Pyroptosis induced by natural products and their derivatives for cancer therapy

Abstract

Natural products, which are compounds extracted and/or refined from plants and microbes in nature, have great potential for the discovery of therapeutic agents, especially for infectious diseases and cancer. In recent years, natural products have been reported to induce multiple cell death pathways to exhibit antitumor effects. Among them, pyroptosis is a unique programmed cell death (PCD) characterized by continuous cell membrane permeability and intracellular content leakage. According to the canonical and noncanonical pathways, the formation of gasdermin-N pores involves a variety of transcriptional targets and post-translational modifications. Thus, tailored control of PCD may facilitate dying cells with sufficient immunogenicity to activate the immune system to eliminate other tumor cells. Therefore, we summarized the currently reported natural products or their derivatives and their nano-drugs that induce pyroptosis-related signaling pathways. We reviewed six main categories of bioactive compounds extracted from natural products, including flavonoids, terpenoids, polyphenols, quinones, artemisinins, and alkaloids. Correspondingly, the underlying mechanisms of how these compounds and their derivatives engage in pyroptosis are also discussed. Moreover, the synergistic effect of natural bioactive compounds with other antitumor therapies is proposed as a novel therapeutic strategy for traditional chemotherapy, radiotherapy, chemodynamic therapy, photodynamic therapy, photothermal therapy, hyperthermal therapy, and sonodynamic therapy. Consequently, we provide insights into natural products to develop a novel antitumor therapy or qualified adjuvant agents by inducing pyroptosis, which may eventually be applied clinically.

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1. Introduction

Immunotherapy has achieved monumental advances in the past decade, but many factors, including drug resistance and side effects, hinder its development and applications in treating solid tumors.^1,2 At the molecular level, the central basis for the eradication of tumor cells by the immune system is sufficient immunogenicity, which mainly relies on the number of tumor antigens that are released from tumor cells.^3,4 Previous studies indicated that dying tumor cells featuring specifically programmed cell death have immunogenic potential to induce effective antitumor responses.^5,6 To date, a dozen types of PCD have been identified, which can be divided into immunologically silent or immunostimulatory forms. For example, apoptosis is immunologically silent or “cold” PCD. By contrast, pyroptosis is immunostimulatory or “hot” PCD.^7–9 Importantly, tailored control of pyroptosis has excellent potential for eliciting antitumor immune responses.

Pyroptosis has been identified as unique PCD compared with apoptosis, where cell destruction occurs within an intact cell membrane. Barely consistent with the explosive rupture caused by necrosis, pyroptosis causes intracellular content leakage in a more continuous manner.^9–11 This form of death is mainly characterized by pore formation on cell membranes and swelling with bubble-like protrusions by gasdermin (GSDM) protein family members. GSDM proteins mainly contain six homologs, among which GSDMD and GSDME are the most well-studied.^12–14 After GSDM-based pores are formed, water influx destabilizes plasma membrane potential, resulting in cell rupture,^12,15 and efflux of inflammatory cytokines (such as IL-1β and IL-18) simultaneously drives an innate immune response.

Natural products, which are compounds extracted and/or refined from nature, have shown substantial potential for the discovery of new drugs and therapeutic agents.^16,17 To date, dozens of natural products, such as camptothecin, paclitaxel, and etoposide, have been approved by the US Food and Drug Administration (FDA), especially in antitumor agents.^18,19 The above facts indicate that natural products have a profound advantage over synthetic molecules. Accumulated evidence suggests that these active compounds not only have a broad range of bioactivities but also exert a synergistic effect on the therapeutic effects with other antitumor therapies, including traditional chemotherapy, radiotherapy, chemodynamic therapy, photodynamic therapy, photothermal therapy, and sonodynamic therapy.^20–24 Besides, bioactive compounds have a high safety profile and reduced side effects when combined with traditional chemotherapy.^25,26 However, despite these advantages, natural products still have several drawbacks, including low bioavailability, low solubility, and low tumor targeting.^27,28 Thus, nanoformations of natural small molecules have been employed to confer better efficacy and lower side effects in tumor treatment.^23,29 Also, nano-drugs are introduced in this study, given that we wish to extend the application of natural products.

In this review, we summarize the recent literature on the natural products or derivatives and their active compounds loaded on nanocarriers via targeting pyroptosis-related signaling pathways. The cellular mechanisms and signaling pathways involved in pyroptosis are also discussed for the recognition of biological targets for tumor therapy. Moreover, to reduce the defects of natural products, nano-drugs of pyroptosis-inducing compounds are also discussed and exhibited. Finally, we provide an outlook on the emerging landscape of natural compounds for novel antitumor therapy or qualified adjuvant agents, which we expect to eventually achieve clinical patient benefits.

2. Molecular mechanisms of pyroptosis

Pyroptosis can be triggered by the canonical pathway of caspase-1 inflammasome or the noncanonical pathway of caspase-4/5/11 inflammasome. Inflammasomes are multiprotein structures that assemble in reaction to pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs).³⁰

2.1 Canonical pathway pyroptosis

The canonical pathway of pyroptosis is initiated via the formation of inflammasomes, which trigger the inflammatory response and innate immunity. Inflammasomes are categorized based on their structural features into nucleotide-binding domain-like receptors (NLRs) and absent in melanoma 2 (AIM2) receptors (ALRs).³¹ When cells detect pathogen-associated or damage-related molecular patterns, they activate the cleavage of caspase-1 and inflammasome formation. Cleaved caspase-1 promotes the maturation and secretion of the inflammatory cytokines IL-1β and IL-18, cleaves GSDMD, and initiates pyroptosis.³²

2.2 Non-canonical pathway pyroptosis

The non-canonical pathway is mediated by caspase-4/5/11.³³ Caspase-4/5/11 has a strong affinity to cytosolic lipopolysaccharide (LPS). Upon LPS stimulation, these caspases oligomerize and cleave GSDMD, generating the GSDMD-N terminal, which creates pores in the plasma membrane. The destructive tumor cells emit inflammatory agents, which trigger the antitumor immune reaction, intensifying the death of additional tumor cells. The caspase activation and recruitment domains (CARD) enhance the cleavage of the GSDMD protein by directly interacting with cytosolic LPS, thus promoting pyroptosis. One of caspase-4/5/11 is unable to process IL-1β and IL-18 into their mature forms directly. Alternatively, caspase-4/5/11 can trigger the release of IL-1β and IL-18 in specific cell types through a mechanism dependent on the NLRP3 inflammasome.^34,35

2.3 Other pathways of pyroptosis

Besides the GSDMD pathways with caspase-1 and the alternative routes involving caspase-4/5/11, recent studies have discovered additional GSDM family proteins such as GSDME and GSDMC. In addition to caspase-1, recent discoveries have identified caspase-3 and caspase-8 as initiators that also trigger pyroptosis. Research indicates that GSDME-triggered pyroptosis can occur without the involvement of inflammasomes through the caspase-3/GSDME pathway.³⁶ Earlier studies showed that caspase-3 creates tiny openings in the mitochondrial membrane, leading to the release of cytochrome C and the development of apoptotic bodies. Furthermore, granzyme secreted by NK cells can trigger caspase-3 and GSDME, resulting in cancer-associated pyroptosis.³⁷ Caspase-8 activation is crucial for triggering pyroptosis by cleaving and activating GSDMC and GSDMD. Research revealed that in low-oxygen environments, TNF-α converts apoptosis to pyroptosis in MDA-MB-231 triple-negative breast cancer cells (PD-L1 positive and GSDMC-negative). This mechanism includes caspase-8 activation and GSDMC cleavage BT549 cells, which are known for their high GSDMC expression and can undergo pyroptosis in both regular and low-oxygen environments. In MCF-7 cells lacking both PD-L1 and GSDMC, pyroptosis fails to happen in standard or low-oxygen environments. Collectively, this indicates that GSDMC is a crucial component of the pyroptosis-related signaling pathway.³⁸

2.4 Discovery pathways

Recent studies showed a close connection between palmitoylation and pyroptosis. Palmitoylation is a post-translational modification that influences protein membrane localization and function by attaching palmitic acid to proteins. Research has found that palmitoylation of GSDMD plays a crucial role in the pyroptosis process. For example, S-palmitoylation at C191 of GSDMD is essential for the membrane translocation of GSDMD and pore formation. This modification is catalyzed by the palmitoyl transferases ZDHHC5 and ZDHHC9 and enhanced by the reactive oxygen species (ROS) generated by mitochondria.^39,40 Furthermore, palmitoylation not only affects GSDMD but other GSDM proteins, such as GSDME,^41,42 which implies that palmitoylation can serve as a widespread regulatory mechanism for activating the GSDM family, significantly influencing the control of pyroptosis. A schematic diagram of the mechanisms of pyroptosis and palmitoylation is shown in Fig. 1.⁴³

Fig. 1 Palmitoylation of GSDMD. (A) In the canonical pathway and the noncanonical pathway. (B) GSDMD is palmitoylated by ZDHHC5/9 at the C191/192 sites. Reprinted with permission from ref. 43 Copyright 2024, Elsevier.

