Shi Kewei, Ye Zichong, Zhu Hengyan, Ren Lulu, Wang Hangxiang
NHC Key Laboratory of Combined Multi-Organ Transplantation, Institute of Organ Transplantation of Zhejiang University, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, Hangzhou 310003, PR China; Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province 250117, PR China.
NHC Key Laboratory of Combined Multi-Organ Transplantation, Institute of Organ Transplantation of Zhejiang University, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang Province, Hangzhou 310003, PR China; Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, Guangdong Province 510515, PR China.
Acta Biomater. 2025 Jul 16. doi: 10.1016/j.actbio.2025.07.035.
Immunotherapy with immune checkpoint blockade (ICB) has revolutionized cancer treatment for patients with unresectable melanoma; however, the majority of patients who harbor immunologically "cold" tumors exhibit poor outcomes. Mitochondria serve as a central hub for enhancing antitumor immune responses. Thus, selective intervention strategies targeting them can rewire mitochondrial metabolism and induce robust immunogenicity in immune-desert tumors. This study describes the development of a pseudo-stealthy nanophotosensitizer platform that effectively induces immunogenic cell death (ICD) in tumor cells. This nanosystem encapsulates a polymer-derived photosensitizer, further surface clocked with a low-density lipophilic triphenylphosphonium cation, for prolonged systemic circulation and mitochondria-targeted delivery. Upon near-infrared photoirradiation, this nanoplatform efficiently generates reactive oxygen species and induces mitochondrial dysfunction, triggering potent ICD. In a preclinical melanoma mouse model, intravenous administration of this stealthy ICD nanoinducer resulted in remarkable tumor regression and antitumor immune activation, synergizing with ICB therapy. This work highlights a promising strategy for mitochondria-targeting photodynamic immunotherapy, which enhances tumor immunogenicity and antitumor responses in melanoma. STATEMENT OF SIGNIFICANCE: Immunotherapeutic outcomes have been limited by immunologically "cold" tumors in patients. Therefore, intervention strategies to inflame these immune desert tumors have attracted substantial interest to improve anticancer immunity. We here propose a conceptually new pseudo-stealthy nanophotosensitizer for mitochondria-targeted immunogenic cell death (ICD) induction and effective rewiring of the cancer-immunity cycle. This delivery platform retains long circulatory property compared with conventional PEG-cloaked nanoparticles that are considered stealthy. Furthermore, the photosensitizer such as pyropheophorbide-a delivered by the rationally engineered nanoparticles shows efficient cellular uptake and precise mitochondrial targeting, thereby causing overwhelming mitochondrial dysfunction and ICD induction. This study represents a rare example of preferential delivery of photosensitizer to the mitochondria for the treatment of aggressive cancers.
免疫检查点阻断（ICB）免疫疗法彻底改变了不可切除黑色素瘤患者的癌症治疗方式；然而，大多数携带免疫“冷”肿瘤的患者预后较差。线粒体是增强抗肿瘤免疫反应的核心枢纽。因此，针对线粒体的选择性干预策略可以重塑线粒体代谢，并在免疫缺陷肿瘤中诱导强大的免疫原性。本研究描述了一种伪隐形纳米光敏剂平台的开发，该平台可有效诱导肿瘤细胞发生免疫原性细胞死亡（ICD）。该纳米系统封装了一种聚合物衍生的光敏剂，并进一步用低密度亲脂性三苯基膦阳离子进行表面修饰，以延长其在体内的循环时间并实现线粒体靶向递送。在近红外光照射下，该纳米平台能高效产生活性氧并诱导线粒体功能障碍，从而引发强效的ICD。在临床前黑色素瘤小鼠模型中，静脉注射这种隐形ICD纳米诱导剂可导致显著的肿瘤消退和抗肿瘤免疫激活，并与ICB疗法协同作用。这项工作突出了一种有前景的线粒体靶向光动力免疫疗法策略，该策略可增强黑色素瘤的肿瘤免疫原性和抗肿瘤反应。重要性声明：免疫治疗的效果一直受到患者体内免疫“冷”肿瘤的限制。因此，激活这些免疫缺陷肿瘤的干预策略引起了人们极大的兴趣，以提高抗癌免疫力。我们在此提出一种概念全新的伪隐形纳米光敏剂，用于线粒体靶向诱导免疫原性细胞死亡（ICD）并有效重塑癌症-免疫循环。与被认为具有隐形性的传统聚乙二醇包覆纳米颗粒相比，该递送平台具有更长的循环特性。此外，由合理设计的纳米颗粒递送的焦脱镁叶绿酸-a等光敏剂表现出高效的细胞摄取和精确的线粒体靶向性，从而导致压倒性的线粒体功能障碍和ICD诱导。本研究是将光敏剂优先递送至线粒体以治疗侵袭性癌症的罕见实例。
