Cell death pathways and targeting therapeutics in cancer therapy

Dysregulated cell death represents a cornerstone of cancer development and therapeutic resistance. This review systematically deciphers the molecular architecture underlying various regulated cell death modalities and their crosstalk. Moving beyond a mere catalog of mechanisms, it critically evaluates the translational landscape of agents that are designed to precisely trigger these pathways. We then critically evaluate the translational strategies that target their key components via diverse agents, from small molecules to PROTACs and nanomedicines. A key focus is the strategic induction of immunogenic cell death to convert tumor cell killing into durable antitumor immunity. This review synthesizes evidence on how distinct death pathways, such as ferroptosis, can be leveraged to remodel the immunosuppressive tumor microenvironment and potentiate immune checkpoint blockade. It further examines the contextual factors that determine the immunogenic outcome of cell death, providing a rationale for combination therapies (e.g., the synergistic effect between ferroptosis inducers and immune checkpoint inhibitors). By integrating mechanistic insights with therapeutic innovations, we provide a framework for developing next-generation therapies that precisely manipulate cell death to overcome treatment resistance and activate immune surveillance. Finally, the review outlines future directions, suggesting the need for the integration of multidisciplinary approaches to discover novel targets, develop selective inducers, and rationally combine cell death modulation with immunotherapy to achieve sustained clinical responses.