Colorectal cancer liver metastasis (CRLM) is a leading cause of mortality, driven by poorly defined molecular interactions within the hepatic niche. Here, we identify a distinct population of pro-metastatic Early Growth Response 1 (Egr1) + neutrophils that accumulate in the pre-metastatic liver. Mechanistically, we show that KIAA1199-high cancer cells secrete granulin-rich extracellular vesicles, which are internalized by hepatocytes. This uptake triggers a subset of functionally reprogrammed hepatocytes, characterized by a profound metabolic reprogramming and the suppression of peroxisome proliferator-activated receptor gamma (PPARγ) signaling, leading to increased secretion of Serum Amyloid A2 (SAA2). Hepatocyte-derived SAA2 subsequently activates Formyl Peptide Receptor 2 (FPR2) on neutrophils, stabilizing Egr1-driven transcriptional program via the PI3K-AKT pathway to enhance neutrophil survival and pro-angiogenic activity. These Egr1 + neutrophils co-localize with reprogrammed hepatocytes at the tumor-liver interface, where they promote vascular remodeling to facilitate metastatic colonization. Pharmacological restoration of PPARγ or FPR2 inhibition abrogate CRLM in preclinical models in female mice. Furthermore, a combined KIAA1199-SAA2 signature predicts liver metastasis risk in patients. Our findings delineate a KIAA1199-PPARγ/SAA2-Egr1 axis orchestrating the pre-metastatic niche and propose metabolic normalization as a preventative strategy for liver metastasis.

Cysteinyl aspartate specific proteinase (caspase)-6 belongs to the caspase family and plays a vital role in mediating cell death. Under certain conditions, three pathways of programmed cell death (PCD), including apoptosis, necroptosis and pyroptosis (PANoptosis), transform one way into another, with enormous therapeutic potential. Initially, scholars reported that caspase-6 is a caspase executor that mediates apoptosis. With the ceaseless exploration of the PCD types, studies have demonstrated that caspase-6 mediates pyroptosis by regulating gasdermin D and mediates necroptosis by regulating mixed lineage kinase domain-like. By regulating PANoptosis, caspase-6 plays a crucial role in tumorigenesis in humans and mediates anti-tumour immunity. Therefore, a comprehensive understanding of caspase-6 function in cancer via PANoptosis is important for the prevention and therapy of tumours. This article summarized the function of caspase-6 in PANoptosis and its impact on cancer development, providing targets and strategies for tumour treatment.

Background: Jumonji C-domain-containing (JMJD) family, a group of genes that regulate epigenetics, is involved in tumor development in several types of cancer. JMJD5 is a member of the JMJD family, and its clinical impact on stomach adenocarcinoma (STAD) remains unclear. Pyruvate kinase M2 (PKM2) promotes metabolism, tumor proliferation, and metastasis in various cancer types. However, the relationship between JMJD5 and PKM2 in STAD is yet to be established. In this study, we investigated the expressions and relationship of JMJD5 and PKM2 in patients with STAD. Furthermore, we evaluated the clinical significance between their expression and prognosis. In addition, we explored the transcriptional and survival effects of other 7 members of the JMJD family including JMJD1B, JMJD1C, JMJD2D, JMJD4, JARID2, HSPBAP1, TYW5 in patients with STAD. Methods: The expression of JMJD5 and PKM2 in STAD was examined using western blot, quantitative real-time polymerase chain reaction (RT-qPCR), and immunohistochemical staining. Statistical analyses were performed using the SPSS 22.0 statistical software program. The roles of JMJD1B, JMJD1C, JMJD2D, JMJD4, JARID2, HSPBAP1, TYW5 in STAD were examined using UALCAN, GEPIA, Kaplan–Meier Plotter,the Human Protein Atlas, STRING, the cBiopotal, Metascape databases. Results: We discovered that the rates of low expression of JMJD5 and high expression of PKM2 in the tumor cells of STAD were 64.52.% and 62.37%, respectively. Moreover, there was a close connection between the expressions of JMJD5 and PKM2. We uncovered that the low expression of JMJD5 was related to poor differentiation (P = 0.002) and large tumor size (P = 0.044). The survival rate was low in patients with low expression of JMJD5 and high expression of PKM2. In addition, we found that JMJD1B, JMJD1C, JMJD2D, JMJD4, JARID2, HSPBAP1, TYW5 were high in the STAD tissues. Besides, gene expression levels were correlated with tumor stage and grade. Survival analysis demonstrated that high expressions of these genes, except JMJD1B, were associated with low survival rates. Moreover, a high mutation rate of these genes (82.22%) was observed in STAD patients. Conclusions: These findings implied that JMJD1B, JMJD1C, JMJD2D, JMJD4, JMJD5, JARID2, HSPBAP1, TYW5, and PKM2 could serve as potential therapeutic targets in patients with STAD and as novel biomarkers for the disease.

