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Nanomaterials evoke pyroptosis boosting cancer immunotherapy
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Zhenhua Li, Ziyue Xi, Chuanyong Fan, Xinran Xi, Yao Zhou, Ming Zhao*, Lu Xu*
Acta Pharmaceutica Sinica B | 2025, 15(2) : 852 - 875
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Acta Pharmaceutica Sinica B | 2025, 15(2): 852-875
• REVIEW •
Nanomaterials evoke pyroptosis boosting cancer immunotherapy
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Zhenhua Li, Ziyue Xi, Chuanyong Fan, Xinran Xi, Yao Zhou, Ming Zhao*, Lu Xu*
Affiliations
  • Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China
About Author:

E-mail addresses: (Ming Zhao)

(Lu Xu).

Author contributions

Zhenhua Li: Writing – review & editing, Writing – original draft. Ziyue Xi: Supervision. Chuanyong Fan: Visualization. Xinran Xi: Visualization. Yao Zhou: Visualization. Ming Zhao: Writing – review & editing, Supervision, Conceptualization. Lu Xu: Supervision, Investigation, Conceptualization.

doi: 10.1016/j.apsb.2024.11.011
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Cancer immunotherapy is currently a very promising therapeutic strategy for treating tumors. However, its effectiveness is restricted by insufficient antigenicity and an immunosuppressive tumor microenvironment (ITME). Pyroptosis, a unique form of programmed cell death (PCD), causes cells to swell and rupture, releasing pro-inflammatory factors that can enhance immunogenicity and remodel the ITME. Nanomaterials, with their distinct advantages and different techniques, are increasingly popular, and nanomaterial-based delivery systems demonstrate significant potential to potentiate, enable, and augment pyroptosis. This review summarizes and discusses the emerging field of nanomaterials-induced pyroptosis, focusing on the mechanisms of nanomaterials-induced pyroptosis pathways and strategies to activate or enhance specific pyroptosis. Additionally, we provide perspectives on the development of this field, aiming to accelerate its further clinical transition.

Pyroptosis  /  Nanomaterials  /  Gasdermin family  /  Mechanism  /  Induction  /  Cancer immunotherapy  /  Programmed cell death  /  Immunosuppressive tumor microenvironment
Zhenhua Li, Ziyue Xi, Chuanyong Fan, Xinran Xi, Yao Zhou, Ming Zhao, Lu Xu. Nanomaterials evoke pyroptosis boosting cancer immunotherapy[J]. Acta Pharmaceutica Sinica B, 2025 , 15 (2) : 852 -875 . DOI: 10.1016/j.apsb.2024.11.011
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1.　Introduction
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Cancer immunotherapy is a breakthrough that mainly improves antitumor immune responses by enhancing the body's defense capability to eliminate tumor cells1-3. Recently, therapies such as immune checkpoint blockade (ICB) have achieved remarkable progress4. However, due to the low immunogenicity and the presence of the ITME, most patients either do not respond to ICB therapy or develop resistance following relapse, leading to unsatisfactory therapeutic effects5-8. Pyroptosis is a new type of programmed cell death (PCD) caused by the gasdermin (GSDM) protein family that targets the membrane and forms pores. First described in 2001, pyroptosis is recognized as a pro-inflammatory, immunogenic cell death predominantly mediated by GSDM family through the caspase family9-13. As a PCD mechanism, it features DNA fragmentation, chromatin condensation, and cell swelling with large bubbles, culminating in the release of inflammatory cytokines like IL-1β, IL-18, HMGB1, and ATP after membrane rupture14-18. These processes have been linked to various human diseases, including inflammatory disorders and malignant tumors. In contrast, apoptosis is an orderly death process leading to cellular structure degradation and morphological changes via caspase cascade activation19, ferroptosis is characterized by iron dependence and increased lipid peroxidation20, while autophagy involves the lysosomal breakdown and recycling of cellular components to meet metabolic demands and renew cellular structures21. Key features of pyroptosis include inflammasome formation, gasdermin (GSDM) protein family activation, and caspase involvement (Table 116,19-21). When tumor cells undergo pyroptosis, they release numerous neoantigens that stimulate the systemic immune, thereby enhancing the antitumor immune response and addressing the issues of low immunogenicity and ITME challenges22. Therefore, pyroptosis offers a new way of immunotherapy and provides critical guidance for tumor treatment23,24.
It has been reported that particular metal ions, molecules, and chemotherapy drugs can initiate GSDM family-induced pyroptosis across various cancers25-27. However, rapid clearance of these pyroptosis inducers from systemic circulation, unfavorable biodistribution, and inevitable side effects have limited their clinical use. Besides, increasing research has indicated that dysregulation of pyroptosis may weaken pathogen elimination and impair the adaptive immune response28-31. Therefore, given the dual role of pyroptosis in either promoting or inhibiting cancer, researchers are diligently exploring how to selectively use this double-edged sword for effective cancer treatment32. Thus, there is an urgent need to develop effective strategies that induce cell pyroptosis while minimizing non-specific tissue damage.
Nanotechnology can provide more effective and safer diagnostic and therapeutic methods, offering opportunities for cancer cure33. Particularly, nanomaterials have developed into a research hotspot in the scientific field. As the core of novel drug delivery systems, nanomaterials, typically ranging from 1 to 100 nm, exhibit unique advantages in cancer treatment, such as reducing drug toxicity, enhancing drug bioavailability, and improving drug penetration into tumors34-38. By delivering pyroptosis inducers, they can activate caspase and GSDM-related proteins, inducing tumor cells to undergo pyroptosis39. Nanomedicine-induced pyroptosis can complement the deficiencies of traditional therapeutic modality and further improve the effectiveness of tumor treatment, so it is necessary to provide an overview of nanomedicine that induces pyroptosis.