2.5 Pyroptosis and cancer

Inflammasomes are widely recognized as a central part of the innate immune system. Inflammation caused by pyroptosis can trigger antitumor immunity.⁴⁴ Wang et al. developed an orthogonal system to treat breast tumors, which selectively delivers GSDM proteins to tumor cells, inducing pyroptosis to eliminate tumor cells.⁴⁵ Zhang and Zhou et al. found that pyroptosis plays an essential role in cytotoxic lymphocyte-mediated cytotoxicity. Pyroptosis induces immunogenic cell death, thereby enhancing antitumor immunity.^46,47 GSDME is a tumor suppressor that can inhibit tumor progression, but its expression is often downregulated in various malignancies through epigenetic mechanisms or loss-of-function mutations. Initially, cytotoxic immune cells recognize and induce pyroptosis in tumor cells. Shao et al. discovered that cytotoxic lymphocytes induce pyroptosis through a mechanism mediated by granzyme A and GSDMB, potentially enhancing antitumor immunity.⁴⁷ Pyroptosis recruits immune cells and enhances macrophage phagocytic activity. Wang's research indicates that in tumor cells, IL-1β is crucial for this recruitment and enhancement, and IL-18 also plays a vital role.⁴⁵ Additionally, inflammatory cytokines released from pyroptosis trigger a considerable antitumor immune response, thereby improving the effectiveness of anti-PD1 therapy and subsequent checkpoint inhibition. Current research suggests a strong link between pyroptosis and antitumor immunity, but whether pyroptosis also plays a role in immune evasion remains to be further explored. Thus, this field has significant research potential.

Chemotherapy is an important method for cancer treatment. However, as the treatment progresses, the sensitivity of cancer patients to chemotherapy drugs gradually decreases until resistance develops. Wu et al. found that the PLK1 inhibitor induces apoptosis through the caspase-3/GSDME pathway, providing a new approach for treating drug-resistant esophageal squamous cell carcinoma.⁴⁸ Yu et al. discovered that inhibiting protective autophagy and enhancing caspase-3/GSDME pathway-mediated pyroptosis can increase the sensitivity of melanoma cells to doxorubicin.⁴⁹

In summary, pyroptosis holds significant importance in antitumor therapy, but its underlying mechanisms require further investigation.

3. Natural products and their derivatives inducing pyroptosis in cancer therapy

Recent studies indicate that various natural compounds have anticancer effects by mediating apoptosis, ferroptosis, and pyroptosis pathways.^50,51 These compounds exhibit characteristics of multitargeting and multi-pathway effects, offering new insights and approaches for antitumor treatment. Herein, we primarily focus on the natural compounds and their derivatives inducing pyroptosis in cancer therapy.

3.1 Flavonoids

Flavonoids have been extracted from many different types of plants and herbs that are commonly consumed. There are more than 10 000 molecules with various structures in the flavonoid family.⁵² A variety of health benefits associated with flavonoids has been discovered, including the prevention of cancer, the reduction of high blood pressure, and the prevention of blood clots.^53–55 There is a wide distribution of flavonoids in plants, a group of natural substances with varying phenolic structures. More than 9000 flavonoids have been identified to date, which have been classified into seven subgroups based on their basic structure. These subgroups include flavones, flavanones, isoflavones, flavonols or catechins, and anthocyanins.⁵⁶

An increasing amount of data suggests that flavonoids can hinder cancer development by decreasing the amounts of reactive oxygen species (ROS).⁵⁷ In the review by Hasan Slika, it was summarized that flavonoids can act as reducing agents in a variety of reactions and exert antioxidant effects due to their structural characteristics. In addition to scavenging ROS, flavonoids inhibit oxidases responsible for producing superoxide anion, chelate trace metals, and activate antioxidant enzymes.⁵⁸ However, some studies have shown that flavonoids can also increase ROS and induce pyroptosis, which is related to cancer types, cell types, and biological mechanisms, as summarized in Table 1.

Table 1 Flavonoid-triggered pyroptosis

Name	Structure	Cancer types	Cancer cell lines	The mechanism of action to induce pyroptosis	Ref.
Neobractatin		Esophageal cancer	KYSE150, KYSE450, Eca-109	ROS/JNK, ROS/MEK/ERK1/2/GSDME	60
Neobavaisoflavone		Hepatocellular carcinoma	Hepg-2, HCCLM3	Tom20/ROS/caspase-3/GSDME	61
Luteolin		Colon cancer	HT29	Caspase-1/GSDMD	62
Nobiletin		Breast cancer, ovarian cancer	MCF-7, A2780, OVCAR3	Mir-200b/JAZF1/NF-κB/ROS	63 and 64
Alpinumisoflavone		Hepatocellular carcinoma	SMMC 7721, Huh7	NLRP3	65
Euxanthone		Hepatocellular carcinoma	Hep3B, SMMC 7721, and LO2	Caspase-1/IL-1β/IL-18	66
Galangin		Glioblastoma multiforme	U251, U87MG, A172	Caspase-3/GSDME/AMPK/mTOR	67
Icariin		Gastric cancer, prostate cancer	MKN-7, HGC-27, AGS, etc. PC3	Hsa_circ_0003159/miR-223-3p/NLRP3/caspase-1/GSDMD	68 and 69
Chalcone analogues		Lung cancer	NCI-H460, A549, H1975	ROS/caspase-3	70
Isobavachalcone		Glioblastoma multiforme	U87MG, U251	ESR1/GSDMD/NLRP3	71
Anthocyanin		Oral squamous cell carcinoma	Tca8113, SCC15	NLRP3/caspase-1/GSDMD/IL-1β	72

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3.1.1 Flavones. Compared to other flavonoids, flavones have a double bond between C2 and C3 in their skeleton, no substitutions at the C3 position, and oxidation at the C4 position.⁵⁹ New Blumea tonkinensis (NBT) is a compound derived from Blumea balsamifera that belongs to the prenylated oxanthrone class. Research has demonstrated that NBT amplifies the ROS levels in KYSE150, KYSE450, and Eca-109 esophageal cancer cells. This activation triggers the ROS/JNK and ROS/MEK/ERK1/2 signaling pathways, leading to GSDME-mediated pyroptosis and apoptosis.⁶⁰ The recent discovery of the novel flavonoid neobavaisoflavone (NBIF) has demonstrated its effect on the expression of the mitochondrial outer membrane protein Tom20 by stimulating the generation of ROS in cells. ROS triggers the recruitment of the BAX protein through the caspase-3/GSDME pathway, leading to the induction of pyroptosis in hepatocellular carcinoma cells. This process effectively hampers the proliferation of these cells.⁶¹ Luteolin is a naturally occurring flavonoid obtained from honeysuckle, which has been reported to induce pyroptosis in human colon cancer HT29 cells in nude animal xenograft models by activating the NLRP3/caspase-1/GSDMD signaling pathway.⁶²

3.1.2 Isoflavones. Isoflavones are compounds with a backbone of flavonoids, and their B-ring connections are different from that of flavonoids. Nobiletin is a flavonoid with several methoxy groups, which is present in the peels of citrus fruits. It can not only promote the pyroptosis of breast cancer via regulation of the miR-200b/JAZF1 axis⁶³ but also trigger ROS-mediated pyroptosis through regulating autophagy in ovarian cancer cells.⁶⁴ Alpinumisoflavone (AIF), a flavonoid found in the Zhuang medicine Millettia pachycarpa, effectively suppresses the growth and spread of hepatocellular carcinoma cells by inducing pyroptosis through the NLRP3/caspase-1/IL-1β/IL-18 pathway. Moreover, AIF-triggered autophagy amplifies pyroptosis in hepatocellular cancer.⁶⁵

3.1.3 Flavonols. Euxanthone is a chemical of the oxanthrone class derived from Polygala caudata, demonstrating a range of pharmacological actions. Euxanthone has antiproliferative and anti-invasive characteristics in hepatocellular cancer by triggering pyroptosis.⁶⁶ The investigation conducted by Kong et al. showed that curcumin effectively suppresses glioblastoma growth in vitro and enhances the survival rates of mice with cancer in vivo. This process involves curcumin stimulating both caspase-3/GSDME-mediated pyroptosis and apoptosis in glioblastoma cells, while activating the AMPK/mTOR pathway to induce autophagy.⁶⁷ Icariin (ICA) is the primary bioactive compound found in Epimedium. ICA suppresses the proliferation of gastric cancer cells by triggering cell pyroptosis.⁶⁸ In addition, the combination of ICA and curcumin stimulates autophagy by activating the mTOR pathway, which promotes the pyroptosis of prostate cancer cells through the caspase-1/GSDMD pathway mediated by cathepsin B.⁶⁹

3.1.4 Chalcones. The α,β-unsaturated ketone is a functional group found in the chalcone framework, which plays a vital role in triggering pyroptosis in cancer cells. Zhu et al. used chalcone as a raw material to synthesize a variety of α,β-unsaturated ketone analogs induced caspase-3-mediated pyroptosis by regulating ROS production, thereby significantly inducing lung cancer cell death.⁷⁰ Isobavachalcone (IBC) interacts specifically with NLRP3 and the transcription factor estrogen receptor α (ESR1 gene), as determined by network pharmacology and molecular docking research. Both in vivo and in vitro investigations confirmed that IBC may be an effective treatment agent for glioblastoma multiforme.⁷¹

