Preamble

Research Progress on Pyroptosis in Colorectal Cancer Inflammation-Cancer Transformation and Disease Development
Shi Zhiyao¹,², Gao Yu², Liu Likun², Guo Zhi², Wang Xixing²*

¹First Clinical College, Shanxi University of Chinese Medicine, Taiyuan 030024, China
²Department of Oncology, Shanxi Institute of Traditional Chinese Medicine, Taiyuan 030012, China

*Corresponding author: Wang Xixing, Chief Physician/Doctoral Supervisor; E-mail: wangxx315@163.com

[Abstract] Colorectal cancer, one of the most prevalent malignancies globally with persistently high incidence and mortality rates, poses a significant threat to human health. Moreover, the early diagnosis rate of colorectal cancer remains relatively low, with many patients diagnosed at intermediate or advanced stages, resulting in suboptimal treatment outcomes and prognoses. However, most current colorectal cancer research remains at the surgical level, with limited investigation into internal cellular and molecular mechanisms. With deepening research in tumor biology, the close relationship between inflammation and tumorigenesis has gradually been revealed. As a novel form of programmed cell death, pyroptosis has attracted considerable attention in tumor immunity and microenvironment regulation. This study systematically reviews research progress on inflammation-cancer transformation and pyroptosis in colorectal cancer, analyzing their interaction mechanisms and the role of pyroptosis in disease progression. The findings indicate that chronic inflammation regulates the transformation of undifferentiated cells into cancer stem cells through cytokines and growth factors, thereby constructing a pro-carcinogenic microenvironment. Pyroptosis, triggered by inflammasome activation and mediated by caspase family and gasdermin family proteins, exhibits dual effects—it promotes tumor cell death while influencing the tumor microenvironment through the release of cytokines such as IL-1β and IL-18. Targeting strategies for inflammation-cancer transformation and pyroptosis demonstrate therapeutic potential. This study provides theoretical foundations at the cellular and molecular levels for understanding colorectal cancer pathogenesis, lays the groundwork for developing precision-targeted therapies, and facilitates the transition of colorectal cancer treatment from surgery-focused approaches to multi-mechanism combined interventions, ultimately improving patient prognosis.

[Key words] Colorectal cancer; Pyroptosis; Inflammation-cancer transformation; Growth factors; Cytokines

[CLC number] R735.34
[Document code] A
DOI: 10.12114/j.issn.1007-9572.2025.0195

Research Progress on Cell Pyroptosis in Colorectal Cancer Transformation and Disease Development
SHI Zhiyao¹,², GAO Yu², LIU Likun², GUO Zhi², WANG Xixing²*

¹First Clinical College, Shanxi University of Chinese Medicine, Taiyuan 030024, China
²Oncology department, Shanxi Institute of Traditional Chinese Medicine, Taiyuan 030012, China

*Corresponding author: WANG Xixing, Chief physician/Doctoral supervisor; E-mail: wangxx315@163.com

[Abstract] Colorectal cancer, one of the most prevalent malignancies globally with persistently high incidence and mortality rates, poses a significant threat to human health. However, its early detection rate remains relatively low, with many patients diagnosed at intermediate or advanced stages, resulting in suboptimal treatment outcomes and prognoses. Current research predominantly focuses on surgical interventions, while studies on cellular and molecular mechanisms remain limited. With the deepening research in tumor biology, the close relationship between inflammation and tumors has gradually been revealed. As a novel programmed cell death mechanism, cellular pyroptosis has attracted significant attention in tumor immunity and microenvironment regulation. This study systematically reviews the research progress on inflammatory carcinogenesis and cellular pyroptosis in colorectal cancer, analyzing their interaction mechanisms and the role of cellular pyroptosis in disease progression. The findings indicate that chronic inflammation regulates the transformation of undifferentiated cells into cancer stem cells through cytokines and growth factors, thereby constructing a procarcinogenic microenvironment. Cellular pyroptosis, triggered by inflammatory body activation and mediated by caspase family and gasdermin family proteins, exhibits dual effects: it promotes tumor cell death while influencing the tumor microenvironment through the release of cytokines such as IL-1β and IL-18. Targeting strategies for inflammatory carcinogenesis and cellular pyroptosis demonstrate therapeutic potential. This study provides theoretical foundations at the cellular and molecular levels to understand colorectal cancer pathogenesis, lays the groundwork for developing precision-targeted therapies, and facilitates the transition of colorectal cancer treatment from surgery-focused approaches to multi-mechanism combined interventions, ultimately improving patient prognosis.