Photodynamic therapy (PDT) uses a photosensitizer (PS) and visible light to induce cancer cell death. Pyroptosis is a new type of programmed cell death that is associated with the gasdermin protein family. However, the precise mechanism of pyroptosis in PDT-induced suppression of esophageal cancer remains unknown. We demonstrate that PDT can induce gasdermin E (GSDME)-mediated pyroptosis, which is characterized by the formation of pyroptotic blebs in esophageal squamous cell carcinoma (ESCC), which burst and release intra-cellular contents and pro-inflammatory mediators. Mechanistically, PDT may inhibit pyruvate kinase M2 (PKM2) and consequently, activate caspase-8 and caspase-3, which ultimately releases N-GSDME and triggers pyroptosis in ESCC. Moreover, PDT decreased the efficiency of pyroptosis in the presence of a glycolytic inhibitor. Overall, our results show that PDT induces pyroptosis in ESCC by targeting the PKM2/caspase-8/caspase-3/GSDME axis. This is the first in-depth study of the specific mechanism underlying PKM2-mediated pyroptosis under PDT in ESCC, and potentially has great implications for the clinical application of PDT in ESCC.

Pyroptosis is a novel type of pro-inflammatory programmed cell death that has been strongly reported to be related to inflammation, immune, and cancer. Dihydroartemisinin (DHA) has good anti-tumor properties. However, the exact mechanism by which DHA induces pyroptosis to inhibit esophageal squamous cell carcinoma (ESCC) remains unclear. After applying DHA treatment to ESCC, we found that some dying cells exhibited the characteristic morphology of pyroptosis, such as blowing large bubbles from the cell membrane, accompanied by downregulation of pyruvate kinase isoform M2 (PKM2), activation of caspase-8/3, and production of GSDME-NT. Meanwhile, it was accompanied by an increased release of LDH and inflammatory factors (IL-18 and IL-1β). Both knockdown of GSDME and application of caspase-8/3 specific inhibitors (z-ITED-FMK/Ac-DEVD-CHO) significantly inhibited DHA-induced pyroptosis. However, the former did not affect the activation of caspase-3. In contrast, overexpression of PKM2 inhibited caspase-8/3 activation as well as GSDME-N production. Furthermore, both si-GSDME and OE-PKM2 inhibited DHA-induced pyroptosis in vivo and in vitro. Therefore, the results suggest that DHA can induce pyroptosis of ESCC cells via the PKM2-caspase-8/3-GSDME pathway. Implication: In this study, we identified new mechanism of DHA in inhibiting ESCC development and progression, and provide a potential therapeutic agent for the treatment of ESCC.

Cysteinyl aspartate specific proteinase (Caspase)-8 has long been considered a promoter of apoptosis and part of the mechanism by which cytotoxic drugs kill cancer cells. With the continuous exploration of the types of programmed cell death, an increasing number of studies have confirmed that caspase-8 plays an important role in cancer. Recently, scholars have proposed the term "PANoptosis," which mainly includes three programmed cell death modes, namely pyroptosis, apoptosis and necroptosis. In addition to mediating endogenous apoptotic pathways, caspase-8 can also participate in the cleavage of gasdermin (GSDM) family proteins to induce pyroptosis. Furthermore, the expression of enzymatically inactive caspase-8 (C362S) can cause embryonic lethality and inflammatory tissue destruction in mice by inducing necroptosis and pyroptosis. Therefore, the activation and deletion of caspase-8 enzyme activity, as well as the knockout of the coding gene, are closely related to "PANoptosis." In addition, caspase-8 can also improve the tumor microenvironment and enhance tumor antiimmunity. Studies have shown that caspase-8 is also associated with tumor growth and invasion, angiogenesis and metastasis, therapeutic resistance and poor clinical outcomes. Therefore, it is very important to measure the cancer-promoting and anticancer effects of caspase-8 and find a balance, and to study its role in the effect of "PANoptosis" in depth. This article reviews the role of caspase-8 in "PANoptosis" in cancer to provide new strategies and targets for cancer.

Background: Although eukaryotic elongation factor 2 kinase (eEF2K) has been reported to be a potential oncogenic factor in many human cancers, its usefulness as a clinical prognostic biomarker for gastric cancer has not been investigated. Methods: In this study, data about 540 patients with stomach adenocarcinoma (STAD) were analyzed from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases to determine the expression of eEF2K. Immunohistochemistry (IHC), western blots, and real-time polymerase chain reaction (RT-PCR) were also performed to determine the clinical significance of eEF2K expression in 96 postoperative patients with gastric cancer. Among the 96 patients, 36 had low expression of eEF2K and 60 had high expression. Results: Analysis of the TCGA and GEO datasets revealed that eEF2K expression was significantly higher in the STAD tissue samples than in the non-tumorous gastric tissues. IHC, western blots, and RT-PCR confirmed these findings. The high expression level of eEF2K was found to be related to the presence of lymph node metastasis (p = 0.002). Moreover, multivariate analysis showed that eEF2K was an independent indicator of prognosis for overall survival (OS) (hazard ratio [HR] = 1.72, 95% confidence interval [CI] = 1.06-2.79; p = 0.03) and disease-free survival (DFS) (HR = 1.66, 95% CI = 0.997-2.765; p = 0.052) in patients with surgically resected STAD. Conclusion: Collectively, our findings suggest that eEF2K is a clinical indicator of metastatic and prognostic significance for STAD survival and could serve as a potential therapeutic target.

