化疗已成为通过诱导免疫原性细胞死亡（ICD）来激活细胞毒性T细胞反应的新兴策略，但由于肿瘤抗原呈递和T细胞不足，奥沙利铂（OXA）等化疗药物诱导的抗肿瘤免疫水平受到限制。激活。诱导自噬细胞死亡（ACD）促进肿瘤抗原的释放和树突状细胞的募集，从而增强抗肿瘤免疫反应。在这里，我们用肿瘤靶向胶束同时激活ICD和ACD，以实现增强的抗肿瘤化学免疫治疗。通过将 OXA 前药与生育酚琥珀酸酯 (TOS) 作为疏水片段结合，形成自递送胶束，并进一步封装自噬激活剂 SMER28，形成 TOPR/SMER28，其通过 c(RGDfK) 特异性靶向肿瘤细胞上的 αvβ3。细胞内化后，OXA 会响应肿瘤细胞中高浓度的还原型谷胱甘肽 (GSH) 从前药中释放出来，触发 ICD 并释放相关分子模式 (DAMP) 信号分子以刺激免疫力。同时，SMER28过度激活自噬，诱导自噬细胞死亡，进一步导致树突状细胞成熟，最终激活抗肿瘤免疫反应。在4T1荷瘤小鼠中，OXA和SMER28的组合有效抑制肿瘤生长并激活抗肿瘤免疫反应。该肿瘤靶向胶束按需释放OXA和SMER28，并通过协同ICD和ACD增强肿瘤化学免疫治疗，为抗肿瘤免疫治疗提供了替代方案。意义声明：化疗诱导免疫原性细胞死亡（ICD）以激活抗肿瘤免疫力。然而，其功效受到低水平的抗原呈递和 T 细胞活化的限制。为了增强 ICD 诱导的抗肿瘤免疫反应，我们首先通过配制共封装自噬激活剂 SMER28 的谷胱甘肽响应性奥沙利铂前药胶束，将自噬细胞死亡 (ACD) 与 ICD 结合起来。 SMER28 激活的自噬水平增强了抗原的释放和 APC 的募集，并最终增强 T 细胞介导的抗肿瘤免疫反应。我们提供了一种通过将自噬激活与化疗相结合来放大抗肿瘤免疫效果的潜在策略。版权所有 © 2024。由 Elsevier Ltd 出版。

Chemotherapy has become an emerging strategy to activate cytotoxic T cell responses by inducing immunogenic cell death (ICD), but the level of antitumor immunity induced by chemotherapeutic agents, such as oxaliplatin (OXA), is limited due to inadequate tumor antigen presentation and T cell activation. Inducing autophagic cell death (ACD) promotes the release of tumor antigen and the recruitment of dendritic cells, therefore strengthening antitumor immune responses. Here we simultaneously activate ICD and ACD with tumor targeting micelle to achieve enhanced antitumor chemo-immunotherapy. A self-delivery micelle is formulated by conjugating OXA prodrug with tocopherol succinate (TOS) as a hydrophobic segment and further encapsulates autophagy activator SMER28 to afford TOPR/SMER28, which specifically targets αvβ3 on tumor cells with c(RGDfK). Upon cellular internalization, OXA is released from the prodrug in response to the high concentration of reduced glutathione (GSH) in tumor cells, triggering ICD and releasing associated molecular patterns (DAMPs) signaling molecules to stimulate immunity. Meanwhile, SMER28 over-activates autophagy to induce autophagic cell death, which further leads to the maturation of dendritic cells and ultimately activates anti-tumor immune response. In the 4T1 tumor-bearing mice, the combination of OXA and SMER28 effectively inhibits tumor growth and activates antitumor immune responses. The tumor targeted micelle releases OXA and SMER28 in an on-demand profile and strengthens tumor chemo-immunotherapy by synergizing ICD and ACD, providing an alternative for antitumor immunotherapy. STATEMENT OF SIGNIFICANCE: Chemotherapy induces immunogenic cell death (ICD) to activate anti-tumor immunity. However, the efficacy is limited by low levels of antigen presentation and T cell activation. To strengthen the antitumor immune responses induced by ICD, we first combine autophagic cell death (ACD) with ICD by formulating a glutathione-responsive oxaliplatin prodrug micelle co-encapsulating the autophagy activator SMER28. The activated autophagic level by SMER28 enhances the release of antigen and the recruitment of APCs, and ultimately bolsters T cell-mediated antitumor immune responses. We provide a potential strategy to amplify antitumor immune effects by combining autophagy activation with chemotherapy.Copyright © 2024. Published by Elsevier Ltd.