In this review, we provide a comprehensive summary and deep discussion of nanomaterial-mediated pyroptosis in tumor immunotherapy, focusing on the strategies for inducing pyroptosis with nanomaterials and the mechanisms by which pyroptosis enhances immunotherapy (Fig. 1). Firstly, we introduce the mechanism of pyroptosis and its impact on tumor immunotherapy. Subsequently, we focus on the strategies using various nanomaterials (including phospholipid and polymer-based nanomaterials, mesoporous nanomaterials, nanogels, metal-based nanomaterials, biomimetic nanomaterials, and carrier-free nanomaterials) to induce pyroptosis. Finally, we discuss the dual nature of pyroptosis and the future development and challenges of nanomaterials to potentiate their further clinical translation. We strongly believe that pyroptosis-induced nanomaterials signify a new strategic direction in the field of tumor immunotherapy, with broad prospects for application and clinical translation.
2.　Pyroptosis strengthens cancer immunotherapy
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2.1.　 The function of pyroptosis in immunotherapy
Pyroptosis, an inflammatory form of cell death, plays a dual role in regulating the tumor immune microenvironment. On one hand, prolonged chronic inflammation induced by pyroptosis promotes tumor growth by sustaining an inflammatory microenvironment around cancer cells. On the other hand, acute activation of pyroptosis triggers the infiltration of various immune cells, inhibiting tumor growth tumor growth40,41. For instance, activation of Gasdermin E (GSDME) during pyroptosis can suppress tumor proliferation by facilitating the recruitment of T lymphocytes and natural killer (NK) cells42.
Following pyroptosis, the release of inflammatory factors such as IL-1β, IL-18, and HMGB1 plays a significant part in the immune response43-45. Recent studies indicate that inflammasome activation in dendritic cells (DCs) induces an overactive state in certain subpopulations, which is dependent on IL-1β that can facilitate the eradication of tumors resistant to anti-programmed cell death1 therapy (aPD-1) therapy46. In addition, IL-18 can induce lymphocytes to produce interferon-γ (IFN-γ), enhancing NK and T cells activity in immunotherapy47. IL-18 is also involved in the differentiation of T-helper 1 (Th1) and T-helper 17 (Th17) cells, contributing to its antitumor effects48. In some cases, pyroptosis releases HMGB1 to promote tumor cell survival49,50. Furthermore, the composition of cytokine types may have tumor-promoting effects. IL-18 stimulates tumor growth in the absence of other cytokines, and IL-6 promotes tumor proliferation, metastatic dissemination, and survival by interacting with a variety of downstream mediators51,52.
As a result, when integrating pyroptosis with immunotherapy, it is critical to guarantee that the immune-promoting effects of pyroptosis induction reduce side effects on normal cells and tissues, improve antitumor efficacy, and enhance therapeutic safety.
2.2.　 Mechanisms of pyroptosis
Pyroptosis is rapidly becoming a new target for inhibiting the occurrence and development of cancer. In recent years, numerous researchers are devoted to elucidating the mechanism of pyroptosis and its role in enhancing immunotherapy53,54. To date, pyroptosis signaling pathways are mainly divided into the canonical pathway, the non-canonical pathway, and other pathways. The canonical pathway, mediated by caspase-1, is triggered by pathogens55, whereas intracellular lipopolysaccharide (LPS) from Gram-negative bacteria causes atypical pathways mediated by caspase-4/5/1156,57. Furthermore, caspase-3 and -8 primarily activated by chemotherapy, viruses, and cytotoxic stimuli, are also involved in pyroptosis58,59. Antigens released by pyroptosis can activate immune cells, thereby enhancing potent antitumor immune responses. Therefore, understanding the molecular mechanism of pyroptosis provides valuable insights into developing tumor immunotherapy (Fig. 2)60.
2.2.1.　 The canonical pathway
The canonical pyroptosis pathway is an inflammasome-mediated caspase-1-dependent pathway. Common pattern recognition receptors (PRRs) in the inflammasome, such as NLRP1, NLRP3, NLRC4, AIM2, and PYRIN, can be activated by various stimuli42,54. Among them, NLRP3 is the most extensively studied PRR, activated by damage signals including bacterial mycin and viral double-stranded RNA61. Activation of the NLRP3 inflammasome leads to the production of cytokines such as IL-1β and IL-1862. In addition, activated caspase-1 cleases gasdermin D (GSDMD) and releases its N-terminal domain, which is translocated to the cell membrane and forms pores that mediate the release of inflammatory cytokines IL-1β and IL-18, leading to inflammation and ultimately pyroptosis63.
2.2.2.　 The non-canonical pathway
The non-canonical pyroptosis pathway is caused by caspase-4/5/11, which act as cytosolic sensor in response to LPS64. LPS directly binds to caspase-4/5/11 on entering the cytoplasm, activating them through autoproteolysis induced by dimerization65. Upon activation, caspase-4,5 and 11 cleave GSDMD, exposing the GSDMD-N terminus that forms nonselective pores in the plasma membrane, causing cell swelling, large bubble formation, rupture, and release of cellular contents, ultimately leading to cell death66,67. As research progressed, Chen et al.68 used bacterial outer membrane vesicles to deliver LPS, triggering a caspase11-GSDMD non-canonical pyroptosis pathway for immunotherapy. In this research, AS1411, serving as a DNA aptamer, was coated on the surface of bacterial outer membrane vesicles (Apt-OMVs), which targeted tumor sites and helped to evade host immunity, thereby enhancing therapeutic outcomes of immunotherapy. In addition, folic acid-cholesterol-sodium alginate nanoparticles (FCA NPs) loaded with metformin (MET) and doxorubicin (DOX) induce melanoma pyroptosis via caspase-7/GSDMD, activating antitumor immunity48.
