Regulated cell death in cancer: Mechanisms, crosstalk, and opportunities for therapy

Regulated cell death (RCD) is a fundamental biological process essential for tissue homeostasis, and the elimination of damaged or malignant cells. In cancer, dysregulation of RCD is closely linked to tumor initiation, progression, therapeutic resistance, and remodeling of the tumor microenvironment (TME). In this review, we classify RCD in cancer into three broad groups. Classical cell death types include apoptosis, autophagy, necroptosis, and pyroptosis, which have well-established roles in controlling cell fate. Metal-dependent pathways, represented by ferroptosis, and cuproptosis, highlight vulnerabilities linked to iron and copper metabolism. Emerging modalities such as entosis, NETosis, disulfidptosis, and parthanatos, further expand the conceptual landscape of RCD, revealing diverse mechanisms by which cancer cells respond to stress. We synthesize the molecular mechanisms and signaling networks governing these processes, emphasizing their intricate crosstalk, shared regulators, and context-dependent dual roles in tumor suppression and promotion. Finally, we discuss translational strategies to exploit RCD, including pharmacologic modulators, nanomaterial-based approaches, and early clinical evidence, outlining future directions for precision oncology. Together, these insights establish RCD as a dynamic and targetable network that provides both mechanistic understanding and opportunities for novel therapeutic interventions in cancer.