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.

Keywords: Bromodomain; Ferroptosis; Immunogenic cell death; Pancreatic cancer; Tumor microenvironment.

© 2025 The Authors.

胰腺癌的预后极为严峻，迫切需要创新的治疗策略。JQ1是一种溴结构域4抑制剂，在临床前模型中表现出强大的抗肿瘤活性，但由于迅速产生耐药性而面临局限性。在这里，我们开发了一种新型多功能纳米平台 JQ1@MSN/FeTA-iRGD，该平台整合了凋亡、铁死亡和免疫原性细胞死亡的三重策略，以优化胰腺癌的治疗效果。这些颗粒能够在小鼠体内精确靶向肿瘤，并在酸性肿瘤环境中通过内吞作用实现JQ1和Fe²⁺的有效释放。该纳米平台放大了活性氧（ROS）和线粒体损伤，破坏氧化还原平衡，从而协同加剧凋亡和铁死亡，以摧毁肿瘤细胞，规避单药治疗快速产生耐药性的问题。同时，垂死的癌细胞会释放损害相关分子模式，促进免疫原性细胞死亡，并触发抗肿瘤免疫反应，确保治疗效果的持久性。此外，该系统表现出良好的生物相容性，支持其临床转化的可能性。我们的结果表明，这一结合凋亡、铁死亡和免疫原性细胞死亡的新策略克服了单药JQ1治疗的局限性，为胰腺癌提供了一种更优越、更具针对性且可持续的治疗选择。

关键词：溴结构域；铁死亡；免疫原性细胞死亡；胰腺癌；肿瘤微环境。