2.2.3.　 Other mediated pyroptosis pathways
Subsequent studies have demonstrated that caspase-3 and -8 are also involved in pyroptosis, with GSDME acting as the substrate for caspase-3-mediated pyroptosis69,70. Chemotherapeutic agents and cytochrome c can cause cleavage of GSDME by caspase-3, producing GSDME-NT that penetrates the cell membrane to induce pyroptosis and pore formation71. Furthermore, studies of CAR T cell therapy show that granzyme B (Gzm B) derived from CAR T cells activates the caspase-3/GSDME pathway and induces pyroptosis by hydrolyzing caspase-372. Gzm B also enhances antitumor immunity by directly cleaving GSDME at the same site as caspase-373. Granzyme A (Gzm A) cleaves gasdermin B (GSDMB), releasing its pore-forming activity and causing pyroptosis in GSDMB-expressing cancer cells74.
Another caspase involved in pyroptosis is caspase-8, which cleaves gasdermin C (GSDMC). Specifically, GSDMC is cleaved by caspase-8 under the action of TNF-α, inducing cell pyroptosis75. Additionally, the non-immune checkpoint function of programmed cell death-ligand 1 (PD-L1) significantly induces GSDMC/caspase 8-mediated pyroptosis76. Upon activation by TNF-α, caspase-8 cleaves GSDMC, releasing its amino-terminus and forming a pore in tumor cells. This process prevents caspase-8 from recruiting caspase-3 for apoptosis process, transforming TNF-α induced apoptosis into pyroptosis77.
3.　Application of nanomaterial-induced pyroptosis in tumor immunotherapy
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With the emergence of nanotechnology, drug delivery systems based on nanomaterials have made great progress in tumor treatment by the induction of pyroptosis. Researchers apply nanomaterials to drug delivery systems and adopt strategies to induce pyroptosis to improve tumor treatment. Therefore, we summarize pyroptosis-induced nanomaterials, including phospholipid and polymer-based nanomaterials, mesoporous nanomaterials, nanogels, metal-based nanomaterials, biomimetic nanomaterials, and carrier-free nanomaterials (Table 282-91,97-105,110,111,113-115,121,125-127,131-135,140-153,155-171,175-179,181-188,191-198,201). In this section, we mainly review the applications of nanodrug delivery systems (NDDS) to induce pyroptosis and enhance immunotherapy in conjunction with chemotherapy (CT), radiotherapy (RT), photothermal therapy (PTT), photodynamic therapy (PDT), sonodynamic therapy (SDT), and ultrasound (US).
3.1.　 Phospholipid and polymer-based nanomaterials
Polymer nanovesicles, with a particle size of only a few hundred nanometers, can carry both hydrophilic and hydrophobic substances and characteristically circulate long in the body (Fig. 3A)78-81.
Lipid nanoparticles (LNPs) encapsulate mRNA containing the N-terminal of GSDMD, effectively delivering GSDM-NT to induce pyroptosis, thereby recruiting immune cells and transforming cold tumors into hot tumors. In addition, LNPs synergize with aPD-1 to enhance the therapeutic effects and achieve long-term overall survival (Fig. 3B)82. LipoDDP, loaded with decitabine (DAC), elevates the expression of methylated genes in tandem with CT, leading to pronounced pyroptosis in tumor cells through the caspase-3 pathway, and releasing IL-1β, HMGB1, and tumor antigens to amplify the immune response (Fig. 3C)83. Long et al.84 synthesized a biomimetic pH-responsive liposomal drug with tumor-targeting capability and immune escape inhibition, composed of a hybrid membrane from red blood cells and cancer cells membranes, encapsulating AP and CS-1. Compared to single drug treatments, this dual drug delivery system demonstrated stronger antitumor activity in a gastric cancer mouse model by inducing pyroptosis, autophagy, and apoptosis (Fig. 3D). In addition, researchers constructed cationic liposomes based on 1,2-dioleoyl-3-trimethylammonium-propane, chloride (DOTAP) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), which effectively accumulated at tumor sites and upregulated GSDME in tumor cells (Fig. 3E)85. By studying the feasibility and molecular mechanism of magnetic fluid hyperthermia (MFH) with temozolomide (TMZ) chemotherapy to treat Glioblastoma, Yao et al.86 found that tumor cell death induced by TMZ/Fe-TSL+AMF occurred through pyroptosis, not apoptosis.
BTN@LND exhibits thermal responsiveness and can deliver lonidamine to the tumor site under PTT conditions87. Its combination with CT maximally prevents tumor growth, representing a viable cancer treatment approach. Xiao et al.88 formulated a physical targeting nanodrug called PCL@GSK-diABZI/aPD-1, capable of delivering the STING agonist diABZI-C2-NH2, aPD-1, and the DNA methyltransferase inhibitor GSK-3484862. This formulation induced a powerful immunogenic cell death (ICD) phenotype, increased DCs maturation, and initiated a cascade of anticancer immune responses. The NCSNP, comprising β-cyclodextrin conjugated with nitric oxide (NO) donors and immune checkpoint inhibitors (NLG), is designed to block indoleamine 2,3-dioxygenase (IDO)-mediated immune suppression and achieves a self-amplifying effect of inflammation-associated cell pyroptosis89. Meanwhile, Zhou's research team used an improved β-cyclodextrin (TMCD) to prepare homomultivalent polymeric nanotraps, which showed significant cytotoxicity to tumor cells by disrupting lipid metabolic homeostasis and inducing pyroptosis, thereby exerting antitumor effects in vivo90. SW8@NPs simultaneously induce necroptosis and apoptosis in cells via PTT, leading to the ablation of osteosarcoma, thereby enhancing its potential for future clinical applications91.
In summary, these materials can induce pyroptosis and elicit a robust immune response independently when used as pyroptosis inducers. Liposomes, notable for their simple preparation methods, are representative of such materials, enhancing their potential for clinical application.
