Current evidence and therapeutic implication of PANoptosis in cancer

Abstract

Regulated cell death (RCD) is considered a critical pathway in cancer therapy, contributing to eliminating cancer cells and influencing treatment outcomes. The application of RCD in cancer treatment is marked by its potential in targeted therapy and immunotherapy. As a type of RCD, PANoptosis has emerged as a unique form of programmed cell death (PCD) characterized by features of pyroptosis, apoptosis, and necroptosis but cannot be fully explained by any of these pathways alone. It is regulated by a multi-protein complex called the PANoptosome. As a relatively new concept first described in 2019, PANoptosis has been shown to play a role in many diseases, including cancer, infection, and inflammation. This study reviews the application of PCD in cancer, particularly the emergence and implication of PANoptosis in developing therapeutic strategies for cancer. Studies have shown that the characterization of PANoptosis patterns in cancer can predict survival and response to immunotherapy and chemotherapy, highlighting the potential for PANoptosis to be used as a therapeutic target in cancer treatment. It also plays a role in limiting the spread of cancer cells. PANoptosis allows for the elimination of cancer cells by multiple cell death pathways and has the potential to address various challenges in cancer treatment, including drug resistance and immune evasion. Moreover, active investigation of the mechanisms and potential therapeutic agents that can induce PANoptosis in cancer cells is likely to yield effective cancer treatments and improve patient outcomes. Research on PANoptosis is still ongoing, but it is a rapidly evolving field with the potential to lead to new treatments for various diseases, including cancer.

Keywords: PANoptosis; cancer; immunity; regulated cell death; therapy.

Figure 1

Application of RCD in cancer. Clinical and experimental studies continue to explore the target of RCDs in cancer. This sets the stage for clinical trials that ultimately lead to the application in human cancer treatment. RCD, regulated cell death.

Figure 2

Key molecular interaction between the types of programmed cell death. ZBP1 is essential for forming the PANoptosome, a protein complex that causes cell death. ZBP1 does this by recruiting RIPK3, another protein in the PANoptosome. RIPK3 then phosphorylates MLKL, a third protein in the PANoptosome. This phosphorylation causes MLKL to move to the plasma membrane, forming pores that kill the cell. In other words, ZBP1 is the glue that holds the PANoptosome together. It recruits the other complex proteins and helps them function properly. MLKL must form clumps (oligomerize) to move to the plasma membrane, forming pores that kill the cell. This movement to the plasma membrane happens before cell death. MLKL, either by itself or with the help of other proteins, causes sodium to flow into the cell. This influx of sodium increases the pressure inside the cell, which eventually causes the cell membrane to burst. DISC, comprising of Fas, FADD, and caspase-8, is a multi-protein complex that initiates PANoptosis, whereas RIPK1 also complexes with RIPK3 and FADD to initiate PANoptosis. ZBP1, Z-DNA binding protein 1; RIPK, receptor interacting serine/threonine kinase; MLKL, mixed lineage kinase domain like pseudokinase; DISC, death-inducing signaling complex; FADD, Fas-associated death domain.

Figure 3

PANoptosis in immunity and its associated molecular mechanisms in cancer. PANoptosome complex consists of ZBP1 and NLRP3 as putative sensors, ASC and FADD as adaptors, and RIPK1, RIPK3, CASP1, and CASP8 as catalytic effectors. AIM2 regulates ZBP1 and pyrin to drive inflammatory signaling and PANoptosis. In other words, AIM2, ZBP1, and pyrin are members of a large multi-protein complex along with CASP1, CASP8, ASC, RIPK3, RIPK1, and FADD, that promote PANoptosis. PANoptosis drives innate immune responses and inflammation, influencing immune cells, cytokines, and chemokines. ZBP1, Z-DNA binding protein 1; AIM2, absent in melanoma 2; CASP, caspase; NLRP1, NLR family pyrin domain containing 1; FADD, Fas-associated death domain; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; RIPK, receptor interacting serine/threonine kinase; IL, interleukin; NK, natural killer, DCs, dendritic cells; JAK, Janus kinase; STAT, signal transducer and activator of transcription; IFN-γ, interferon-gamma.

