癌症免疫疗法因其持久性、靶向性和杀伤肿瘤细胞的能力等优势而受到广泛关注。然而，肿瘤免疫治疗在实际应用中的功效受到肿瘤异质性和复杂的肿瘤免疫抑制微环境的限制，其中存在丰富的M2巨噬细胞和免疫检查点（IC）。在此，设计并合成了两种具有不同活性氧（ROS）生成效率的I型聚集诱导发射（AIE）活性光敏剂。首先从 4T1 肿瘤细胞中获得表达 IC Siglec-10 的工程化细胞外囊泡 (EV)。然后将工程化的 EV 与负载 AIE 光敏剂的脂质纳米系统融合，形成 SEx@Fc-NP。 SEx@Fc-NPs内部的I型AIE光敏剂通过光动力疗法（PDT）产生的ROS可以将M2巨噬细胞转化为M1巨噬细胞，从而改善肿瘤免疫抑制微环境。携带4T1肿瘤相关抗原的外部EV抗原直接刺激树突状细胞成熟，激活不同类型的肿瘤特异性T细胞，克服肿瘤异质性。此外，阻断 Siglec-10 可逆转巨噬细胞耗竭，从而增强抗肿瘤能力。这项研究表明，PDT、免疫检查点和 EV 抗原的组合可以大大提高肿瘤免疫治疗的效率，有望成为改善肿瘤免疫抑制微环境和克服免疫逃逸的新兴策略。© 2023 Wiley-VCH GmbH。

Cancer immunotherapy has attracted considerable attention due to its advantages of persistence, targeting, and ability to kill tumor cells. However, the efficacy of tumor immunotherapy in practical applications is limited by tumor heterogeneity and complex tumor immunosuppressive microenvironments in which abundant of M2 macrophages and immune checkpoints (ICs) are present. Herein, two type-I aggregation-induced emission (AIE)-active photosensitizers with various reactive oxygen species (ROS)-generating efficiencies are designed and synthesized. Engineered extracellular vesicles (EVs) that express ICs Siglec-10 are first obtained from 4T1 tumor cells. The engineered EVs are then fused with the AIE photosensitizer-loaded lipidic nanosystem to form SEx@Fc-NPs. The ROS generated by the inner type-I AIE photosensitizer of the SEx@Fc-NPs through photodynamic therapy (PDT) can convert M2 macrophages into M1 macrophages to improve tumor immunosuppressive microenvironment. The outer EV-antigens that carry 4T1 tumor-associated antigens directly stimulate dendritic cells maturation to activate different types of tumor-specific T cells in overcoming tumor heterogeneity. In addition, blocking Siglec-10 reversed macrophage exhaustion for enhanced antitumor ability. This study presents that a combination of PDT, immune checkpoints, and EV-antigens can greatly improve the efficiency of tumor immunotherapy and is expected to serve as an emerging strategy to improve tumor immunosuppressive microenvironment and overcome immune escape.© 2023 Wiley-VCH GmbH.