3.2.　 Mesoporous nanomaterials
Mesoporous nanomaterials, characterized by pore diameters between 2‒50 nm, exhibit an extremely high specific surface area, regular pore structure, and adjustable pore diameter. These properties have led to their widespread use in the medical field92, particularly in drug delivery systems where they improve drug dissolution, bioavailability, controlled release, and targeted delivery93,94. In this section, the application of mesoporous materials in inducing pyroptosis is mainly introduced from metal-organic frameworks (MOFs), zeolitic imidazolate frameworks (ZIFs), covalent organic frameworks (COFs), and mesoporous silica-based nanoparticles (MSNs).
MOFs, organic-inorganic hybrid materials bonded by metallic bonds and covalent bonds95, have been designed through various synthetic strategies and received widespread attention in cancer therapy (Fig. 4A)96.
Researchers have reported that MOFs modified with mannose and Fe3O4 effectively remodel the immune microenvironment and promote the infiltration of T lymphocytes. M-FNM significantly increases reactive oxygen species (ROS), activating the PERK-eIF2α-ATF4-CHOP signaling pathway and showing outstanding targeting and antitumor effectiveness97. Feng et al.104 developed FeMn@R@H that concurrently delivered therapeutic metal ions and immune adjuvant R848 to enhance immunotherapy and overcome both innate immune evasion and immunological compensatory regulation of the tumors (Fig. 4B). In addition, cholesterol oxidase (COD) can increase cell membrane tension, reassemble the cytoskeleton, and improve intracellular osmotic pressure in vitro. The photosensitive Hf-TBP and COD synergistically induce pyroptosis and enhance the antitumor effects of PDT, meanwhile, cholesterol depletion downregulates immunosuppressive checkpoints, thereby revitalizing T cells98. Wang et al.99 designed TPL@TFBF to induce both ferroptosis and pyroptosis, enhancing antitumor immunity by generating large amounts of damage-associated molecular patterns (DAMPs) and integrating with ICB to inhibit tumor growth. Xu et al.100 synthesized Tf-LipoMof@PL, a pH-sensitive nanomedicine, which exhibited desirable anticancer effects. Lipid-coated iron-based MOF nanoparticles can directly affect primary tumors and induce pyroptosis in acidic environment (Fig. 4C)101. A polydopamine (PDA) coated MOF nanoparticle, which delivers chemotherapy drug piperlongumine (PL) and photosensitizer IR820 to induce pyroptosis, kills tumor cells, and evokes immune response to antitumor (Fig. 4D)102. To deliver glucose oxidase (GOx) intracellularly, Shao et al.103 designed a biodegradable MOF, GOx@Cu, selectively inducing pyroptosis in cancer cells and promoting intracellular cascade biocatalysis. Cu-THBQ/AX simultaneously triggers pyroptosis, cuproptosis and secondary necrosis, successfully converting the “cold” tumors into a “hot” state, inducing a continuous immune effect, and providing a potent antitumor effect105.
ZIF-8, a MOF constructed with a zinc base, exhibits high porosity and a large specific surface area106,107. In particular, it is prone to degradation in acidic environments108, allowing drug-loaded ZIF-8 to release the therapeutic agent in the acidic tumor microenvironment (TME), thereby enhancing the antitumor effect (Fig. 5A)109.
Zhu et al.110 prepared DOX@ZIF-8@PCBMA-DAC, which potently activated caspase-3 to induce GSDME-dependent pyroptosis through sustained release of decitabine (DAC) and doxorubicin (DOX), achieving excellent tumor suppression. AE@ZIF-8 NPs significantly increase intracranial distribution and tumor tissue accumulation, providing the possibility for glioblastoma (Fig. 5B)111. With the development of antitumor immune mechanisms, tumors actively adopt various immune evasion mechanisms to weaken immunotherapy112. Therefore, the primary challenge is designing a delivery platform that can trigger immune responses and inhibit immune evasion. A MOF-based nanoplatform encapsulating mitoxantrone (MIT) and hydralazine (HYD) demonstrates robust apoptosis-to-pyroptosis conversion that disrupts myeloid-derived suppressor cells (MDSCs)-mediated T cell paralysis. This two-pronged nanoplatform stimulates immune responses, inhibits immune evasion, and supports long-term immune memory (Fig. 5D)113. As one of the most commonly used MOFs, ZIF-8 is suitable for the treatment of various tumors. F127ZIF-8CCCPNPs can induce pyroptosis through the caspase-1/GSDMD pathway to activate antitumor immunity and reprogram the ITME for efficient tumor growth inhibition (Fig. 5C)114. IDN@MC, a macrophage-based biohybrid microrobot constructed through the fusing macrophages with MOF, induces pyroptosis under PTT conditions115.
COFs, as porous polymers formed by connecting active building blocks via dynamic covalent bonds, exhibit outstanding light absorption, photostability, and biocompatibility in cancer photodynamic therapy (Fig. 6A)116-120.
COF-909-Cu is the first COF pyroptosis inducer, which can simulate various enzyme activities, destroy H2O2 homeostasis, and synergize with CDT/PTT to enhance the immunotherapeutic effect of aPD-1 (Fig. 6B)121. However, aggregation-caused quenching (ACQ) effect reduces the fluorescence intensity and ROS generation capacity of COF-based photosensitizers122-124. COF-919 acts as a dual-inducer of pyroptosis and ferroptosis, improving these processes through PTT125. Zhang et al.126 designed TPy-vinyl COF, which leveraged an aggregation-induced emission effect (AIEgens) to overcome undesirable ACQ effect, eliciting pyroptosis and boosting cancer immunotherapy (Fig. 6C and D). In addition, Liu's team used a combination of PDT and CT to provide valuable insights into cancer immunotherapy. TD@COFs, loaded with AIEgen and DAC, synergistically enhance PDT efficacy and control drug release, effectively inducing pyroptosis and eliciting a strong immune response127.
