Programmed cell death network in cancer drug resistance: A framework for therapeutic intervention.

Cancer remains a major global health burden, and therapeutic progress is frequently undermined by acquired drug resistance. A key contributor to drug resistance is the ability of malignant cells to evade programmed cell death (PCD). In this review, we summarize six canonical PCD modalities-apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and cuproptosis-and emphasize their interdependence within a densely connected regulatory network. We highlight how PANoptosis links apoptosis, necroptosis, and pyroptosis, how ferroptosis and cuproptosis converge on shared redox circuitry, and how immunogenic cell death communicates bidirectionally with the tumor microenvironment. Because cancer cells can escape PCD through adaptive rewiring, single-agent interventions are often insufficient. We therefore propose synergistic, multitarget strategies that modulate multiple signaling cascades while engaging alternative death pathways to avert compensatory drug resistance. Finally, we discuss emerging tools-including single-cell omics, AI-assisted modeling, CRISPR screening, and nanoparticle delivery-that enable mechanistic dissection and precision targeting of PCD networks. Future studies should adopt a holistic, context-dependent view of PCD, identify cancer-type-specific biomarkers that could predict drug response in vitro and in vivo, and accelerate translation of rational combination therapies to overcome pharmacological resistance in malignant disorders.