3.1.5 Anthocyanins. Anthocyanins are natural pigments that are widely distributed in the flowers, leaves, fruits, and rhizomes of colored plants. Research has demonstrated that anthocyanins stimulate pyroptosis by increasing the production of NLRP3, caspase-1, GSDMD, and IL-1β. Consequently, this reduces the survival of oral squamous carcinoma cells and hinders their capacity for migration and invasion.⁷²

3.2 Terpenoids

Terpenoids in traditional Chinese medicine are a valuable group of natural compounds that can serve as useful resources for treating tumors. It has been shown that seven terpenoid molecules, such as triptolide and botulinic acid, have anticancer properties by causing cancer cell pyroptosis, as summarized in Table 2. Triptolide is a highly potent epoxidized diterpene lactone molecule found in the traditional Chinese medicinal plant Tripterygium wilfordii. Triptolide triggers pyroptosis in head and neck cancer by blocking mitochondrial hexokinase II through GSDME. Triptolide-based therapy explicitly inhibits the production of c-myc and mitochondrial hexokinase II (HK-II) in cancer cells. This inhibition results in the activation of the BAD/BAX-caspase-3 cascade and the cleavage of GSDME by active caspase-3.⁷³

Table 2 Terpenoid-triggered pyroptosis

Name	Structure	Cancer types	Cancer cell lines	The mechanism of action to induce pyroptosis	Ref.
Triptolide		Head and neck cancer	HK1, Fadu	BAD/BAX-caspase-3/GSDME	73
Betulinic acid		Esophageal cancer	TE-11	ASC/caspase-1	74
Cucurbitacin B		Non-small cell lung cancer	A549, H1299 HLF	TLR4/NLRP3/GSDMD	75
Diosbulbin-B		Gastric cancer	CR-GC, CS-GC	PD-L1/NLRP3	76
Croyanhuins		Multiple types of tumors	SHSY5Y, SW480, A549, ACHN, HepG2	Caspase-3	77
Alantolactone		Anaplastic thyroid cancer	KHM-5M, KMH-2, C643, cal62	ROS/Bcl-2/BAX/caspase-9/caspase-3, GSDME	78
Tanshinone IIA		Cervical cancer	HeLa, HK1	miR-145/GSDMD/miR-125b/FOXP3/caspase-1	79 and 80
Miltirone		Hepatocellular carcinoma	Origin tumor cells	ROS/ERK1/2-BAX/caspase-9/caspase-3/GSDME	81

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Betulinic acid (BA) is a pentacyclic triterpenoid of the lupine type, which is obtained from the bark of the white birch tree. BA enhanced esophageal cancer cell pyroptosis and reduced their stemness, making them more sensitive to cisplatin.⁷⁴ Cucurbitacin is a compound that originates from plants belonging to the Cucurbitaceae family. Cucurbitacin B (CuB) is a compound that exhibits substantial effects on antitumor treatments. Research has demonstrated that CuB efficiently suppresses the growth of tumor cells in both non-small cell lung cancer (NSCLC) cell cultures and mouse models. CuB directly binds to Toll-like receptor 4 (TLR4) to activate the NLRP3 inflammasome, which triggers the cleavage of GSDMD, resulting in the initiation of pyroptosis. In addition, CuB increases the levels of mitochondrial ROS, the accumulation of the mitochondrial membrane protein Tom20, and the release of cytoplasmic calcium ions, ultimately leading to pyroptosis in NSCLC cells.⁷⁵

Through both in vivo and in vitro experiments, Li et al. discovered that a dosage of 12.5 μM of diosbulbin-B (DB) could effectively hinder the properties of tumor stem cells and the growth of gastric tumor cells, which was achieved by reducing the expression of PD-L1 in gastric tumor cells, consequently activating NLRP3-mediated pyroptosis.⁷⁶ Li et al. reported the isolation of five novel diterpenoid compounds named croyanhuins A–E (1–5), as well as a new C13 nor-isoprenoid molecule called croyanhuin F (6), from the leaves and branches of Premna microphylla. Compounds 1 and 3, which are novel terpenoid compounds, were found to reduce cell proliferation and viability in a manner that depends on the dosage and duration. Additionally, both compounds triggered the cleavage of caspase-3 or PARP-1 in the SW480 cell line.⁷⁷ Alantolactone is a prominent constituent of Saussurea lappa, which is a chemical classified as a sesquiterpene lactone. Alantolactone demonstrates substantial antitumor effects against anaplastic thyroid carcinoma in laboratory settings and living organisms without any reported negative effects. Alantolactone triggers both apoptosis and pyroptosis in anaplastic thyroid carcinoma cells by facilitating the cleavage of PARP and GSDME via activated caspase-3. Additionally, it triggers immunogenic cell death by causing the movement of calreticulin and the release of IL-1β.⁷⁸ Tanshinones, which are primarily diterpenoid chemicals, are the primary active constituents found in the roots of Salvia miltiorrhiza. More than 50 types of tanshinones have been identified, including tanshinone IIA and neotanshinone. Tanshinone IIA is the primary constituent of tanshinones, and research has demonstrated its substantial antitumor properties. Liang et al. demonstrated that tanshinone IIA substantially increases the expression of GSDMD in human cervical cancer cells, leading to the induction of pyroptosis. These findings indicated that the miR-145/GSDMD signaling pathway plays a crucial role in mediating the effects of tanshinone IIA on HeLa cells.⁷⁹ Another study showed that tanshinone IIA controls the miR-125b/FOXP3/caspase-1 signaling pathway to promote pyroptosis, suppressing the growth of nasopharyngeal tumorHK1 cells.⁸⁰ Moreover, neotanshinone effectively suppressed the growth of tumors and triggered tumor necrosis in the Hepa1-6 mouse hepatocellular carcinoma homolog model. Neotanshinone effectively induced the accumulation of ROS within cells, inhibited the phosphorylation of mitogen-activated extracellular signal-regulated kinase (MEK) and extracellular signal-regulated protein kinase (ERK), and consequently induced pyroptosis in liver cancer cells.⁸¹

3.3 Polyphenols

Polyphenols are a diverse set of organic chemicals that are naturally found in plants. Currently, over 8000 distinct phenolic structures have been identified. Scientific studies have shown that natural polyphenolic compounds can inhibit tumors, display antioxidant and anti-inflammatory properties, and diminish the adverse effects of traditional antitumor agents. The process of polyphenol-triggered pyroptosis has shed fresh light on their ability to act as antineoplastic agents, as summarized in Table 3. Curcumin, a polyphenol extracted from turmeric, has been intensively researched for its ability to inhibit tumors. Elevated levels of components of the NLRP3 inflammasome were observed in the SW480 and HCT116 cell lines, which were treated with curcumin. Nevertheless, the activation of NLRP3 inflammasome did not occur in LoVo and HT29 cells.⁸² Additionally, curcumin triggers apoptosis and pyroptosis in HepG2 cells, in which ROS plays a crucial role.⁸³ Another study discovered that curcumin can alleviate pyroptosis caused by other chemicals, reducing liver toxicity. Aflatoxin B1 (AFB1) is a potent carcinogen that can cause liver cancer in both humans and animals when consumed over a long period. AFB1 triggers hepatocyte pyroptosis by activating the ITPR2/caspase-12/caspase-3 pathway. In contrast, curcumin hinders this mechanism and effectively reduces AFB1-induced pyroptosis. Moreover, the L61H10 compound is a heterocyclic ketone derivative that belongs to the thienopyran family and is structurally similar to curcumin.⁸⁴ L61H10 has been demonstrated to induce cell cycle arrest at the G2/M phase and facilitate the production of proteins associated with apoptosis, as evidenced by both in vitro and in vivo studies. Furthermore, it demonstrates therapeutic promise in lung cancer treatment by transitioning from apoptosis to pyroptosis through the NF-κB pathway.⁸⁵

Table 3 Polyphenol-triggered pyroptosis

Name	Structure	Cancer types	Cancer cell lines	The mechanism of action to induce pyroptosis	Ref.
Curcumin		Colon cancer, hepatocellular carcinoma, liver injury	SW480, HCT116, LoVo, HT29, HepG2	NLRP3/GSDME/ROS/ITPR2/caspase-12/caspase-3	82–84
L61H10		Lung cancer	H460, A549	NF-κB	85
Polydatin		Non-small cell lung cancer, breast cancer	A549, H1299, 4T1	NLRP3/NF-κB/JAK2/STAT3	86 and 87
Cannabidiol		Hepatocellular carcinoma	Hepg2, HUH7, HCCLM3, MHCC97H, HEK293T	Caspase-3/GSDME/ATF4/IGFBP1/AKT	88
EGCG		Melanoma	1205Lu, HS294T	IL-1β/NLRP1/NF-κB	89
Quercetin		Colon cancer	HCT116, HT29	NEK7/NLRP3/GSDMD	90
Ophiopogonin B		Non-small cell lung cancer	NCI-H460, A549, A549/DDP, A549/PTX	Caspase-1/GSDMD	91