Another material featuring a porous structure is mesoporous silica-based nanoparticles, which, due to their high loading capacity and adjustable pore size, are also used to induce pyroptosis (Fig. 7A)128-130.
Chen et al.131 developed MMSN-cRGD@Ce6, a cRGD-modified and pyroptosis-engineered theranostic agent (PETA) that used Fe3O4 embedded magnetic mesoporous silica nanoparticles (MMSN) as a carrier to transport chlorin e6 (Ce6). In combination with PDT, Ce6 photosensitizer increased intratumoral ROS accumulation, ultimately boosting the antioxidant impact of pyroptosis activation (Fig. 7B). NaCl@ssss-VHMS can circumvent the cell membrane's ion transporter via endocytosis, transporting a significant amount of Na+/Cl‒ into tumor cells, disrupting ion homeostasis, and efficiently producing ROS, which can effectively kill tumor cells (Fig. 7C)132. Furthermore, DMSN nanomedicine activates DCs through caspase-1-dependent pyroptosis, inducing enhanced immune responses mediated by NK cells and T cells (Fig. 7E)133. Nadeem et al.134 discovered VTPA therapy that induced the activation of the NLRP3 inflammasome and the release of lactate dehydrogenase in tumor cells to evoke pyroptosis (Fig. 7D). Due to the unsatisfactory prognosis of hepatocellular carcinoma (HCC), Du et al.135 induced pyroptosis through the dual pathway of caspase-1/GSDMD and caspase-3/GSDME. The nanovaccine (MF@SOR) responds intelligently to specific chemical signals in TME, such as low pH and high GSH, boosting DCs maturation.
After putting the aforementioned instances together, it can be shown that the pyroptosis pathway's activation is highly compatible with the characteristics and applications of mesoporous materials. These materials are related to PTT, PDT, or CDT to activate pyroptosis by the generation of ROS, and they possess adequate internal space to accommodate various pyroptosis inducers.
3.3.　 Nanogels
Nanogels are three-dimensional (3D) network polymers, formed by physical or chemical cross-linking of hydrophilic polymers136. They possess characteristics such as high drug loading capacity, good biocompatibility, long blood circulation time, stimulus responsiveness, and targeted release137,138. As innovative biomaterials, nanogels have received considerable attention, exhibiting great potential and broad application prospects (Fig. 8A)139.
Pyroptosis, an inflammatory process, activates and proliferates immune cells, and has great potential for tumor treatment. PDONPs regulate drug release in response to the acidity of tumors, boosting tumor accumulation and therapeutic efficacy, producing tumor cell pyroptosis, and eliciting T cell-mediated immunity in mouse models of head and neck squamous cell carcinomas (HNSCC) models140. In PTT/PDT, VB12-sericin-PBLG-IR780 stimulates NLRP3/caspase-1/GSDMD-dependent pyroptosis and provokes DCs maturation via pyroptosis141. Researchers constructed CANP nanogels that generated ROS by releasing Ce6 and 17-AAG (heat shock protein 90 inhibitor tanespimycin) under PDT conditions, thereby inducing GSDME-mediated pyroptosis and inhibiting the growth of primary tumors and distant tumors (Fig. 8B)142. LDNPS combines histone deacetylase inhibitors (HDACI) LAQ824 and DOX to reshape tumor immunity through pyroptosis, significantly improving the response rate and survival of aPD-1 treatment (Fig. 8C and D)143. Moreover, AOZN and CDNP, which are glutathione (GSH)-responsive, effectively trigger pyroptosis and enhance antitumor immunity144,145. Upon exposure to near-infrared light, OA@IR820 may prevent the synthesis of mitochondrial ATP, which increases the release of ROS and triggers cell pyroptosis146. Xu et al.147 covered IMs, a GSH/ROS dual-responsive nanogel system, as a pyroptosis inducer to improve tumor immunogenicity. IMs are characterized by their small volume, ultra-stable photothermal performance, and active targeting of cancer cells, providing an excellent platform for light-triggered apoptosis and offering insights for future immunotherapy strategies (Fig. 8E). Furthermore, Wang et al.148 developed a magnetic thermoresponsive hydrogel (GelTAMNPs) that induced sustained immune activation when used postoperatively to address post-surgical tumor recurrence and metastasis.
Additionally, researchers suggested cascading oxidative stress may be an effective approach to treat cancer25. RSL3/BP@PLEL is a biocompatible and biodegradable hydrogel formulation that can induce pyroptosis, repolarize macrophages from M2 to M1, and enhance antitumor efficacy149. IRA/aPD-L1 gel effectively induces apoptosis and pyroptosis150. Studies have shown that it can persist at the tumor site for 15 days and significantly prolong the survival time of 4T1 tumor-bearing mice (Fig. 8F and G). The survival rate remains above 75% within 100 days (Fig. 8H), which has a good curative effect. H-CNP@pGMD can be degraded in an acidic environment to release plasmid pGMD into the cytoplasm of tumor cells, which activates SRY-box transcription factor 4 (Sox4), expresses GSDMD and is cleaved by MMP2 to induce tumor cell-specific pyroptosis151. Yang et al.152 synthesized IR780-ZnS@HSA, which synergistically enhanced the immune response by activating the caspase-3-GSDME signaling pathway and the Cyclic GMP-AMP synthase cGAS-STING signaling pathway, providing new ideas for tumor treatment. Jin et al.153 developed OPDEA-PDCA, triggering pyroptosis by mitochondrial oxidative stress. When combined with aPD-L1, it can significantly reduce osteosarcoma proliferation and extend T cells activation.
In short, nanogels exhibit excellent responsive characteristics, such as pH, ROS, and GSH responsiveness, facilitating the development of diverse drug delivery systems tailored to the TME. This establishes the foundation for the creation of new and more effective prodrugs.
