Abstract
Pancreatic cancer's dire prognosis urgently calls for innovative therapeutic strategies. JQ1, a bromodomain 4 inhibitor, exhibits potent anti-tumor activity in preclinical models but faces limitations due to rapid resistance development. Here, we developed a novel multifunctional nanoplatform, JQ1@MSN/FeTA-iRGD, which implemented a triple-mode strategy integrating apoptosis, ferroptosis, and immunogenic cell death for optimized treatment of pancreatic cancer. The particles could precisely target tumors in mice and achieve efficient release of JQ1 and Fe2+ through internalization in the acidic tumor environment. The nanoplatform amplified reactive oxygen species and mitochondrial damage to disrupt the redox homeostasis, thus synergistically escalating apoptosis and ferroptosis for the destruction of tumor cells, circumventing the rapid drug resistance associated with monotherapy. Meanwhile, dying cancer cells released damage-associated molecular patterns, which facilitated immunogenic cell death and triggered antitumor immune responses, guaranteeing the sustained efficacy of the treatment. Moreover, the system exhibited favorable biocompatibility, supporting its feasibility for clinical translation. Our results demonstrated that this novel strategy, combining apoptosis, ferroptosis, and immunogenic cell death, overcame the limitations of monotherapy with JQ1, providing a superior, targeted, and sustainable treatment option for pancreatic cancer.