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Polydatin has been demonstrated to decrease the expression of NLRP3, ASC, and procaspase-1, subsequently resulting in a reduction in pyroptosis levels and inhibition of the advancement of NSCLC.⁸⁶ Another study showed that polydatin can also trigger apoptosis and pyroptosis by blocking the JAK2/STAT3 signaling pathway. Thus, decreased blood lipid levels have been detected in animal models with triple-negative breast cancer (TNBC) produced by a high-fat diet. Eventually, polydatin exhibits antitumor properties against TNBC.⁸⁷ Cannabidiol (CBD) efficiently suppresses the proliferation of liver tumor cells in vivo and in vitro and triggers pyroptosis through a mechanism that involves caspase-3/GSDME. The activation of the CBD-induced pyroptotic pathway may result from the buildup of integrated stress response and mitochondrial stress. Moreover, CBD can hinder aerobic glycolysis through the regulation of the ATF4-IGFBP1-AKT axis, leading to a decrease in adenosine triphosphate (ATP) and essential intermediate metabolites.⁸⁸ Ellis et al. reported that epigallocatechin gallate (EGCG) hinders melanoma growth and reduces the production of the pyroptosis-related proteins IL-1β, IL-18, and NLRP1.⁸⁹ Quercetin inhibits colon tumor cell growth through GSDMD-mediated pyroptosis, which upregulates the expression of the NIMA-associated kinase 7 (NEK7) protein, thereby promoting NLRP3 inflammasome assembly and GSDMD cleavage.⁹⁰ Administering ophiopogonin B (OP-B) has been discovered to increase the sensitivity to cisplatin in cisplatin-resistant lung tumor cells. This impact occurs through the activation of caspase-1/GSDMD-dependent pyroptosis. Consequently, OP-B demonstrates substantial inhibitory effects on A549/DDP orthotopic tumors in nude mice and zebrafish xenograft tumors.⁹¹

3.4 Quinones

Quinone compounds are bioactive chemicals that exist naturally in more than 100 kinds of plants. These compounds include naphthoquinones, anthraquinones, benzoquinones, and phenanthrenequinones. Some of these substances demonstrate antitumor activity by inducing pyroptosis, as shown in Table 4. Osthole has been demonstrated to decrease the mitochondrial membrane potential and stimulate the production of ROS in ovarian cancer cells. Ultimately, this effect triggers LC3-mediated autophagy and GSDME-dependent pyroptosis.⁹² A further investigation discovered that osthole triggers the specific type of inflammatory cell death (pyroptosis) mediated by GSDME in cervical cancer cells. Through the effect discussed above, osthole leads to the inhibition of cell growth by blocking the NQO1 enzyme and promoting the generation of ROS.⁹³

Table 4 Quinone-, artemisinin-, and alkaloid-triggered pyroptosis

Name	Structure	Cancer types	Cancer cell lines	The mechanism of action to induce pyroptosis	Ref.
Osthole		Ovarian carcinoma, cervical cancer	A2780, OVCAR3, HeLa	LC3/GSDME/NQO1/ROS	92 and 93
Dihydroartemisinin		Breast cancer, esophageal squamous cell carcinoma	MCF-7, MDA-MB-231, Eca109, Ec9706	AIM2/caspase-3/DFNA5, GSDME/PKM2-caspase-8, 3	94 and 95
Berberine		Hepatocellular carcinoma	Hepg2	Caspase-1/Ac-YVAD-CMK	96
Piperlongumine		Squamous cell carcinoma	KYSE-30	NRF2/ROS/TXNIP/NLRP3	97
Piperlongumine analogue		Non-small-cell lung cancer	A549, NCI-H460	ROS/NF-κB	98

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Artemisinins, primary antimalarial components, are obtained from the traditional Chinese medicinal herb Artemisia annua. It belongs to the sesquiterpene lactone class. Dihydroartemisinin (DHA), a compound derived from artemisinin, is produced by reducing artemisinin using sodium borohydride. The processes of DHA-triggered pyroptosis are summarized in Table 4. DHA has been demonstrated to increase the expression of AIM2, caspase-3, and GSDME. In vivo tests demonstrated that it effectively suppresses the growth of breast cancer cells by activating the AIM2/caspase-3/DFNA5 axis, which leads to the induction of pyroptosis.⁹⁴ In addition, DHA also hinders the growth of esophageal squamous carcinoma cells. Molecular mechanistic studies have shown that esophageal squamous carcinoma cells have the characteristic pyroptotic morphology after being treated with DHA, which is followed by an increase in the levels of IL-18 and IL-1β, and a decrease in the expression of tumor M2 pyruvate kinase (PKM2). These findings indicate that DHA triggers pyroptosis in esophageal squamous carcinoma cells through the PKM2/caspase-8, 3/GSDME pathway.⁹⁵

3.6 Alkaloids

Alkaloids belong to a class of nitrogen-containing alkaline organic compounds that are biologically active. They serve as crucial active components in traditional Chinese medicine. Studies have documented that alkaloids derived from traditional Chinese medicine are extensively employed in the management of various types of cancer, including liver cancer and breast cancer. The processes of alkaloid-triggered pyroptosis are summarized in Table 4. Berberine, also known as berberine hydrochloride, is a type of alkaloid extracted from the medicinal plant Coptis chinensis, which is commonly used in traditional Chinese medicine. Research has demonstrated that berberine leads to a high expression of caspase-1 in HepG2 cells. According to these findings, berberine promotes pyroptosis, which inhibits hepatocellular carcinoma growth.⁹⁶ Piperlongumine, an alkaloid derived from the Piper longum plant used in traditional Chinese medicine, exhibits significant antitumor properties. Piperine induces pyroptosis in esophageal squamous cell carcinoma (ESCC) cells through the ROS/TXNIP/NLRP3 pathway by suppressing NRF2. Consequently, it hampers the in vitro and in vivo proliferation, migration, invasion, and colony formation of ESCC cells.⁹⁷ A derivative of piperlongumine called L50377 is derived from the trimethoxybenzyl group found in piperlongumine. Li et al. discovered that L50377 can trigger apoptosis and pyroptosis in NSCLC cells. This effect is likely due to the suppression of NF-κB through the mediation of ROS.⁹⁸

3.7 Other natural compound

Besides the types of compounds listed above, other natural compounds from plants can induce pyroptosis in tumor cells, as shown in Table 5. Dioscin has been shown to have inhibitory effects on osteosarcoma in both in vivo and in vitro tests. Upon further investigation of its mechanism, it was discovered that dioscin halts the G2/M phase of the cell cycle and initiates programmed cell death by controlling the JNK/p38 signaling pathway. Additionally, it triggers caspase-3/GSDME-mediated pyroptosis.⁹⁹ Sesamin, a lignan obtained from sesame, has been demonstrated to augment the antitumor effects against murine T-cell lymphoma by stimulating autophagy-induced apoptosis and pyroptosis.¹⁰⁰ Schisandrin B (Sch B) is a type of lignan extracted from the plant Schisandra chinensis. Sch B alone decreases the viability of HepG2 cells and triggers apoptosis. Nevertheless, the apoptosis produced by Sch B in HepG2 cells is transformed into pyroptosis when NK cells are present. Sch B triggers pyroptosis in HepG2 cells via the perforin/granzyme B/caspase 3/GSDME pathway, with the participation of NK cells.¹⁰¹ A Cordyceps extract triggered programmed cell death in lung cancer A549 cell lines by concurrently stimulating caspase-3/PARP-dependent apoptosis and caspase-3/GSDME-dependent pyroptosis.¹⁰² Alisol A, which is derived from the rhizome of Alismatis (Zexie), is known to induce both cell death and apoptosis in colorectal cancer cells following treatment.¹⁰³

Table 5 Other natural compound-triggered pyroptosis

Name	Structure	Cancer types	Cancer cell lines	The mechanism of action to induce pyroptosis	Ref.
Dioscin		Osteosarcoma	MG63, MNNG/HOS cell	NLRP3/caspase-1/JNK/p38	99
Sesamin		Murine T-cell lymphoma	EL4	T cell	100
Schisandrin B		Hepatocellular carcinoma	HepG2	B-caspase 3/GSDME	101
C. Militaris extract		Non-small cell lung cancer	A549	Caspase-3/PARP/caspase-3/GSDME	102
Alisol A		Colon cancer	HCT-116, HT-29	PI3K/AKT/mTOR	103
4-Hydroxybenzoic acid		Lung adenocarcinoma cells	A549	Caspase-1/IL-1/IL-18	104

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Pyroptosis can also be induced by natural products derived from marine organisms. For example, the crude extract of Pseudoalteromonas haloplanktis TAC125, primarily composed of 4-hydroxybenzoic acid, inhibits the proliferation of A549 lung cancer cells and induces pyroptosis.¹⁰⁴

The research on the anti-cancer efficacy of the active ingredients of traditional Chinese medicine by activating pyroptosis has high value, which is revealing a new mechanism of its anti-cancer efficacy, providing a reference for the research and development of new drugs and supplementing the shortcomings of current treatment regimens, especially in the field of chemotherapy drug resistance. However, several issues still need to be addressed in this research, where some traditional Chinese medicine active ingredients suffer from low utilization due to the lack of advanced processing methods and extraction techniques, resulting in a low absorption rate and limited effectiveness of the drug. Structural optimization, formulation screening, and derivative development can effectively enhance their therapeutic efficacy. However, nanoparticle technology combined with natural compounds can promote the pyroptosis of tumor cells, which may be a potential solution to address the above-mentioned problems.

