The Dual Role of Cell Death in Cancer Pathogenesis and Antitumor Therapy: From Linear Models to Integrative Representations

Regulated cell death (RCD) is a central mechanism for maintaining tissue homeostasis. Dysregulation of RCD plays a key role in the emergence of transformed clones, tumor progression, the development of drug resistance, and the interaction of tumor cells with their microenvironment. Over the past several years, the conceptual framework of RCD has undergone substantial revision. Rather than viewing apoptosis as a predominant form of programmed cell death, current evidence supports a complex network of interconnected and partially redundant RCD pathways, including apoptosis, necroptosis, autophagy, pyroptosis, ferroptosis, cuproptosis, and others. This review summarizes current knowledge of the molecular mechanisms and the role of major forms of RCD in carcinogenesis, focusing on the classical "big three" (apoptosis, necroptosis, and autophagy), as well as pyroptosis and ferroptosis, which have received increasing attention in recent years. We discuss molecular triggers and signaling pathways that determine the choice of cell death programs and examine how genetic, metabolic, and immunological factors regulate the transition between alternative RCD modalities. Particular emphasis is placed on the context-dependent dual role of RCD in cancer: although RCD can eliminate transformed cells, certain forms of cell death may also sustain chronic inflammation, remodel the tumor microenvironment, facilitate therapeutic resistance, and contribute to immune evasion. Increasing evidence suggests that further advances in anticancer treatment may require a shift from the selective activation of individual cell death pathways toward context-dependent modulation of the integrated RCD network. Such strategies should account for tumor-specific biology, intratumoral heterogeneity, and the dynamic tumor microenvironment. The review examines current approaches to the pharmacological modulation of RCD and evaluates the efficacy of antitumor agents both as monotherapies and in combination with targeted therapies, chemotherapy, and immunotherapy. These advances may provide a foundation for therapeutic strategies designed to eliminate even highly adaptive tumor subpopulations that are capable of surviving therapeutic stress, including persister, circulating, and cancer stem cells.