Nanoparticle-based strategies targeting disulfidptosis, anoikis, and PANoptosis for enhanced cancer therapy

The evasion of regulated cell death (RCD) is a distinct hallmark of cancer that drives tumor progression, metastatic dissemination, and therapeutic resistance. Recent discoveries of non-canonical cell death pathways, namely disulfidptosis, anoikis, and PANoptosis, have provided promising new directions for overcoming resistance to conventional therapies. Disulfidptosis is characterized by intracellular disulfide stress and actin cytoskeleton collapse under glucose starvation; anoikis serves as an extracellular matrix detachment-induced barrier to metastasis; and PANoptosis acts as a highly regulated inflammatory cascade integrating pyroptosis, apoptosis, and necroptosis, exhibiting heightened potential for immune activation. However, the clinical utility of small-molecule inducers for these RCD pathways is currently hindered by off-target toxicity, poor pharmacokinetics, and the potential for compensatory resistance. To address these limitations, advanced nanomedicine platforms have been developed to enable tumor-targeted delivery and controlled release of therapeutic agents, while also synergizing with multiple treatment modalities to remodel the tumor microenvironment. Herein, this review summarizes the molecular mechanisms of these three RCD pathways and provides an in-depth analysis of nanotherapeutic strategies designed to exploit them. Furthermore, we explore the synergistic approaches that combine nano-platforms with conventional therapies, including chemotherapy, radiotherapy, immunotherapy, phototherapy, and sonodynamic therapy, to enhance antitumor efficacy and remodel the tumor immune microenvironment. Finally, critical challenges are discussed, including the specificity of tumor targeting, management of inflammatory responses, and the development of personalized therapeutic approaches. The review concludes by highlighting the clinical prospects of using nanotechnology to precisely regulate non-canonical cell death pathways for effective tumor eradication and metastasis suppression.