The role and regulation of cell death in cancer

Regulated cell death (RCD) is an essential aspect of cellular homeostasis and coordinates important physiological processes, such as immune regulation, embryogenesis, and tissue remodeling. In cancer, the regulation of RCD is disrupted to allow tumor cells to resist apoptosis, modify their function to survive microenvironmental stresses, and become resistant to standard therapies. Beyond apoptosis, new modalities of RCD including necroptosis, pyroptosis, ferroptosis, and parthanatos, play multifaceted roles in tumor suppression and progression, determined by interactions with the tumor microenvironment (TME). These RCD pathways possess unique molecular regulators and exhibit distinctive immunological and pathological connotations with novel therapeutic potential. Here, in the current study, the mechanistic complexity of RCD pathways and their interactions with the TME, particularly in their immune evasion, tumor progression and therapy resistance roles, are reviewed. Furthermore, the therapeutic potential of the modulation of RCD pathways by using small-molecule inhibitors, immune checkpoint inhibitors, and combination therapies that repurpose the TME, were tested. The newly emerging technologies, such as nanotechnology and biomimetic delivery systems, are proposed to deliver novel solutions to escalating the specificity and potency of RCD-targeted therapy and confronting systemic toxicity as well as adaptive resistance. By combining mechanistic knowledge with innovative therapy, the transformative potential of RCD modulation in treating cancers is highlighted in the current review to improve precision oncology strategies that augment the efficacy of therapies and increase patient benefit.