[Key words] Colorectal cancer; Pyroptosis; Inflammatory cancer transformation; Growth factors; Cell factor

Funding: Shanxi Provincial Natural Science Foundation General Project (202103021224437); Fourth National Traditional Chinese Medicine Master Inheritance Studio Project (National Chinese Medicine Office Personnel Education Letter [2022] No. 245 1123-04); National Traditional Chinese Medicine Inheritance Innovation Center Construction Project (202203); Shanxi Provincial Traditional Chinese Medicine Clinical Medical Research Center (Cultivation) Project (Jin Ke She Fa [2019] No. 61); Shanxi Provincial Health Commission Shanxi Provincial Medical Science and Technology Innovation Team Project (2020TD04); Shanxi Provincial Health Commission Shanxi Provincial Medical Major Science and Technology Research Project (2022XM10)

Citation: Shi ZY, Gao Y, Liu LK, et al. Research progress on cell pyroptosis in colorectal cancer transformation and disease development [J]. Chinese General Practice, 2025. DOI: 10.12114/j.issn.1007-9572.2025.0195. [Epub ahead of print] [www.chinagp.net]
SHI Z Y, GAO Y, LIU L K, et al. Research progress on cell pyroptosis in colorectal cancer transformation and disease development [J]. Chinese General Practice, 2025. [Epub ahead of print]

© Editorial Office of Chinese General Practice. This is an open access article under the CC BY-NC-ND 4.0 license.

Introduction

Since the beginning of the 21st century, rapid advances in molecular biology, genomics, and immunology have deepened our understanding of tumors to the molecular level. Tumors are no longer viewed as single diseases but as highly heterogeneous disease groups. Research on colorectal cancer has revealed that inflammation is closely associated with tumorigenesis and progression. The inflammatory microenvironment not only provides suitable growth conditions for tumor cells but also influences tumor invasion and metastasis through complex signaling networks. Pyroptosis, as a novel form of programmed cell death, has attracted widespread attention in tumor immunity and tumor microenvironment research in recent years. Traditional treatment modalities such as surgical resection, chemotherapy, and radiotherapy have remained the primary approaches for colorectal cancer patients. However, these conventional methods have inherent limitations: surgical resection may fail to completely eliminate micrometastases, while chemotherapy and radiotherapy can damage normal cells and cause various side effects. With the development of high-throughput sequencing technologies, significant progress has been made in tumor genomics research. By analyzing genomic data from colorectal cancer patients, multiple genes and signaling pathways associated with colorectal cancer development have been identified. Tumor microenvironment studies have confirmed that interactions between tumor cells and surrounding cells and extracellular matrix are crucial for tumor progression. Microenvironmental factors such as inflammatory cell infiltration, fibroblast activation, angiogenesis, and extracellular matrix remodeling all participate in tumor progression. Although relevant therapeutic strategies have been developed targeting these factors, the high heterogeneity and dynamic changes of the tumor microenvironment still limit treatment efficacy. Based on these considerations, this study systematically reviews and analyzes research progress on inflammation-cancer transformation and pyroptosis in colorectal cancer, exploring their mechanisms in cancer development to provide deeper theoretical foundations for colorectal cancer treatment.