Pyroptosis refers to the process of gasdermin (GSDM)-mediated programmed cell death (PCD). Our understanding of pyroptosis has expanded beyond cells and is known to involve extracellular responses. Recently, there has been an increasing interest in pyroptosis due to its emerging role in activating the immune system. In the meantime, pyroptosis-mediated therapies, which use the immune response to kill cancer cells, have also achieved notable success in a clinical setting. In this review, we discuss that the immune response induced by pyroptosis activation is a double-edged sword that affects all stages of tumorigenesis. On the one hand, the activation of inflammasome-mediated pyroptosis and the release of pyroptosis-produced cytokines alter the immune microenvironment and promote the development of tumors by evading immune surveillance. On the other hand, pyroptosis-produced cytokines can also collect immune cells and ignite the immune system to improve the efficiency of tumor immunotherapies. Pyroptosis is also related to some immune checkpoints, especially programmed death-1 (PD-1) or programmed death- ligand 1 (PD-L1). In this review, we mainly focus on our current understanding of the interplay between the immune system and tumors that process through pyroptosis, and debate their use as potential therapeutic targets.

Apoptosis has long been recognized as a mechanism that kills the cancer cells by cytotoxic drugs. In recent years, studies have proved that pyroptosis can also shrink tumors and inhibit cells proliferation. Both apoptosis and pyroptosis are caspase-dependent programmed cell death pathways. Cysteinyl aspartate specific proteinase-3 (Caspase-3) is a common key protein in the apoptosis and pyroptosis pathways, and when activated, the expression level of tumor suppressor gene Gasdermin E (GSDME) determines the mechanism of tumor cell death. When GSDME is highly expressed, the active caspase-3 cuts it and releases the N-terminal domain to punch holes in the cell membrane, resulting in cell swelling, rupture, and death. When the expression of GSDME is low, it will lead to the classical mechanism of tumor cell death, which is apoptosis. More interestingly, researchers have found that GSDME can also be located upstream of caspase-3, connecting extrinsic, and intrinsic apoptotic pathways. Then, promoting caspase-3 activation, and forming a self-amplifying feed-forward loop. GSDME-mediated pyroptosis is correlated with the side effects of chemotherapy and anti-tumor immunity. This article mainly reviews the caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer, to provide new strategies and targets for cancer treatment.

Gasdermin B (GSDMB) belongs to the gasdermin (GSDM) family which may adopt different mechanisms of intramolecular domain interactions to modulate their lipid-binding and pore-forming activities. The GSDM family has regulatory functions in cell proliferation and differentiation, especially in pyroptosis process. Pyroptosis is a pro-inflammatory form of regulated cell death and is designed to attract a nonspecific innate response to the site of infection. For cancer cells, the activation of pyroptosis may promote cell death and exert anticancer properties. Also, recent studies have observed the pyroptosis-like features in GSDMB and some researches have shown that GSDMB overexpression occurred in several kinds of cancers; these findings bring a contradiction with the participation of GSDMB in pyroptosis. Although people pay less attention to GSDMB, it still has some essential research value. It is a paradox that GSDMB might participate in programmed cell death, which might put forward a research direction of therapeutic targets for cancer. Here, we review the possible progress of how GSDMB participated in this inflammatory regulation mechanistically and the potential functions of GSDMB in cancer.

Esophageal cancer, especially esophageal squamous cell carcinoma (ESCC) threatens so many lives in China every year. Traditional treatment of ESCC has usually been disappointing. The development of novel therapy is worth investigation. We have previously demonstrated that dihydroartemisinin (DHA) has anticancer effect on esophageal cancer. However, the mechanism has not been completely known. In this present study, we explored the effect of DHA on cancer cell glycolysis, also known as Warburg effect. Pyruvate kinase M2 (PKM2) is a key regulatory factor of glycolysis, and our results showed that it is significantly overexpressed in patients with ESCC and ESCC cell lines. In DHA treatment cells, PKM2 was down-regulated and lactate product and glucose uptake were inhibited. Overexpression of PKM2 by lentiviral transfection abrogated the inhibition effect of DHA. These results suggested that DHA might repress esophageal cancer glycolysis partly by down-regulating PKM2 expression. We believe that DHA might be a prospective agent against esophageal cancer.