4. Nano-drugs from natural products and their synergic effect with other therapies to induce pyroptosis

The treatment of tumors has advanced significantly over the past decade, including chemotherapy, radiotherapy, chemodynamic therapy (CDT), photodynamic therapy (PDT), photothermal therapy (PTT), hyperthermia, sonodynamic therapy (SDT), and other therapies. Nanotechnology can help overcome the limitations of using natural product molecules, such as rapid clearance in vivo, severe systemic side effects, and weak tumor-targeting capability. Additionally, these strategies amplify intracellular oxidative stress and mitochondria damage, enhance pyroptosis in tumor cells, and suppress tumor growth.

4.1 Nanomaterial-assisted chemotherapy triggers pyroptosis

Previous research has established that many chemotherapeutic drugs used in clinical practice are derived from natural products, such as paclitaxel (PTX) and camptothecin (CPT), which have been shown to convert apoptosis to pyroptosis.^105–107 CPT is a quinoline alkaloid that exhibits potent anticancer activity by selectively trapping DNA topoisomerase I, making it a commonly chosen chemotherapeutic agent. As a cellular respiration inhibitor, CPT can trigger the mitochondria to produce a large amount of ROS. S-Nitrosothiol is an emerging NO donor with GSH-triggered NO release properties. Based on the above-mentioned theories, Ye et al. developed a cascade-amplified pyroptosis inducer, CSC CPT/SNAP (Fig. 2A), which is a supramolecular nanomedicine assembled based on host–guest molecular recognition and hydrophobic interaction of CD-Fc.¹⁰⁸ Both the endogenous mitochondrial ROS stimulated by the release of camptothecin and the released NO initiate pyroptosis, and simultaneously diffusion between ROS and nitric NO is used to control the response with self-supplied reactive nitrogen species (RNS) to enhance pyroptosis and immunotherapy. The RNS has a long lifespan and can act as a pyroptosis trigger, effectively compensating for the inherent defects of ROS, resulting in long-lasting pyroptosis, which is beneficial for immunotherapy.

Fig. 2 Nanomaterial-assisted chemotherapy-triggered pyroptosis. (A) Synthesis and therapeutic mechanism of CSC CPT/SNAP. Reprinted with permission from ref. 105 Copyright 2024, the American Chemical Society. (B) Synthesis and therapeutic mechanism of Mn-HSP. Reprinted with permission from ref. 106 Copyright 2024, Elsevier.

In addition, Wang and colleagues developed a nano platform (Mn-HSP) (Fig. 2B) that loads manganese ions (Mn²⁺) and a hyaluronic acid (HA)-based PTX prodrug.¹⁰⁹ HA can specifically bind to the CD44 receptors overexpressed on the surface of tumor cells, promoting the uptake of Mn-HSP by tumor cells. PTX induces pyroptosis in tumor cells, and Mn²⁺ activates the STING pathway to release type I interferons (IFNs), which activate innate immunity. In vitro and in vivo experiments demonstrated that Mn-HSP effectively inhibits primary breast tumors and rechallenges against tumor and lung metastasis.

4.2 Nanomaterial-assisted radiotherapy-triggered pyroptosis

Radiotherapy has irreplaceable advantages in clinical tumor treatment.^110–113 However, it focuses on local treatment rather than tumor metastasis. Although radiotherapy is clinically effective for immune activation, it focuses on cancer cell elimination, instead of systemic immune activation. The phenomenon of immune tolerance incited by radiotherapy seems ubiquitous despite the reported abscopal immunity. In a recent study by Wang et al., they designed a multifunctional radiosensitizer metal-phenolic network based on EGCG and W⁶⁺ called PWE NPs, which induced cell pyroptosis after radiotherapy through an epigenetic strategy (Fig. 3A).¹¹⁴ The rare tungsten ions, which serve as X-ray sensitizers, promote the production of intracellular ROS through the BAX/Cytochrome c/caspase-9/caspase-3 pathway. The activation of caspase-3 cleaves the demethylation-upregulated GSDME by EGCG, producing GSDME-N, which promotes cell membrane perforation (Fig. 3B and C). The resulting pores allow the intracellular contents of HMGB1 and lactate dehydrogenase (LDH) to pass through the membrane into the extracellular region, stimulating the immune system and reactivating the antitumor immune response. Treatment with PWE nano-coordination agents has effectively inhibited primary tumors, distant tumors, and even systemic metastatic tumors in various mouse models constructed with 4T1. Furthermore, the pyroptosis induced by PWE resulted in systemic antitumor immune activity and inhibition of metastasis (Fig. 3D and E). Consequently, PWE affects the immunology of traditional radiotherapy and inhibits radiotherapy-upregulated regulatory T cells, which provides new insights into tumor radiotherapy.

Fig. 3 Nanomaterial-assisted radiotherapy-triggered pyroptosis. (A) Synthesis and therapeutic mechanism of PWE NPs. (B) PWE (+)-induced pyroptosis (red arrow). Scale bar: 20 μm. Confocal images of 4T1 cells stained with PI and annexin V–FITC. Scale bars: 10 μm. (C) Western blot analysis. (D) Representative percentage of CD3⁺CD8⁺ T cells collected from TDLN. (E) Representative percentage of CD3⁺CD8⁺ T cells collected from the distant tumor. Reprinted with permission from ref. 111 Copyright 2024, Wiley.

4.3 Nanomaterial-assisted CDT-triggered pyroptosis

CDT, which induces redox reactions through Fenton or Fenton-like reactions to produce large amounts of toxic ROS, is considered an effective treatment for tumors.^115–117 In recent years, an increasing amount of literature on nanomedicine has been devoted to enhancing CDT, promising a comprehensive optimization of CDT efficacy.

Increasing intracellular metal ion levels are closely related to CDT. For example, Zheng et al. designed Ca²⁺ nano-modulators (CaNMs) (Fig. 4A) as cell pyroptosis inducers for tumor immunotherapy by utilizing CaCO₃ as a carrier to load curcumin (Cur).¹¹⁸ CaCO₃ generates Ca²⁺ in tumor cells and Cur stimulates the release of Ca²⁺ from the endoplasmic reticulum to the cytoplasm, thereby causing mitochondrial Ca²⁺ overload. Ultimately, this mechanism leads to increased ROS and cytochrome C release, which further activates caspase-3 to cleave GSDME, inducing cell pyroptosis.

Fig. 4 Nanomaterial-assisted CDT-triggered pyroptosis. (A) Synthesis and therapeutic mechanism of CaNMs. Reprinted with permission from ref. 115 Copyright 2024, Wiley. (B) Synthesis and therapeutic mechanism of TPL@TFBF. Reprinted with permission from ref. 116 Copyright 2024, Springer Nature. (C) Synthesis and therapeutic mechanism of BEM NPs. Reprinted with permission from ref. 120 Copyright 2024, Wiley. (D) Synthesis and therapeutic mechanism of CQG. Reprinted with permission from ref. 121 Copyright 2024, Wiley.

In addition to Ca²⁺, the intracellular Fenton reaction revolves around Fe ions catalyzing the production of highly reactive hydroxyl radical (˙OH). Wang et al. constructed a BSA-FA-functionalized iron-containing metal–organic framework (TPL@TFBF) (Fig. 4B), which has shown promising efficacy against melanoma lung metastasis in vivo.¹¹⁹ In this nanoplatform, tannic acid (TA) and Fe³⁺ are coordinated, and triptolide (TPL) is coated with FA-modified BSA, which forms a metal–organic framework (MOF). By reducing Fe³⁺ to Fe²⁺, TA initiates the Fenton reaction, leading to the production of ROS. In addition, TPL inhibits the expression of nuclear factor erythroid-2 related factor (Nrf2), which increases intracellular ROS production. Therefore, cancer cells undergo ferroptosis and pyroptosis and release large amounts of DAMPs.