1.1 Current Status of Colorectal Cancer Research

Colorectal cancer, as one of the most common tumor types, poses a significant threat to human health. Numerous scholars have investigated its disease characteristics and pathology. Siegel et al. [14] statistically analyzed colorectal cancer data through 2023, finding it has become the second leading cause of cancer death in the United States. The study revealed significant gender disparities in overall incidence: 41.5 per 100,000 in men, 33% higher than in women (31.2 per 100,000). This difference was particularly pronounced across anatomical sites, with substantially higher male incidence rates in proximal colon and rectal cancers. Age distribution analysis showed that incidence rates for all colorectal cancer sites increased with age, particularly among those over 65. Although individuals aged 65 and above represent the primary affected population, those under 50 account for 13% of cases, while the 50-64 age group comprises about 32%, indicating that middle-aged populations should not be overlooked. Additionally, colorectal cancer incidence, survival rates, and mortality demonstrate racial and regional variations, with Native Americans and Alaska Natives having the highest risk and Asian Americans and Pacific Islanders the lowest. Over 50% of cases and deaths are attributable to modifiable risk factors including smoking, unhealthy diet, alcohol abuse, physical inactivity, and overweight [15]. Sedlak et al. [16] revealed that colorectal cancer cells support rapid proliferation through metabolic reprogramming characterized by aerobic glycolysis to generate biosynthetic molecules, while requiring efficient nutrient acquisition and waste removal. Diet plays a critical role in pathogenesis, with high-fat and high-sugar diets both associated with disease onset. The gut microbiome influences colon stem cell biology through metabolites; for example, lactic acid-producing bacteria can promote colon stem cell proliferation by activating integrin signaling pathways, thereby participating in tumorigenesis. In the treatment domain, Ciardiello et al. [17] found that approximately 20% of colorectal cancer patients have metastasis at initial diagnosis, and 50% of patients with localized disease eventually progress to metastatic disease. Current metastatic colorectal cancer treatment is based on molecular stratification, with first- and second-line regimens incorporating genetic variation detection, combined anti-angiogenic drugs and anti-epidermal growth factor receptor (EGFR) agents. Subsequent treatment strategies must be formulated based on rat sarcoma viral oncogene homolog (RAS) family, B-type mouse sarcoma viral oncogene homolog B1 (B-Raf) gene mutation status, and microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) characteristics. For patients showing significant response to first- or second-line chemotherapy combined with cetuximab/panitumumab, EGFR inhibitor rechallenge therapy may be employed. Targeting the EGFR family and its intracellular signaling pathways represents the core of molecular targeted therapy for metastatic colorectal cancer, with Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) gene mutation analysis serving as key criteria for molecular characterization and providing important basis for treatment selection.

1.2 Existing Research on Inflammation-Cancer Transformation Mechanisms

Studies have demonstrated that cancer development is closely related to inflammation. Afify et al. [18] explored how chronic inflammation promotes cancer development, proposing that cancer tissue growth is driven by cancer stem cells with self-renewal, differentiation, and tumorigenic potential. Under chronic inflammatory conditions, various cytokines and growth factors can stimulate undifferentiated cells to transform into cancer stem cells (Figure 1 [FIGURE:1]). Cancer can originate from differentiated cells or undifferentiated stem/progenitor cells, with the latter exhibiting strong plasticity and regenerative capacity. Under conditions such as chronic inflammation, altered levels of cytokines and growth factors can induce transformation of undifferentiated cells into cancer stem cells. Chronic inflammation, caused by long-term exposure to inflammatory mediators, accelerates cancer progression by promoting continuous cell proliferation and survival. Afify et al. [18] hypothesized that chronic diseases can construct cancer-inducing niches that create microenvironments supporting the emergence of cancer-associated cells, with these niches varying across different organs and being maintained by cancer cells themselves for survival. Stevens et al. [19], in studies on inflammation-cancer transformation-related cancers, identified inflammatory breast cancer as a rare, highly aggressive subtype. Through multicolor immunofluorescence analysis, they confirmed that CD44⁺, CD24⁻ cells most commonly expressed phosphorylated signal transducer and activator of transcription 3 (pSTAT3). Combined chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) analysis of pSTAT3 revealed that pSTAT3 regulates genes related to inflammation, epithelial-mesenchymal transition (EMT), and phosphodiesterase 4A (PDE4A) in drug-resistant cells. Metabolomic analysis showed elevated cyclic adenosine monophosphate (cAMP) signaling pathways in drug-resistant cells, with cAMP response element-binding protein (CREB) identified as a potential therapeutic target. Bhat et al. [20] identified inflammation as a known risk factor for colorectal cancer, with the resulting inflammation-rich local environment encompassing tumor cells, endothelial cells, immune cells, cancer-associated fibroblasts, immunosuppressive cells, and secreted growth factors. Through complex interactions, these components drive colorectal cancer pathogenesis and trigger systemic responses that affect disease outcomes. Abnormally expressed cytokines and chemokines recruit immunosuppressive cells, confer cancer stem cell-like properties on tumor cells, and enable drug resistance, invasiveness, and formation of pre-metastatic niches in distant organs, thereby promoting metastasis and invasive growth.

