Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research

Abstract

Many types of human cells self-destruct to maintain biological homeostasis and defend the body against pathogenic substances. This process, called regulated cell death (RCD), is important for various biological activities, including the clearance of aberrant cells. Thus, RCD pathways represented by apoptosis have increased in importance as a target for the development of cancer medications in recent years. However, because tumor cells show avoidance to apoptosis, which causes treatment resistance and recurrence, numerous studies have been devoted to alternative cancer cell mortality processes, namely necroptosis, pyroptosis, ferroptosis, and cuproptosis; these RCD modalities have been extensively studied and shown to be crucial to cancer therapy effectiveness. Furthermore, evidence suggests that tumor cells undergoing regulated death may alter the immunogenicity of the tumor microenvironment (TME) to some extent, rendering it more suitable for inhibiting cancer progression and metastasis. In addition, other types of cells and components in the TME undergo the abovementioned forms of death and induce immune attacks on tumor cells, resulting in enhanced antitumor responses. Hence, this review discusses the molecular processes and features of necroptosis, pyroptosis, ferroptosis, and cuproptosis and the effects of these novel RCD modalities on tumor cell proliferation and cancer metastasis. Importantly, it introduces the complex effects of novel forms of tumor cell death on the TME and the regulated death of other cells in the TME that affect tumor biology. It also summarizes the potential agents and nanoparticles that induce or inhibit novel RCD pathways and their therapeutic effects on cancer based on evidence from in vivo and in vitro studies and reports clinical trials in which RCD inducers have been evaluated as treatments for cancer patients. Lastly, we also summarized the impact of modulating the RCD processes on cancer drug resistance and the advantages of adding RCD modulators to cancer treatment over conventional treatments.

Keywords: Cuproptosis; Ferroptosis; Nanoparticles; Necroptosis; Pyroptosis; Tumor microenvironment.

Fig. 1

Detailed mechanism of necroptosis. Necroptosis is initiated by the cell surface death receptors (including FasRs, TNFR, IFN receptors, and TLRs) and ZBP1 in cells, and downstream proteins which contain RHIM bind to RIPK3. Subsequently, the necrosome is formed and led to cell lysis

Fig. 2

Summary of pyroptosis mediated by different cellular mechanisms. A Pyroptosis induced by the TNF-α/TRADD pathway and the mechanism of pyroptosis induced by granzymes A and B. B Chemotherapy and CAR-T therapy induce cell death mediated by nonclassical pyroptotic pathways. C Interactions of PAMPs and DAMPs with pattern recognition receptors on the cell surface trigger the classical pyroptotic pathway, leading to the release of HMGB1, IL-1β, and IL-18. (Gzm A: Granzyme A; Gzm B: Granzyme B; PRRs: pattern recognition receptors; PAMPs: pathogen-associated molecular patterns; DAMPs: damage-associated molecular patterns; GSDMD-CT: GSDMD-C-terminus; and GSDME-CT: GSDME-C-terminus.)

Fig. 3

The interaction between MΦs and tumor cells in the TME and details of the ferroptosis pathway in tumor cells (by Figdraw). A MΦs engulf red blood cells and digest them into hemoglobin, which is further degraded into heme. Heme is catabolized into Fe(III) and Fe(III), which are released from MΦs or promote ROS production, leading to ferroptosis. B Ferroptotic cell death is induced by the inhibition of system Xc⁻, resulting in the abrogation of GSH biosynthesis and inactivation of GPX4, which subsequently cause cell death through excess lipid ROS production. PUFAs-OOH and Fe(II) facilitate tumor cell ferroptosis mediated by the Fenton reaction. (ROS: reactive oxygen species; system Xc⁻: cystine–glutamate antiporter; GSH: glutathione; GPX4: glutathione peroxidase 4; and RBC: red blood cell.)

Fig. 4

An excess Cu(II) supply can lead to cell pyroptosis (By BioRender). The uptake of Cu(II) into cells triggers pyroptosis via protein lipoylation, which is an important mechanism for the enzymatic function of proteins in the TCA (tricarboxylic acid) cycle

Fig. 5

Summary of novel RCD modalities in tumor cells that influence the TME (By BioRender). We summarize the effects of tumor cell necroptosis, pyroptosis, ferroptosis, and cuproptosis on the number of immune cells and the levels of immune-related factors in the TME

Fig. 6

Summary of the modulators of novel RCDs in cancer treatment