EGCG is one of the most critical compounds among tea polyphenols, and due to its widespread adhesion and high biocompatibility, nanoparticles consisting of EGCG possess enhanced drug potency and fewer side effects.¹²⁰ Metal-phenolic networks (MPNs) formed by the coordination of phenolic ligands with metal ions combine the characteristics of polyphenols and metal ions, demonstrating unique advantages in enhancing antitumor effects.^121,122 Zhen et al. discovered that quinone in oxidized EGCG molecules can undergo Michael addition with the amino and thiol groups of GSH, providing a novel strategy for GSH depletion.¹²³ Based on this finding, they further introduced molybdenum chloride, and under the protection of bovine serum albumin (BSA), BSA-EGCG-Mo nanocomposites (BEM) (Fig. 4C) were prepared by forming coordination bonds between phenolic hydroxyl groups and Mo⁵⁺ ions. Using the same method, BSA-EGCG (BE) NPs and BSA-Mo (BM) NPs were prepared without adding molybdenum chloride or EGCG. BEM nanoparticles are internalized by cancer cells, where they can deplete overexpressed GSH through Michael addition reactions, converting it from nanoparticles to large aggregates, significantly reducing the GSH levels. Simultaneously, Mo and polyoxometalates (POM) can regulate the ROS levels through Fenton-like reactions and the Russell mechanism, further depleting GSH and disrupting the redox balance. These aggregates can mechanically disrupt endosomal and plasma membranes, inducing pyroptosis and ICD and releasing DAMPs. Notably, BE alone can also trigger pyroptosis, subsequently inducing a strong ICD effect.

Currently, there are few effective clinical treatment strategies for tumor recurrence. Activating the immune system is the key to combating dormant tumors and preventing their recurrence. As a defense mechanism unique to dormant tumors, the nuclear factor-erythroid 2-related factor 2 (NRF2)/quinone oxidoreductase 1 (NQO1) signaling pathway may help maintain redox homeostasis and protect tumor cells from oxidative stress. However, activation of the NRF2-NQO1 pathway can inhibit the activity of the NLRP3 inflammasome, thereby suppressing cell pyroptosis. Therefore, developing a pyroptosis inducer that inhibits the NRF2-NQO1 antioxidant pathway can be a novel and effective strategy for preventing the recurrence of dormant tumors. Qiao et al. developed a self-destructive copper-quinone-GOx nanoparticle (CQG NP) (Fig. 4D) therapeutic platform.¹²⁴ Upon reaching the tumor site, CQG NPs mimicked the activities of glutathione peroxidase (GPx) and catalase (CAT), depleting GSH and generating a substantial amount of oxygen. The CQG NPs inhibited the expression of hypoxia-inducible factor-1α (HIF-1α), suppressed the expression of NQO1 and NRF2 proteins, and eventually disrupted the antioxidant defense mechanism of tumor cells. Meanwhile, CQG NPs exhibited superoxide dismutase (SOD)-like and peroxidase (POD)-like activities, rapidly producing a large amount of ROS to aggregate the NLRP3 inflammasome. Coupled with the starvation therapy effect of GOx co-activated caspase-1, they further cleaved GSDMD, resulting in cell membrane perforation and the release of inflammatory factors, leading to intense cell pyroptosis.

4.4 Nanomaterial-assisted PDT-triggered pyroptosis

Photodynamic therapy (PDT) involves binding photosensitizers to tumor sites. When irradiated with laser light of specific wavelengths, a large amount of ROS is generated, thereby damaging tumor cells.^125–128 PDT not only directly kills tumor cells by generating ROS but also has been increasingly recognized as an effective method to induce immunogenic pyroptosis in tumor cells, providing an additional avenue for tumor treatment.

Some photosensitizers are derived from natural products.¹²⁹ Second-generation photosensitizers can generate more ROS, and thus exhibit greater significant cytotoxicity against tumor cells.¹³⁰ For instance, chlorin e6 (Ce6), a derivative of chlorophyll-a, is known for its excellent light absorption properties, making it an effective photosensitizer with advantages.¹³¹ Numerous studies have confirmed the anticancer effects of Ce6-mediated PDT and SDT.^132,133 In addition, anthraquinone-based photosensitizers are natural photosensitizers discovered from fungal plants, primarily including hypericin, curcumin, and emodin.^134–138

In the past few years, many researchers have been interested in using Ce6 to produce nanomaterials for CDT to induce pyroptosis. For example, Wan et al. synthesized a small molecule prodrug, paclitaxel-oxaliplatin (PTX-OXA), which was covalently self-assembled with a Ce6 and a diselenide crosslinker to form a diselenide nanoprodrug (DSe@POC) (Fig. 5A).¹³⁹ This nano-prodrug combined chemotherapy and PDT to enhance tumor immunotherapy through the induction of pyroptosis. The diselenide bonds in DSe@POC can be cleaved by the high concentration of glutathione in the TME and reactive oxygen species induced by PDT, providing excellent TME-targeting effects. Additionally, DSe@POC can trigger intense pyroptosis to reshape the immune-stimulatory TME and elicit a robust immune response. The combination of DSe@POC with αPD-1 therapy effectively inhibited the growth of distant tumors through the abscopal effect, enhanced long-term immune memory responses to reject recurrent tumors, and prolonged survival.

Fig. 5 Nanomaterial-assisted PDT-triggered pyroptosis. (A) Synthesis and therapeutic mechanism of CCNP. Reprinted with permission from ref. 136 Copyright 2024, Wiley. (B) Synthesis and therapeutic mechanism of A-C/NPs. Reprinted with permission from ref. 137 Copyright 2024, Elsevier. (C) Synthesis and therapeutic mechanism of MCPP. Reprinted with permission from ref. 141 Copyright 2024, the American Chemical Society. (D) Synthesis and therapeutic mechanism of Cu-TBB. Reprinted with permission from ref. 142 Copyright 2024, Elsevier.

In another example, Ma et al. designed a class of endogenous/exogenous stimulus-responsive single-molecule prodrugs as nanoinductors (CCNP) (Fig. 5B) to regulate the process of tumor cell pyroptosis mediated by the GSDME protein, thereby enhancing the effectiveness of tumor immunotherapy.¹⁴⁰ This polymer nanoinductor can be activated explicitly by non-invasive laser irradiation in the presence of tumor microenvironment ROS and GSH, facilitating the controlled release of the photosensitizer and chemotherapy drug molecules. Together, they activated caspase-3, regulate tumor cell pyroptosis, and in combination with PD-1 therapy, induced systemic immune responses capable of eliminating distant tumors, effectively prolonging the survival period of mice.

Cytarabine (AraC) is the first natural marine anticancer drug isolated from deep-sea sponges. However, it has poor stability and fast metabolism in vivo, which is challenging to use in the treatment of solid tumors.¹⁴¹ Li et al. designed a carrier-free chemical photodynamic nano-platform (A-C/NPs) employing a co-assembly strategy with cytarabine (Ara-C) and Ce6 to induce cell pyroptosis and subsequent anti-breast cancer immune response.¹⁴² Mechanistically, A-C/NPs can accumulate ROS in a controlled manner, triggering cell pyroptosis mediated by GSDME, resulting in ICD, where dying cells release HMGB1, ATP, and CRT. Additionally, Ara-C stimulates the maturation of cytotoxic T lymphocytes, synergizing with Ce6-mediated ICD to collectively enhance the anticancer efficacy of A-C/NPs. In vivo studies demonstrated that A-C/NPs effectively inhibited the growth of primary, metastatic, and recurrent tumors in a mouse model of breast cancer.

Besides Ce6, purpurin-18 (P18) is also one of the essential photosensitizers in PDT, which can be easily isolated from green plants ranging from seaweed to spinach leaves.¹⁴³ Xiao et al. designed a smart tumor microenvironment-responsive nanoprodrug (abbreviated as MCPP) (Fig. 5C) loaded with high doses of PTX and P18, which is one of the chlorophyll derivatives.¹⁴⁴ Utilizing the high levels of ROS and GSH in the tumor microenvironment, they proposed a nanoprodrug that releases drugs optimally at the tumor site. They simplified the preparation of a remote-controlled drug release system by polymerizing thioether-functional monomers via reversible addition–fragmentation chain transfer (RAFT) polymerization. The GSH-responsive SPTX dimer drug strategy not only effectively increased the payload of PTX but also depleted GSH in the tumor environment, enhancing the cytotoxicity through ROS amplification. P18, triggered by laser irradiation, generated ROS through chemical photodynamic therapy to control PTX release, inducing tumor cell pyroptosis. Pyroptosis causes tumor cells to release DAMPs, thereby initiating adaptive immunity, enhancing ICB efficiency for tumor treatment, and generating immune memory to prevent tumor recurrence. This multifunctional self-assembled chemical photodynamic nanograin, abbreviated as MCPPNPs, shows promise due to its high drug-loading capacity, controlled drug release in the tumor microenvironment, deep tumor penetration, pyroptosis-inducing ability, and mitigated systemic side effects. The above-mentioned four projects well combined natural plant antitumor drugs with photosensitizers to prepare nanomedicines, which significantly improved the utilization of chemotherapy drugs and introduced PDT to improve the antitumor efficacy.