Different types of immune cells participate in colorectal cancer inflammation by secreting various cytokines and chemokines, exerting either tumor-promoting or tumor-suppressing effects (Figure 2 [FIGURE:2]). Th1 cells and M1 macrophages are typically associated with pro-inflammatory responses, while M2 macrophages contribute to inflammation resolution. In colorectal cancer treatment, targeting specific cytokines or their receptors can modulate inflammatory responses to inhibit tumor growth and metastasis. Epithelial-mesenchymal transition represents the core process by which tumor cells acquire migration and invasion capabilities, accompanied by loss of cell-cell adhesion and cell-matrix adhesion. Various cytokines such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) can trigger epithelial-mesenchymal transition in colorectal cancer cells through different signaling pathways, thereby promoting tumor cell migration and invasion. Meanwhile, systemic inflammation can induce immunosuppression and provide favorable conditions for tumor metastasis [22].

1.3 Research on Pyroptosis and Its Mechanisms

Pyroptosis can activate the immune system and influence the tumor microenvironment, exerting either tumor-suppressing or tumor-promoting effects. Elias et al. [23] identified pyroptosis as a form of programmed cell death mediated by the gasdermin family of proteins. Initially described as a caspase-1- and inflammasome-dependent cell death pathway, pyroptosis is characterized by loss of plasma membrane integrity and secretion of cytokines such as IL-1β. Gasdermins form pores that cause plasma membrane rupture, leading to release of cellular contents. During pyroptosis, gasdermin proteins exist in an auto-inhibited state in their inactive form, with key regions mediating lipid binding and membrane insertion hidden through interactions between carboxy-terminal and amino-terminal domains. Protease cleavage of the linker region releases the active amino-terminal domain, resulting in pore formation on the cell membrane. Although evidence suggests pyroptosis participates in pathogenesis, its specific roles and mechanisms require further investigation. Zhang et al. [24] deeply investigated the mechanisms of pyroptosis technology in cancer therapy, discovering that autophagy is not only a key regulatory point for cancer cell pyroptosis but also a self-protective mechanism that weakens therapeutic efficacy. The team successfully developed a novel nanoregulator that both induces pyroptosis and blocks autophagy regulatory nodes, thereby achieving precise pyroptosis therapy (Figure 3 [FIGURE:3]).

The nanoregulator can promote synthesis and accumulation of the photosensitizer protoporphyrin IX in cancer cell mitochondria, directly generating mitochondrial reactive oxygen species and triggering pyroptosis. Autophagy inhibitors generated in situ through palladium-catalyzed bioorthogonal chemical reactions can disrupt pyroptosis checkpoints. Disruption of pyroptosis checkpoints refers to enhancing pyroptosis by inhibiting autophagy. NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) plays a crucial role in apoptosis by activating caspase-1. Autophagosomes are vesicular structures formed during autophagy that encapsulate and transport intracellular materials to lysosomes. During treatment, a platform for regulating apoptosis can be constructed using biomimetic cancer cell membrane coating—this coating specifically targets cancer cells while being harmless to normal tissues, thereby achieving efficient and safe antitumor therapy.

Some compounds and drugs can activate pyroptosis pathways, becoming potential anticancer molecules. Meanwhile, PANoptosis has been identified as a form of cell death combining pyroptosis, apoptosis, and necrosis, mediated by the PANoptosome complex [31]. This process involves inflammatory responses and holds potential application value in tumor therapy.

Inflammasome activation is a prerequisite for caspase-1 and caspase-11 activation [32]. Inflammasomes consist of sensor proteins, adaptor proteins, and zymogen forms. When inflammasomes receive signals from pathogen-associated molecular patterns or damage-associated molecular patterns, they trigger caspase activation. The role of caspases in pyroptosis is illustrated in Figure 5 [FIGURE:5].

