Mitochondria-targeting pseudo-stealthy nanophotosensitizer as a potent immunogenic cell death inducer to unleash the cancer-immunity cycle for melanoma therapy

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.