肿瘤细胞的免疫抑制表型极大地削弱了传统治疗的免疫激活效果。在这项工作中，制备了一种转铁蛋白受体 (TfR) 靶向免疫刺激剂 (PTI)，用于通过中断 β-连环蛋白信号通路来对抗转移性肿瘤的光动力免疫疗法。为了合成 PTI，将光敏剂缀合的 TfR 靶向肽部分 (Palmitic-K(PpIX)-HAIYPRH) 组合起来封装 ICG-001 的转录中断子。一方面，PTI和TfR的识别可以促进药物递送到肿瘤细胞中，通过光动力疗法破坏原发性肿瘤，并通过释放肿瘤相关抗原启动免疫原性细胞死亡。另一方面，PTI会中断β-catenin和cAMP反应元件结合蛋白（CREB）之间的结合，调节基因转录，下调程序性死亡配体1（PD-L1），同时上调C-C基序趋化因子配体4（CCL4） 。此外，升高的CCL4可以招募树突状细胞呈递肿瘤特异性抗原，促进T细胞活化和浸润，而下调的PD-L1可以避免肿瘤细胞的免疫逃避，激活全身抗肿瘤免疫，从而根除肺转移。这项工作可能会激发无抗体策略的发展，以在考虑免疫抑制条件的情况下激活全身免疫反应。© 2024 作者。

The immunosuppressive phenotype of tumor cells extensively attenuates the immune activation effects of traditional treatments. In this work, a transferrin receptor (TfR) targeted immunostimulant (PTI) is fabricated for photodynamic immunotherapy against metastatic tumors by interrupting β-catenin signal pathway. To synthesize PTI, the photosensitizer conjugated TfR targeting peptide moiety (Palmitic-K(PpIX)-HAIYPRH) is unitized to encapsulate the transcription interrupter of ICG-001. On the one hand, the recognition of PTI and TfR can promote drug delivery into tumor cells to destruct primary tumors through photodynamic therapy and initiate an immunogenic cell death with the release of tumor-associated antigens. On the other hand, PTI will interrupt the binding between β-catenin and cAMP response element-binding protein (CREB), regulating the gene transcription to downregulate programmed death ligand 1 (PD-L1) while upregulating C-C motif chemokine ligand 4 (CCL4). Furthermore, the elevated CCL4 can recruit the dendritic cells to present tumor-specific antigens and promote T cells activation and infiltration, and the downregulated PD-L1 can avoid the immune evasion of tumor cells and activate systemic anti-tumor immunity to eradicate lung metastasis. This work may inspire the development of antibody antibody-free strategy to activate systemic immune response in consideration of immunosuppressive conditions.© 2024 The Authors.