2.1 Interaction Between Inflammation-Cancer Transformation and Pyroptosis

Pyroptosis, triggered by inflammasome activation and typically associated with pathogen infection or cell damage, represents a key issue in immune cell cytotoxicity research [25]. Wei et al. [26] discovered that pyroptosis is regulated by various inflammatory caspases. Activated caspases can cleave gasdermin D (GSDMD), releasing its N-terminal domain that binds to membrane lipids and penetrates the plasma membrane. Inflammasomes serve as critical regulators of apoptosis, responding to internal and external stimuli such as pathogen-associated molecular patterns. When regulated by inflammasomes, pyroptosis can promote tumor cell death, while released cytokines (such as IL-1, IL-18) also facilitate tumor invasion and metastasis. Additionally, mycobacteria induce pyroptosis in macrophages through the mycobacterial secreted protein EST12 [27]. EST12 can bind to host sensor protein RACK1 to form the EST12-RACK1 complex, which subsequently recruits ubiquitin carboxyl-terminal hydrolase L5 (UCHL5), leading to deubiquitination of NLRP3 protein at lysine 48 (Lys48) and triggering Gasdermin D-induced macrophage pyroptosis with interleukin-1 secretion. Bromodomain protein 4 (Brd4), an important epigenetic transcriptional activator, regulates NAIP-NLRC4 activation during Salmonella infection of macrophages [28]. Brd4 colocalizes with macrophage lineage-determining transcription factor PU.1 and interferon regulatory factor 8 (IRF8) at the neuronal activity-regulated pentraxin (NARP) promoter, promoting its transcription and inducing maturation of caspase-1 and cleavage of Gasdermin D and pro-IL-1β, ultimately promoting infection-mediated inflammatory responses and pyroptosis [29] (Figure 4 [FIGURE:4]).

Yang et al. [30] found that pyroptosis can be activated through both non-canonical and canonical inflammasome pathways. The non-canonical inflammasome pathway is characterized by caspase-4/5/11-mediated GSDMD cleavage, while the canonical inflammasome pathway features caspase-1-mediated GSDMD cleavage.

2.2 Current Research on Potential Therapeutic Strategies Targeting Inflammation-Cancer Transformation and Pyroptosis

Understanding the mechanisms of pyroptosis in colorectal cancer and inflammation-cancer transformation can facilitate development of novel prevention and treatment strategies. Peng et al. [33] discovered that Gasdermin D is a cytoplasmic effector protein primarily functioning in immune cell pyroptosis. The nuclear localization of Gasdermin D (GSDMD) in colorectal cancer differs from its role in pyroptosis, as nuclear Gasdermin D promotes apoptosis by regulating its subcellular distribution rather than through pyroptosis-related cleavage. Hypoxia in the tumor microenvironment is a factor for GSDMD nuclear translocation. Under hypoxic conditions, Gasdermin D translocates from the cytoplasm to the nucleus, and this translocation is associated with tumor cell proliferation and apoptosis. The study found that in colon adenocarcinoma survival curve analysis, no significant difference existed between high and low Gasdermin D mRNA expression groups. Similarly, in rectal adenocarcinoma survival analysis, no significant difference was observed between high and low Gasdermin D mRNA expression groups, suggesting that Gasdermin D mRNA expression levels may not be a reliable biomarker for predicting prognosis in colorectal cancer patients.

Chen et al. [34] developed a compound therapeutic material called secoisolariciresinol diglucoside (SDG) for treating colorectal cancer with inflammation-cancer transformation. This substance, a lignan extracted from flaxseed, possesses multiple biological activities including anticancer properties. SDG induces pyroptosis in colorectal cancer cells by enhancing cleavage of the Gasdermin D protein N-terminal fragment while increasing caspase-1 levels. Additionally, the compound inhibits human colon cancer cell line HCT116 cell activity, induces cell swelling and large bubble formation, producing typical necrotic characteristics. SDG can induce GSDMD-dependent pyroptosis through the ROS/PI3K/AKT/BAX mitochondrial apoptosis pathway, providing a reference for novel applications of SDG in cancer therapy.

