Targeting metabolic cell death in cancer to reverse drug resistance

Evasion of apoptosis is a typical feature of malignant tumors developing to survive therapeutic stress. As a result, chemotherapeutic drugs that primarily induce apoptosis can no longer effectively kill tumor cells, which brings challenges to clinical cancer treatment. Recent evidence indicates that targeting key nodes in cellular metabolic pathways can bypass apoptotic routes and induce metabolic cell death in tumor cells to overcome drug resistance. Different from the traditional ways of defining cell death that rely on morphological features, metabolic cell death focuses more on the inducing factors and the associated dysregulation of cellular metabolic pathways. Metabolic cell death can be classified into four categories based on the driver factors of cell death: (1) metal ion dyshomeostasis-mediated cell death; (2) redox-collapse cell death; (3) pH dyshomeostasis-driven cell death; and (4) metabolic byproduct accumulation-mediated cell death. According to these metabolic cell death patterns, several therapeutic strategies targeting the metabolic vulnerabilities have attracted considerable attention. Here, we summarize the major metabolic cell death patterns of tumor cells, examine how these death modalities engage anti-tumor immunity, and discuss how exploiting them can reverse drug resistance. We further discuss the therapeutic window, tumor metabolic heterogeneity, and metabolic network therapeutic implications.