As highly reduced derivatives of porphyrins and chlorins, bacteriochlorins possess several distinct features to overcome the challenges faced by conventional photosensitizers.¹⁴⁵ Consequently, Zhang et al. designed a nano-sheet based on Cu-TBB (Fig. 5D), consisting of Cu²⁺ and 5,10,15,20-tetrakis(4-bromophenyl) bacteriochlorin (TBB), a derivative of natural photosensitizers.¹⁴⁶ Cu-TBB remains in a “closed” (inactive) state in normal cells. However, in tumors with high levels of GSH, Cu-TBB undergoes degradation, activating GSH to an “open” state, leading to the specific release of Cu⁺ and TBB. Subsequently, the released Cu⁺ catalyzes the conversion of endogenous molecular oxygen (O₂) into the superoxide anion (O₂⁻˙). The generated O₂⁻˙ further undergoes superoxide dismutase (SOD) catalysis and Haber–Weiss reaction, producing recyclable O₂ and highly toxic hydroxyl radicals (˙OH). Moreover, under 750 nm light irradiation, “open” TBB generates O₂⁻˙ and singlet oxygen (¹O₂) simultaneously. During this process, ROS production activates pyroptosis mediated by GSDMD, promoting the release of inflammatory factors (IL-1 and IL-18), thereby enhancing DC maturation and activation of T lymphocytes, ultimately leading to systemic adaptive immune response activation.

4.5 Nanomaterial-assisted PTT-triggered pyroptosis

In PTT, photothermal materials are enriched at the tumor site via either active or passive targeting. Aggregating these targeted tumors allows PTT to reduce the toxicity and selectively destroy tumor cells. When the tumor site is irradiated with a laser, the photothermal material at the tumor site absorbs light energy and converts it into heat energy, and the tumor cells are damaged by thermal ablation, resulting in apoptosis of the tumor cells.^147–149 According to recent research, PTT can also activate pyroptosis in tumor cells.

More researchers are interested in combining plants and PTT to tackle cancer. In the investigation by Deng et al., they developed a synergistic nanotherapy system (MP@PI) (Fig. 6A) based on CDT and PTT to induce ferroptosis/pyroptosis. This nanosystem was comprised of a polydopamine (PDA)-modified metal–organic framework (MOF) decorated with IR820 and loaded with piperlongumine (PL).¹⁵⁰ MOF and PL serve as the sources of iron and H₂O₂, respectively, for CDT to induce ferroptosis. Simultaneously, the iron source induces tumor cell pyroptosis. PDA exhibits the pH-responsive release of PL, assisted by CDT, and reduces the expression of glutathione peroxidase by consuming glutathione. Additionally, PDA serves as a photothermal agent inducing mild PTT. Integrating the photosensitizer IR820 enhanced the PTT efficacy within the nano complex, further promoting ferroptosis/pyroptosis. The MP@PI nanoplatforms induce tumor cell death via dual mechanisms of ferroptosis and pyroptosis in vivo, triggering an immune response, and thereby enhancing its anticancer efficacy.

Fig. 6 Nanomaterial-assisted PTT-triggered pyroptosis. (A) Synthesis and therapeutic mechanism of MP@PI. Reprinted with permission from ref. 147 Copyright 2024, the American Chemical Society. (B) Synthesis and therapeutic mechanism of MnGA. Reprinted with permission from ref. 148 Copyright 2024, Springer Nature. (C) Synthesis and therapeutic mechanism of MFG@TCM NPs. Reprinted with permission from ref. 149 Copyright 2024, Wiley.

In a recent study, Liu et al. utilized gallic acid (GA), a bioactive compound in green tea, known for its anti-inflammatory and anticancer properties.¹⁵¹ They employed GA in a straightforward synthesis method to coordinate with metal ions (Ca²⁺, Fe²⁺, and Mn²⁺) (Fig. 6B), forming metal gallic acid ester nanoparticles. The nanoformulated GA activates cancer cell pyroptosis pathways by depleting ATP and downregulating HSPs, achieving enhanced mild photothermal therapy efficiency. This effect was validated in both in vitro and in vivo studies, demonstrating the efficacy of inducing pyroptosis for anticancer therapy.

Soon after, Liu et al. again utilized GA to design dual-metal polyphenol-based nanoplatforms named MFG@TCM (Mn/Fe gallic acid ester nanoparticles coated with tumor cell membranes) (Fig. 6C).¹⁵² This platform was combined with mild photothermal therapy to induce both pyroptosis in osteosarcoma cells and activate DCs via the cGAS-STING pathway to reverse the immunosuppressive tumor microenvironment. The immunostimulatory pathways promoted the secretion of DAMPs and pro-inflammatory cytokines through paracrine effects, facilitating the reshaping of the immune microenvironment. In conclusion, PTT can be effectively combined with phytotherapy, and combining pyroptosis will result in a more prominent and promising vaccine against various cancers.

4.6 Pyroptosis promoted by hyperthermal therapy

The principle of hyperthermia is that when the temperature exceeds 41–42 °C, it produces a direct hot cell-killing effect on the tumor but not on normal cells.¹⁵³

Wang et al. developed a carrier-free dual-functional nano-inhibitor using EGCG for intraperitoneal hyperthermic chemotherapy (HIPEC) treatment of peritoneal metastasis.¹⁵⁴ They utilized flash nanocomplexation technology to form a controlled mixture of Mn²⁺ with EGCG, which self-assembled into nano-inhibitors (Fig. 7A). This nano-inhibitor functioned by directly inhibiting HSP90 and disrupting the HSP90 chaperone cycle, thereby reducing the intracellular ATP levels. Furthermore, under synergistic conditions of heat (43 °C) and manganese ions, it induced oxidative stress and upregulated caspase-1 expression. This cascade activates GSDMD (Fig. 7D) via protein hydrolysis, leading to tumor cell pyroptosis (Fig. 7C) and the release of IL-1 and LDH (Fig. 7E), triggering immunogenic inflammatory cell death. Moreover, it induces dendritic cell maturation through the release of tumor antigens. This innovative approach addresses the heat resistance caused by HSPs in HIPEC-treated tumor cells and enhances the therapeutic efficacy through the combination of oxidative stress induction and ICD pathways (Fig. 7B).

Fig. 7 Pyroptosis promoted by hyperthermal therapy. (A) Schematic of the strategy for the synthesis of MnEGCG nanoparticles. (B) Illustration of the proposed antitumor mechanism of the nano-inhibitor. (C) Pyroptosis induced by different treatments. The top-right images are shown at twofold magnification. (D) Western blot analysis of pyroptosis-related proteins. (E) Expression of LDH. Reprinted with permission from ref. 151 Copyright 2024, Springer Nature.

4.7 Nanomaterial-assisted SDT-triggered pyroptosis

Ultrasound (US) is considered one of the most promising and widely applicable physical stimuli due to its precise controllability, non-invasiveness, and high tissue penetration. It enables SDT to infiltrate tumor tissues with dense extracellular matrices deeply. However, despite its unparalleled advantages in tumor therapy, ultrasound-sensitive agents often face challenges due to the hypoxic environment and elevated expression of intra-tumoral reducing agent GSH, which significantly diminishes their ability to produce ¹O₂, thereby impacting the therapeutic efficacy of SDT. Moreover, the immunotherapeutic strategy enhanced by sonodynamic-triggered apoptosis induction poses challenges and has rarely been reported.^155,156 Many sonosensitizers in the literature are derived from photosensitizers, such as Ce6.^132,133,157

In a related attempt, Wang et al. synthesized a biodegradable copper-tannic acid nanoneedle (CuTA) Ce6 nanocomplex (Fig. 8A).¹⁵⁸ This approach enabled pyroptosis-mediated immunotherapy with minimal adverse systemic reactions. Glutathione peroxidase (GSH-Px) and peroxidase (POD)-like activities are activated to the “on” state in TME overexpressing GSH and hydrogen peroxide (H₂O₂). This disruption of the activated antioxidant system of tumor cells initiates their self-degradation, effectively alleviating the hypoxic environment and significantly increasing the intratumoral ROS levels. To effectively harness the excellent oxygen generation capabilities of CuTA nanoneedles and the unique advantages of ultrasound, they were combined with the photosensitizer Ce6, further converting generated O₂ into ¹O₂. The results demonstrated that the CuTA-Ce6 nanocomplex-driven cascade reactions and dual strategy of SDT pathways can generate a stronger ROS storm, including ˙OH and ¹O₂, further enhancing pyroptosis induction, polarization of tumor-associated macrophages (TAMs), maturation of DCs, and T-cell immune responses.

Fig. 8 Nanomaterial-assisted SDT-triggered pyroptosis. (A) Synthesis and therapeutic mechanism of CuTA-Ce6 NPs. Reprinted with permission from ref. 155 Copyright 2024, Elsevier. (B) Synthesis and therapeutic mechanism of Ce6@Cu NPs. Reprinted with permission from ref. 156 Copyright 2024, the American Chemical Society.

Similarly, Zhu et al. constructed carrier-free nanoparticles (Ce6@Cu NPs) (Fig. 8B) that were self-assembled by the coordination of Cu²⁺ ions and the sonosensitizer chlorin (Ce6).¹⁵⁹ Ce6@Cu NPs effectively induced ferroptosis and cuproptosis in situ in glioblastoma through highly efficient sonodynamic effects. Upon uptake by U87MG cells, Ce6@Cu NPs exhibited remarkable sonodynamic effects under ultrasound irradiation, generating large amounts of ¹O₂.