Vafaei et al. [35] demonstrated that NLRP3 inflammasome, an important member of the NOD-like receptor (NLR) family, influences tumor development through multiple pathways including immune system function, apoptosis, cell proliferation, and gut microbiota balance. Upon recognition of pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), NLRP3 inflammasome can be activated, subsequently activating nuclear transcription factor NF-κB through primary signal transduction. Persistent activation of NLRP3 inflammasome and its mediated NF-κB signaling pathway can induce chronic inflammatory states, a pathological process confirmed to be closely associated with colorectal cancer development. Activated interleukin-1β and interleukin-18 can significantly affect the tumor microenvironment and promote tumor progression by regulating immune responses. Notably, caspase-1 activated by NLRP3 inflammasome not only promotes proteolytic maturation of interleukin-1β and interleukin-18 precursors but also induces pyroptosis, an inflammatory programmed cell death process that leads to massive release of pro-inflammatory cytokines. Research indicates that NLRP3 inflammasome-mediated inflammatory cell death through Gasdermin-D is a key mechanism of innate immune response and plays an important role in maintaining intestinal homeostasis, including regulation of intestinal epithelial barrier function and immune responses to gut microbiota [36]. Regarding intervention strategies, small molecule compounds such as andrographolide can inhibit NLRP3 inflammasome activation in macrophages by inducing mitophagy, thereby effectively preventing azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colon cancer in mice [37]. Additionally, the synthetic flavonoid derivative GL-V9 also demonstrates good anti-inflammatory and antitumor effects by inducing autophagy-dependent NLRP3 inflammasome degradation to exert protective effects against colitis and associated cancer [38]. Studies have confirmed that using inactivated probiotics can also reduce the incidence of NLRP3-mediated colitis and inflammation-associated colon cancer [39]. The mechanism of NLRP3 inflammasome in colorectal cancer is illustrated in Figure 6 [FIGURE:6].

4 Summary and Outlook

This study systematically reviewed research progress on inflammation-cancer transformation and pyroptosis in colorectal cancer, clarifying that chronic inflammation promotes transformation of undifferentiated cells into cancer stem cells through signaling pathways involving cytokines, growth factors, and NLRP3 inflammasome, thereby providing a suitable microenvironment for tumor growth. Simultaneously, pyroptosis, as an inflammatory programmed cell death mechanism regulated by gasdermin family proteins and caspases, participates in tumor cell death while influencing the tumor microenvironment through release of cytokines such as IL-1β and IL-18, providing potential targets for targeted therapy. Additionally, strategies such as SDG-induced pyroptosis and NLRP3 inflammasome inhibition demonstrate new therapeutic potential for colorectal cancer, promising more personalized and efficient treatment options for patients.

However, current research has limitations: most mechanistic explorations are based on cellular or animal models, with clinical translation efficacy and safety yet to be validated; the cross-regulatory network between inflammation-cancer transformation and pyroptosis remains incompletely understood, requiring further analysis of differential effects of various inflammatory factors on pyroptosis. Future research should focus on three aspects: First, expand clinical sample validation to promote clinical trials of candidate compounds such as SDG and GL-V9, clarifying their therapeutic value in human colorectal cancer. Second, deepen molecular mechanism research to analyze the dynamic interaction network between inflammation-cancer transformation and pyroptosis, identifying key regulatory nodes as novel targets. Third, develop specific biomarkers, integrate multi-omics technologies to improve early diagnosis and prognostic assessment accuracy, and explore combination regimens of pyroptosis inducers with immunotherapy and chemotherapy, providing more comprehensive theoretical support and practical basis for precision treatment of colorectal cancer.

Author Contributions: Shi Zhiyao was responsible for data collection and analysis and manuscript writing; Gao Yu participated in data collection and organization; Liu Likun was responsible for manuscript revision, quality control, and proofreading; Guo Zhi was responsible for figure editing and organization; Wang Xixing was responsible for project design, guiding manuscript writing, and final approval.

Conflict of Interest Statement: The authors declare no conflict of interest.

ORCID: Shi Zhiyao: https://orcid.org/0000-0002-0838-1448

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(Received: May 21, 2025; Revised: July 18, 2025)

(This article edited by: Li Weixia)