Topic: Therapeutic Targeting of Regulated Cell Death in Cancer

Cells die through diverse molecular mechanisms. Historically, cell death was broadly classified as either necrosis or apoptosis, with apoptosis being referred to as programmed cell death. Programmed cell death pathways play a critical role in determining tumor sensitivity to conventional chemotherapy and radiotherapy. Increasing evidence also indicates that these pathways, together with other cell death mechanisms, are crucial to the therapeutic efficacy of protein kinase inhibitors, including tyrosine kinase inhibitors, as well as immunotherapy.

Advances in the understanding of intrinsic and extrinsic apoptotic pathways, as well as their cross-talk, have facilitated the therapeutic targeting of apoptosis in cancer. Several apoptosis-targeted inhibitors have been developed, including small molecules (MW <500) directed against apoptosis-inhibitory proteins and agonistic antibodies or recombinant proteins targeting cell death receptors, such as TRAIL receptors. These approaches are often more effective when combined with conventional DNA-targeted agents, other apoptosis inhibitors, radiotherapy, or immunotherapy.

Recent advances have highlighted the therapeutic relevance of specialized forms of regulated cell death, including ferroptosis and cuproptosis. Ferroptosis is driven by iron-dependent phospholipid peroxidation, whereas cuproptosis is associated with copper overload, leading to mitochondrial dysfunction. Increasing evidence links these pathways to cancer initiation, growth, and metastasis. Pharmacological induction of ferroptosis or cuproptosis may therefore provide promising strategies for targeting specific tumor types and drug-resistant cancer cells. Pyroptosis, another form of programmed cell death, is independent of caspase activation and distinct from both apoptosis and necrosis.

The evolving understanding of traditional and emerging apoptotic pathways has accelerated the development of innovative cancer therapeutic strategies, including small molecules, nanolipids, and PROTACs. This Special Issue on “Therapeutic Challenges in Targeting Cell Death in Cancer” aims to feature Original Articles, Reviews, and Commentaries that highlight recent advances and novel therapeutic developments for both solid and hematological malignancies