗药物只能引起轻微的细胞保护性自噬，无法诱导足够的ICD效力。自噬诱导剂的参与能够增强自噬，从而提高ICD水平，大大增强抗肿瘤免疫疗法的效果。因此，我们构建了量身定制的自噬级联放大聚合物纳米颗粒STF@AHPPE来增强肿瘤免疫疗法。精氨酸（Arg）、聚乙二醇-聚己内酯和表阿霉素（EPI）通过二硫键接枝到透明质酸（HA）上形成AHPPE纳米颗粒，并载入自噬诱导剂STF-62247（STF）。当STF@AHPPE纳米颗粒靶向肿瘤组织并在HA和Arg的帮助下有效进入肿瘤细胞时，高谷胱甘肽浓度导致二硫键的断裂以及EPI和STF的释放。最后，STF@AHPPE诱导剧烈的细胞毒性自噬和强效的ICD效力。与AHPPE纳米颗粒相比，STF@AHPPE纳米颗粒杀死了最多的肿瘤细胞，并展现出更明显的ICD效力和免疫激活能力。这项工作提供了一种将肿瘤化学免疫疗法与自噬诱导相结合的新策略。© 2023 Wiley-VCH GmbH。

Chemotherapeutics can induce immunogenic cell death (ICD) by triggering autophagy and mediate antitumor immunotherapy. However, using chemotherapeutics alone can only cause mild cell-protective autophagy and be incapable of inducing sufficient ICD efficacy. The participation of autophagy inducer is competent to enhance autophagy, so the level of ICD is promoted and the effect of antitumor immunotherapy is highly increased. Herein, tailor-made autophagy cascade amplification polymeric nanoparticles STF@AHPPE are constructed to enhance tumor immunotherapy. Arginine (Arg), polyethyleneglycol-polycaprolactone, and epirubicin (EPI) are grafted onto hyaluronic acid (HA) via disulfide bond to form the AHPPE nanoparticles and autophagy inducer STF-62247 (STF) is loaded. When STF@AHPPE nanoparticles target to tumor tissues and efficiently enter into tumor cells with the help of HA and Arg, the high glutathione concentration leads to the cleavage of disulfide bond and the release of EPI and STF. Finally, STF@AHPPE induces violent cytotoxic autophagy and strong ICD efficacy. As compared to AHPPE nanoparticles, STF@AHPPE nanoparticles kill the most tumor cells and show the more obvious ICD efficacy and immune activation ability. This work provides a novel strategy for combining tumor chemo-immunotherapy with autophagy induction.© 2023 Wiley-VCH GmbH.