3.4.　 Metal-based nanomaterials
With their excellent biocompatibility and easy modification, metal nanomaterials are a type of nanomaterials containing metal elements, widely used in tumor drug delivery154. By integrating these metal-based nanomaterials into various therapeutic modalities, we can overcome the current limitations of single therapies that struggle to completely eliminate tumors (Fig. 9A).
PWE can activate the epigenetic inheritance of cell pyroptosis during RT, converting apoptosis into pyroptosis and amplifying the immune effect of traditional RT155. Zhang et al.156 designed an RF-responsive bivalent gold nanocluster (biGC@PNA) and decitabine (DCA) co-delivery strategy, which activated caspase-3 under radiofrequency irradiation, while DCA can upregulate GSDME, thereby inducing pyroptosis. Due to the multiple improvements of radiofrequency-activated pyroptosis on the tumor immune microenvironment, biGC@PNA effectively enhances the antitumor efficacy of aPD-1 immunotherapy (Fig. 9D). Li et al.157 synthesized EI-NP and VNP-GD which ensured the intracellular delivery of GSDM, prevented endosomal sorting complexes required for transport (ESCRT)III-mediated cell membrane repair, and achieved pyroptosis-mediated cancer immunotherapy.
Researchers designed a nanosheet containing copper ions (Cu-TBB) that generated ROS under light conditions and activated GSDMD-mediated pyroptosis, thereby enhancing DC maturation and the initiation of cytotoxic T lymphocytes (CTLs), and triggering systemic immune response (Fig. 9B)158. Zhao et al.159 injected Cu2(PO4) (OH) NPs into colon cancer sites, inducing copper apoptosis and pyroptosis. Niu et al.160 used hexahistidine (His6)-metal assemble (HmA) to load nigericin (Nig) and DAC, which avoided lysosomes and distributed the drugs at the tumor site, inducing pyroptosis that polarized M2 macrophages into M1 macrophages (Fig. 9C). Moreover, Su et al.161 synthesized CA-Re, which promoted the generation of ROS and lipid peroxidation, exhibited extremely high PDT efficiency under hypoxic conditions, effectively induced GSDMD-mediated pyroptosis, and also demonstrated strong antitumor immune activity. Furthermore, TiO2@Ru@siRNA, a photothermal and immunotherapeutic nanosystem, is adapted to hypoxic conditions, capable of inducing lysosomal damage under PDT, effectively enhancing siRNA escape, and triggering pyroptosis in oral squamous cell carcinoma (OSCC) cells, thereby activating the cancer immune response162. In addition, Hu et al.163 covered As2O3 therapy could induce pyroptosis in hepatocellular carcinoma (HCC) cells expressing GSDME, likely due to the upregulation of GSDME-N and the downregulation of PCNA and DNMT-related proteins. MnGA can avoid heat shock protein (HSP) restriction, enhance the effect of PTT, and induce pyroptosis164. DSe@POC is used as a pyroptosis inducer because the diselenium bond can be broken by elevated glutathione levels in the TME and ROS produced by PDT. When combined with aPD-1 treatment, it efficiently inhibits distal tumor growth and improves long-term immunological memory165.
To achieve efficient tumor fluorescence localization and RT, Wu et al.166 developed 177Lu-YNP@FA nano-prodrug (NPD), which precisely targeted cervical cancer cells in the abdominal cavity of BALB/c nude mice under NIR-II lights, exhibiting excellent antitumor effects. Re(I)-g-C3N4 can deliver type II ICD inducers, overcoming TNBC's resistance to DOX and enhancing immune response167. MCSP activates both pyroptosis and the STING pathway via metal immunotherapy and H2S gas therapy, significantly boosting antitumor immune responses in cervical cancer168. Chen et al.169 first proposed the redox imbalance triggered by cysteine (Cys) depletion. PVPCuO nanoparticles can activate ferroptosis mediated by lipid peroxidation and also induce caspase-1/GSDMD-dependent pyroptosis, with synergistic effects that enhance antitumor therapeutic efficacy and achieve efficient targeting of pancreatic cancer with Cys. A novel nanoplatform (Mn-HSP) enables closed-loop circulating immunotherapy (Pyroptosis-CTLs-GZMB-Pyroptosis) to effectively inhibit primary, distant, and metastatic tumors in vivo170. Lu et al.171 prepared dual-metal nanoparticles (FZOH), which simultaneously induced ferroptosis and pyroptosis, bridging the constraints of cancer immunotherapy, and significantly enhancing the antitumor immune response.
In summary, researchers have prepared various types of nanoparticles using metal-based nanomaterials, with copper-based, manganese-based, and iron-based applications being the most widespread. These nanomaterials are widely utilized not only in tumor treatment but also in diagnostics.
3.5.　 Biomimetic nanomaterials
Biomimetic nanomaterials, inspired by natural sources and biological materials, exhibit excellent biocompatibility, non-toxicity, and low immunogenicity172-174. At present, biomimetic nanomaterials mainly include bionic nanozymes, bionic microorganisms, and bionic biofilm drug delivery systems (Fig. 10A).
The initial focus is on the application of bionic microorganisms as pyroptosis inducers. Bionic microorganisms function as nanoparticles composed of oncolytic viruses. Su et al.175 proposed a strategy combining activators of transcription 3 inhibitor nanoprodrugs (MPNP) with oncolytic viruses (Ovs), which demonstrated enhanced tumor penetration ability and significantly mediated GSDME pyroptosis, thereby reshaping the TME and transforming “cold” tumors into “hot” tumor. Listeria monocytogenes (Lmo) encapsulated by red blood cells can induce caspase-8 activation and upregulate the expression of GSDMD by NADPH oxidase-mediated ROS, triggering tumor cell pyroptosis, reversing immune suppression, and promoting a strong and sustained systemic antitumor immune response (Fig. 10B)176. DNF@LIPO, a virus-like particle, causes pyroptosis mediated by the AIM2 (absent in melanoma 2) inflammasome and cGAS-STING activation, offering a reliable and effective method for cancer immunotherapy177.