4.8 Other nanomaterial-triggered pyroptosis

Besides the nanomaterials listed above, some biomaterials based on natural product synthesis have also been found to activate pyroptosis.

LPS is a component of the outer wall of the cell wall of Gram-negative bacteria and triggers a robust immune response. In cancer immunotherapy, noncanonical LPS-sensing pathways have not yet been explored as a mechanism for eliminating damaged cells during pyroptosis. Chen et al. utilized bacterial outer membrane vesicles (OMVs) as a natural LPS carrier to trigger a noncanonical pyroptosis pathway for immunotherapy. Molecule-engineered OMVs (Apt-OMVs) (Fig. 9A) include DNA aptamers to address the concern of systemic toxicity.¹⁶⁰ Besides improving tumor targeting, Apt-OMVs also evade immunogenicity and immunity by using a spherical nucleic acid structure. By selectively pyroptosizing tumor cells, not only was tumor immunogenicity enhanced, but also the amount of immunosuppressive regulatory T cells reduced, which resulted in tumor growth being significantly suppressed. This study reported the first pyroptosis inducer via the noncanonical pathway, paving the way for pyroptosis-mediated immunotherapies that are safe and effective.

Fig. 9 Other nanomaterial-triggered pyroptosis. (A) Synthesis and therapeutic mechanism of Apt-OMVs. Reprinted with permission from ref. 157 Copyright 2024, the American Chemical Society. (B) Synthesis and therapeutic mechanism of OA NMs. Reprinted with permission from ref. 158 Copyright 2024, Wiley.

Natural small molecules can be spontaneously assembled into nanoparticles based on their unique structure. Luo's research used oleanolic acid (OA) as a molecular template to construct self-assembling nanomicelles (Fig. 9B).¹⁶¹ It was discovered that OA nanomicelles significantly activate the cellular proteasome function without the need for functional ligands by directly binding to the 20S proteasome subunit alpha 6 (PSMA6). The interaction of OA nanomicelles with PSMA6 resulted in the dynamic modulation of its N-terminal domain conformation, thereby controlling the entry of proteins into 20S proteasomes. Consequently, the OA nanomicelles accelerated the degradation of several critical proteins, driving cancer cells into pyroptosis. The nanomicelles containing OA exhibited anticancer activity in tumor-bearing mouse models and stimulated the infiltration of immune cells.

5. Conclusions and future prospective

Pyroptosis is identified as an immunostimulatory programmed cell death for eliciting immune responses, characterized by transmembrane pores and intracellular content leakage. Mechanistically, chemicals trigger pyroptosis mainly by the canonical and noncanonical pathways. Recently, it has also been reported that some novel mechanisms, such as ROS-mediated palmitoylation, play a critical role in the formation of GSDMD-based membrane pores. This research can facilitate the good recognition of biomarkers and mechanisms of drug action, which contribute to the discovery of novel drugs for targeting pyroptosis. In this review, we summarized the newly reported studies that identified key mediators of pyroptosis for a target, including ROS-related mediators, caspase-1, caspase-3, and NLRP 3. By targeting these molecules, the drugs may induce pyroptosis to enhance the treatment of tumors. On the one hand, pyroptosis-directed agents can promote tumor-killing capabilities by inducing antitumor immune responses. On the other hand, this type of drug may also reshape the tumor microenvironment to enhance the immune response to tumors.

Natural products and their derivatives have long been a reliable source of new drugs. The cost of utilizing natural products is usually much lower than chemically synthetic agents. Additionally, most natural products have a broad range of bioactivities and high biosafety. In this review, most of the natural products or their derivates discussed are pyroptosis inducers for preventing tumor growth, which are mainly derived from plants and microbes in nature. Flavonoids, terpenoids, and polyphenols rank as the top three well-studied natural products extracted from plants, and there are still many products waiting to be developed. Some of them could sensitize tumor cells to pyroptosis, while some could sensitize tumor cells to two or more PCD, including apoptosis and autophagy. At the molecular level, the mechanism mainly depends on the generation of ROS and upregulation of the downstream molecule, including NLRP3, MEK/ERK1/2, JNK pathways, which subsequently tend to provoke the antitumor immune response through indirect and direct ways. Excitingly, many traditional Chinese medicines provide a large number of ideal drug candidates that replenish pyroptosis-induced drug reservoirs. However, only phenotype-based investigations have been performed on many natural products, and research on their in-depth mechanisms is further needed to translate them from bench to bedside.

Nanotechnology has been used to overcome the drawbacks of natural products, including poor solubility, low bioavailability, and off-target side effects. Because of these drawbacks, patients have to be exposed to high-dose drugs from natural products, which may increase the risk of side effects. The nanometerization of bioactive compounds results in the higher solubility and stability of drugs, which can improve the bioavailability of natural products. More importantly, nanosized particles can reduce the side effects by enhancing the targetability of natural products, including passive targeting (the enhanced permeability and retention effect) and active targeting (antibodies or ligands). Based on these advantages, pyroptosis-inducing nanomaterials effectively increase the therapeutic effects of natural products and exhibit a better celling-kill effect over single nanotherapy via their synergic effect with other therapies, including chemotherapy, radiotherapy, chemodynamic therapy, photodynamic therapy, photothermal therapy, hyperthermia, and sonodynamic therapy. Therefore, the nanodelivery systems promote natural products as better pyroptosis inducers for tumor immunotherapy.

In the future, there are several challenges that should be overcome to make natural products more effective in clinical antitumor therapy. Firstly, an optimal screening strategy is the key to isolating and developing novel drugs. The main approaches used in modern drug discovery are phenotypic and target-based drug discovery. Most of the discovery strategies ranging from natural products to small molecule pyroptosis-inducing agents were phenotypic screening based on therapeutic effects in this review. Generally, on-target identification may be more productive because of the purposeful screening for the bioactive compounds playing a role. With the development of chemistry and molecular biology, more bioactive compounds will be discovered by the target-based screening strategy, but identifying optimal therapeutic targets in pyroptosis remains challenging. Secondly, chemical modification is an efficient method to improve the activity of bioactive compounds extracted from natural products, for example, adding hydrophilic groups increased the water solubility of these compounds and nanometerization of the original compound resulted in higher stability and targetability. However, it is crucial to find the optimal modification sites or carriers for better activity by natural products. Thirdly, given that the heterogeneity of the tumor and TME poses challenges to a single therapy, combinatorial treatments will be strategic opportunities to potentiate the antitumor efficacy by associating the pyroptosis-inducing agents with other therapies that contribute to pyroptosis. Subsequently, it is also of great interest how to use these synergistic effects with natural products to induce pyroptosis. Finally, the effectiveness and safety evaluation of natural products and their derivatives need to be emphasized. The Response Evaluation Criteria In Solid Tumours (RECIST) is the most commonly used criteria to assess the tumor response in the clinic, where according to the relative change in the tumor volume, the efficacy of tumor therapy is divided into four grades including complete response (CR), partial response (PR), stable disease (SD), and disease progression (PD). Additionally, the therapeutic effect can be evaluated by survival time, including overall survival and median survival. In basic research, the methods of oncologic evaluation are highly consistent with the clinical standards. However, there is no uniform evaluation standard. Thus, to better understand the efficacy of clinical cancer treatments, it is recommended to introduce models derived from clinical patient tissue where possible, such as organoids and patient-derived xenografts (PDXs). According to China's Safety Toxicology Evaluation Procedure, the safety evaluation mainly involves four stages of testing including acute toxicity test, accumulation toxicity mutation test, subchronic toxicity test, and chronic toxicity test. Oral poisoning to determine the LD50 value is a standard method for acute toxicity testing.

Therefore, future studies are required to promote the development of new stages of pyroptosis-inducing agent discovery from natural products, facilitating the design of safe and efficient agents for tumor therapy.

Author contributions

Yingfei Wen, Shangbo Zhou, Qiang Wang, Jing Zhao wrote, reviewed, edited, and supervised the work; Yingfei Wen, Shangbo Zhou, Qiang Wang wrote the original draft; You Li, Bin-bin Li, Zihang Li, Jiaqi Xu, Bo Bi, Shiqiang Zhang investigated the work; Miaojuan Qiu, Bo Bi, Shiqiang Zhang, Xinyi Deng, Kaiyuan Liu curated the data; all authors discussed, reviewed, and edited the final manuscript. All authors have read and agreed to the published version of the manuscript.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts of interest.

Acknowledgements

This work was in part supported by: Shenzhen Science and Technology Program (Grant No. RCYX20231211090346060), Shenzhen Medical Research Fund (D2301010), Science and Technology Planning Project of Shenzhen Municipality Grant JCYJ20210324122612032 and JCYJ20220530144613030, Shenzhen Key Laboratory of Chinese Medicine Active substance and Translational Research Grant ZDSYS20220606100801003 (to Jing Zhao). National Natural Science Foundation of China Grant 81902426 (to Binbin Li). The Provincial Natural Science Foundation of Hunan in China Grant 2024JJ6661 and The China Postdoctoral Science Foundation (Grant GZC20233182) (to Qiang Wang).

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Footnote

† These authors contributed equally to this work.

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