Wu Ye-Yang, Zhang Ke-Yang, Huang Jia-Qi, Nie Jun-Mei, Cheng Hong
School of Biomedical Engineering & Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangzhou, 510515, China.
Acta Pharmacol Sin. 2025 Jun 4. doi: 10.1038/s41401-025-01583-x.
Most aggressive malignancies exhibit low immunogenicity, exacerbated by tumor immune evasion mechanisms that undermine immunotherapy efficacy. Studies indicate that AMP-activated protein kinase (AMPK) directly phosphorylates programmed cell death ligand 1 (PD-L1), promoting its degradation via the endoplasmic reticulum (ER)-associated pathway to restore and sustain cytotoxic T lymphocyte-mediated immunity. Here, we developed an ER-targeting photodynamic AMPK agonist (called PPFC) for breast cancer immunotherapy. PPFC comprised a chimeric peptide (PpIX-(PEG8-FFKDEL)) integrating a photosensitizer protoporphyrin IX (PpIX), a hydrophilic PEG8 linker, and the ER-targeting peptide sequence FFKDEL. The amphiphilic structure of the chimeric peptide facilitated its self-assembly into nanomicelles capable of encapsulating the AMPK agonist COH-SR4 (CS) within the chimeric peptide, forming PPFC. The findings demonstrated that this formulation enabled PPFC to accumulate in the ER of breast cancer cells, where photodynamic therapy (PDT)-generated reactive oxygen species (ROS) induced substantial ER stress, thereby amplifying immunogenic cell death (ICD) and improving tumor immunogenicity. Concurrent AMPK activation by PPFC downregulated PD-L1, counteracting immune evasion of breast cancer. The combined effects of PPFC triggered robust systemic anti-tumor immunity, eradicating primary tumors and lung metastases in 4T1 breast cancer-bearing mice. This subcellular-targeting photodynamic agonist offers a promising strategy to overcome immunosuppressive tumor microenvironments in metastatic cancers.
大多数侵袭性恶性肿瘤表现出低免疫原性，肿瘤免疫逃逸机制会加剧这种情况，而肿瘤免疫逃逸机制会削弱免疫治疗的疗效。研究表明，AMP激活的蛋白激酶（AMPK）直接磷酸化程序性细胞死亡配体1（PD-L1），通过内质网（ER）相关途径促进其降解，以恢复和维持细胞毒性T淋巴细胞介导的免疫。在此，我们开发了一种用于乳腺癌免疫治疗的内质网靶向光动力AMPK激动剂（称为PPFC）。PPFC由一种嵌合肽（PpIX-(PEG8-FFKDEL)）组成，该嵌合肽整合了一种光敏剂原卟啉IX（PpIX）、一个亲水性PEG8接头和内质网靶向肽序列FFKDEL。嵌合肽的两亲结构促进其自组装成纳米胶束，能够将AMPK激动剂COH-SR4（CS）包裹在嵌合肽内，形成PPFC。研究结果表明，这种制剂使PPFC能够在乳腺癌细胞的内质网中积累，在那里光动力疗法（PDT）产生的活性氧（ROS）诱导大量内质网应激，从而放大免疫原性细胞死亡（ICD）并提高肿瘤免疫原性。PPFC同时激活AMPK可下调PD-L1，抵消乳腺癌的免疫逃逸。PPFC的联合作用引发了强大的全身抗肿瘤免疫，根除了4T1荷乳腺癌小鼠的原发性肿瘤和肺转移瘤。这种亚细胞靶向光动力激动剂为克服转移性癌症中的免疫抑制肿瘤微环境提供了一种有前景的策略。