The second area involves the application of bionic enzymes. By hybridizing nanozymes with GOx, it is possible to create nanoparticles that possess dual enzyme activity, effectively inhibiting tumor metastasis and recurrence while also regulating tumor glucose metabolism and immunotherapy178. LFO@GOx combines US and enzyme kinetics to produce ROS that induce specific pyroptosis, expected to regulate the pyroptosis-dominated therapeutic process179. Moreover, nanozymes in cancer cells initiate a self-accelerating cascade that consumes glucose and suppresses the production of HSPs, thereby intensifying thermotherapy in response to near-infrared light, activating pyroptosis and inducing a powerful immune response180. NiCoOx nanosheets serve as multi-enzyme simulated pyroptosis inducers, with their catalytic activity enhanced under acidic conditions and US, promoting cancer treatment181. Chen et al.182 created Pt-NS/HCS, which showed selectively improved peroxidase (POD)-like activity. It significantly induced GSDMD and GSDME-mediated pyroptosis, with in vivo data further confirming the therapeutic effect of Pt-NS/HCS when combined with PD-L1 immunotherapy. DNA nanocomposites (DNFs@ZnMn) promote pyroptosis by utilizing dynamic cascades to impair autophagy and ameliorate tumor hypoxia183. LPZ possesses POD and superoxide dismutase (SOD)-like properties that produce significant quantities of ROS on cancer cell membranes and intracellularly, resulting in pyroptosis and powerful antitumor immunity184.
Finally, the application of bionic biofilms in inducing pyroptosis is discussed. Biomimetic nanoparticles (BNP) are a nanodrug delivery system that uses cancer cell membranes to coat indocyanine green (ICG) and decitabine (DCT), inducing pyroptosis by caspase-3/GSDME and promoting systemic antitumor immunity185. In addition, Prussian blue nanoparticles (PB NPs) were loaded with Cinobufagin (CS-1) and then coated with a mixed membrane of erythrocyte, and triple-negative breast cancer (TNBC) cell membrane form CS-1@PB[HM] NPs186. Upon accumulation, laser irradiation of the tumor area rapidly induces GSDME-dependent tumor cell pyroptosis, promotes the release of tumor antigens and DAMPs, and ultimately induces DCs maturation and enhances T cell immune responses (Fig. 10C). Targeted and concentrated on tumor cells, the M-Cu-T initiates pyroptosis upon laser activation, further triggering immunogenic cell death and initiating antitumor immunity187. ZTC@M contains the chemotherapy drug tirapazamine (TPZ), which can be combined with SDT/US to enhance pyroptosis188.
Although the above methods effectively induce pyroptosis, cancer cells exhibit higher autophagy activity than normal cells, resulting in reduced pyroptosis effect189,190. Zhang's group developed ZPHM coated with cancer cell membranes that induce pyroptosis and disrupt checkpoints191. Under light conditions, the nanoparticles release hexyl 5-aminolevulinate hydrochloride (HAL), which induces the photosensitizer protoporphyrin IX (PpIX) to produce ROS, activating the NLRP3 inflammasome and the caspase 1/GSDMD pathway. Additionally, nanoparticles can produce the autophagy inhibitor 3-methyladenine (3-MA) in situ, which can prevent the degradation of NLRP3, caspase 1, and IL-1β, thus enhancing the efficiency of pyroptosis (Fig. 10E). ROZM nanoparticles effectively counteract the drawbacks of small molecule chemotherapeutic drugs through receptor-mediated endocytosis, such as poor water solubility and non-targeting, producing significant in vitro and in vivo impacts on tumor control and immune response192.
Ir-HecN is a metal photosensitizer and bacterial heterozygote, which is self-actuated and hypoxic, and targets tumor tissues to cause solid tumor regression under the combined application of PDT and immunotherapy193. Deng et al.194 discovered a delivery strategy using Ca@GOx, consisting of calcium phosphate and glucose oxidase coated by erythrocyte and cancer cell membranes. This system induces mitochondria to produce a large amount of ROS and activate caspase-3/GSDME to cause pyroptosis. Chloroquine, loaded into the nanosystem, inhibits mitophagy and enhances pyroptosis, improving antitumor immune responses (Fig. 10D). In addition, Li et al.195 proposed a strategy to load Ce6 and DOX into bacterial outer membrane vesicles (denoted as DOX/Ce6-OMVs@M), which, combined with PDT, CT, and immunotherapy, could eradicate TNBC in mice and prevent tumor metastasis. Furthermore, Zheng et al.196 designed an M1 macrophage membrane (EMM) biomimetic nanoplatform (EMM@DJHAD) for treating breast cancer with bone metastases, showing excellent inhibitory effects on tumor development, metastasis, and analgesic activities. Among these, JTC801 stimulated caspase-3 to cleave GSDME and trigger tumor pyroptosis, whereas DAC enhanced the level of GSDME via demethylating the DFNA5 gene. Finally, exosomes, with minimal immunogenicity, can deliver drugs to tumor sites, such as C-PMet, loaded with ectoenzyme (CD39) inhibitor POM-1 (sodium polyoxotungstate) and AMP-activated protein kinase (AMPK) agonist metformin, stimulating macrophage pyroptosis and improving DC maturation to trigger antitumor immunity197. Another study team developed the MFG@TCM nanoplatform to combat the ITME in osteosarcoma (OS) via stimulating cGAS-STING pathway in conjunction with mild PTT198.
This section elaborates on three types of biomimetic drug delivery systems that primarily activate the downstream GSDMD signaling pathway through caspase-1/3/8 to induce pyroptosis. Due to their high biocompatibility and the ability to mimic natural drug and release processes, they have attracted extensive attention from researchers.