Figure 4

The involvement of macrophage and DC in PANoptosis. CASP6 plays a key role in the innate immune system, inflammasome activation, and PANoptosis. It does this partly by promoting the differentiation of macrophages into M2 macrophages. CASP6 also plays an essential role in activating macrophages by cleaving IRAK-M, and exposure to IL-4 also enhances M2 activation, further increasing the expression of CASP6. DCs express cytosolic innate immune sensors and regulators such as ZBP1, AIM2, and RIPK1. These proteins help to assemble the PANoptosome, which triggers PANoptosis. IFN-γ produced by DCs promotes PANoptosis in mice. IFN-γ deficiency impairs the activation of PANoptosis-specific markers such as CASP3, GSDMD, and MLKL and reduces the expression of IL-1β. The combined effects of TNF-α and IFN-γ also drive PANoptosis. ZBP1, Z-DNA binding protein 1; AIM2, absent in melanoma 2; CASP, caspase; RIPK, receptor interacting serine/threonine kinase; MLKL, mixed lineage kinase domain like pseudokinase; IFN-γ, interferon-gamma; IL, interleukin; TNF-α, tumor necrosis factor alpha; DCs, dendritic cells; IRAK-M, interleukin-1 receptor-associated kinase-M; GSDMD, Gasdermin D.

Figure 5

The participation of neutrophils in PANoptosis. STING agonists trigger a series of events that lead to neutrophilic inflammation and PANoptosis. First, STING activation leads to the phosphorylation of TBK1/IRF3, which triggers the production of type I interferons and NF-κB activation. This results in the production of pro-inflammatory cytokines, such as TNFα and IL-6. Next, the activation of IFNAR1 and TNFR1 signaling pathways leads to the activation of ZBP1 and RIPK3/ASC/CASP8, all involved in PANoptosis. This cascade of events, linked with neutrophil recruitment, amplifies the inflammatory response and leads to STING-dependent PANoptosis. STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1; IRF, interferon regulatory factor; NF-κB, nuclear factor kappa B; IL, interleukin; TNF-α, tumor necrosis factor alpha; IFNAR1, interferon alpha/beta receptor subunit 1; TNFR1, tumor necrosis factor receptor-1; ZBP1, Z-DNA binding protein 1; CASP, caspase; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; RIPK, receptor interacting serine/threonine kinase; JAK, Janus kinase; STAT, signal transducer and activator of transcription; IκB, IkappaB kinase; P, GAS, gamma-interferon-activated sequence; ISRE, interferon-stimulated response elements; ISGF, IFN-stimulated gene factor; ISG, IFN-stimulated gene; diABZI, diamidobenzimidazole; TYK2, tyrosine kinase 2.

Figure 6

Targeting key PANoptosis regulators. A, ADAR1 impedes the interaction between ZBP1 and RIPK3, preventing ZBP1-mediated PANoptosis and promoting tumorigenesis; B, Treatment with NEI and IFN induce PANoptosis to impede tumor progression; C, The interaction of CASP6 with RIPK3 enhances that of RIPK3 and ZBP1, leading to PANoptosome assembly, which promotes ZBP1-mediated inflammasome activation and PANoptosis; D, STING enhances anti-tumor immune responses by activating TNFR1 and IFNAR1 signaling pathways, resulting in ZBP1 and RIPK3/ASC/CASP8 activation and consequently, MLKL phosphorylation and cell death. ZBP1, Z-DNA binding protein 1; ADAR1, adenosine deaminase acting on RNA 1; RIPK, receptor interacting serine/threonine kinase; NEI, nuclear export inhibitors; IFN, interferon; CASP, caspase; STING, stimulator of interferon genes; IFNAR1, interferon alpha/beta receptor subunit 1; TNFR1, tumor necrosis factor receptor-1; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; MLKL, mixed lineage kinase domain like pseudokinase.

Figure 7

Other therapeutic targets of PANoptosis in cancer. Deleting NFS1 using CRISPR-CASP9 makes CRC cells more sensitive to the chemotherapy drug oxaliplatin by enhancing PANoptosis. Thus, oxaliplatin-triggered PANoptosis serves as a viable therapeutic target in cancer. Sulconazole inhibits cancer by inducing PANoptosis through the trigger of mitochondrial oxidative stress, inhibition of glycolysis, and elevation of the radiosensitivity of cancer cells. Other targets of PANoptosis in cancer therapy include PANoptosis-related genes, other PANoptosis regulators, and inducing PANoptosis to improve the efficacy of traditional cancer therapies. CRISPR, clustered regularly interspaced short palindromic repeats; NFS1, a gene that encodes cysteine desulfurase; CASP, caspase; CRC, colorectal cancer.