3.6.　 Carrier-free nanomaterials
Carrier-free nanomaterials enable drug delivery directly to tumor sites without the need for additional carrier199. The nanodrug delivery system formed by the self-assembly of small molecule prodrugs acts as both carrier and cargo, significantly enhancing drug delivery efficiency200. Li et al.201 developed a stable and controllable carrier-free nanoplatform (A-C/NPs) which was a co-assembly method of cytarabine (Ara-C) and Ce6, showing excellent suppressive effects on cancer and enhancing anticancer immune response by GSDME-mediated pyroptosis in a breast cancer mouse model.
Taken together, nanomaterial-induced pyroptosis represents a novel therapeutic method for tumors and an interdisciplinary field of study. Researchers have developed several novel nanodrug delivery systems that target tumor cells and adapt to the TME, such as pH and ROS responsiveness. These adaptations help improve therapeutic effects and minimize damage to normal cells. Furthermore, nanomaterials can trigger pyroptosis and synergize with PDT, CT, and RT to enhance the immune system's response to tumor cells, thereby improving the overall efficacy of immunotherapy. Recently, various nanomaterials have demonstrated promising therapeutic effects in animal models, providing a solid foundation for their potential clinical application. Despite the progress made in developing nanomaterials that induce pyroptosis through antitumor immunotherapy, there are still some challenges, such as the development of new nanomaterials, the potential toxicity of nanomaterials, and the efficiency of inducing pyroptosis.
4.　Conclusions and outlooks
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In recent years, pyroptosis has garnered widespread attention as a promising approach for treating cancer, rapidly becoming a hot research area. When cells undergo pyroptosis, they release pro-inflammatory factors that enhance the immune response, thereby improving the efficacy of cancer immunotherapy. Nanomaterials are also favored by researchers in the field of drug delivery due to their unique physical and chemical properties, emerging as a promising avenue in cancer therapy, particularly for their ability to induce pyroptosis, which can reduce side effects and improve immunotherapeutic outcomes. In summary, with the advancement of nanomaterials and cancer immunotherapy, as well as our further understanding of the pyroptosis mechanism, a variety of nanodrug delivery systems have been developed for cancer treatment, offering potential therapeutic solutions. This article aims to provide an overview of the three main mechanisms of action related to pyroptosis, as well as the latest progress in employing nanomaterials to coordinate pyroptosis in treating various tumors. In addition, this article focuses on the recent advancements in tumor therapy and nanomaterials in enhancing cancer immunotherapy through the induction of pyroptosis.
The combined use of delivery systems and pyroptosis is a breakthrough in cancer treatment, but clinical applications remain limited. Therefore, future research should focus on addressing the following challenging questions and exploring other possibilities (Fig. 11):
First, the antitumor immune response induced by pyroptosis requires precise modulation. With further research, the tumor-promoting effect of pyroptosis has also been revealed. Therefore, controlling the induction of pyroptosis requires a nuanced approach to stimulate its positive effects on tumor diseases while minimizing the potential for tumor promotion. In addressing this issue, diagnostic tools are crucial as they can effectively mitigate the pro-tumor effects of pyroptosis. After pyroptosis occurs, specific biomarkers are released, such as members of the GSDM protein family, pro-inflammatory factors, and caspase proteases202. Diagnostic probes targeting these biomarkers can be developed to detect cellular pyroptosis and enable real-time monitoring. For example, dual-locking and tandem activatable probes can perform non-invasive real-time detection of cancer chemo-immunotherapy based on near-infrared signals203. Multicolor fluorescent nanoprobes (Cas-NP) can detect the activation sequence of caspase-1/3/4, providing new support for the detection of multiple pathways204.
Second, the biosafety of drug delivery systems based on nanomaterials has not been fully confirmed. Although preliminary data indicates that some drug delivery systems possess excellent biological safety, their long-term toxicity and biological effects have not been fully proven. For example, nanoparticles composed of metal nanomaterials act on cancer cells, but retained metal ions may also induce pyroptosis in normal cells, posing potential risks. In addition, certain nanomaterials are complex to synthesize, which can result in residues of organic solvents, thereby causing biosafety concerns and increasing the difficulty of scaling up production on an industrial scale for clinical applications. Thus, nanomaterials that are biodegradable, easy to synthesize, and require low doses are of great significance for translating pyroptosis-mediated antitumor immune responses into clinical applications.
Third, the mechanism that triggers cell pyroptosis is incomplete. When combined with nanomaterials for cancer treatment, the complexity of the TME in vivo may alter pyroptosis processes and mechanisms. In addition, the relevant mechanisms of pyroptosis treatment based on nanomedicines remain largely unexplored, hindering further optimization of pyroptosis efficiency. Therefore, it is important to develop strategies that combine nanodrug delivery systems with diagnostic tools that can assess treatment response in real-time, allowing oncologists to dynamically adjust treatments and significantly improve patient outcomes.
Fourth, racial differences affect treatment efficacy. Human and rodent tumors differ in complexity, human tumors are smarter, and each tumor may have a different TME, thus significantly reducing the efficiency of nanomaterial-based drug delivery. It is necessary to construct nanomedicines decorated with more active targeting ligands to improve this situation in the future.
The use of nanomaterials to regulate pyroptosis is an increasingly focused topic in the field of cancer treatment. With researchers delving deeper into the connection between pyroptosis and cancer, there's a growing anticipation for the clinical application of nanomaterials that regulate this process. In conclusion, the development of innovative nanomaterials that focus on modulation of pyroptosis presents a promising avenue for the treatment of different types of cancer. Consequently, we expect that in the coming years, highly effective nanoparticles will show great capacity in cancer treatments that rely on the regulation of pyroptosis.
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Year 2025 volume 15 Issue 2
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doi: 10.1016/j.apsb.2024.11.011
  • Receive Date：2024-07-10
  • Online Date：2026-09-17
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  • Received：2024-07-10
  • Revised：2024-09-12
  • Accepted：2024-10-15
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    Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China

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表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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