Necroptosis has been shown to play an important role in various pathologies, including pancreatic cancer (PDAC). However, its role in the progression of oral cancer (OSCC) remains unclear.

To determine the expression of key necroptosis pathway markers in an OSCC mouse model and evaluate the therapeutic effect of a necroptosis inhibitor on the progression of OSCC.

4-NQO-induced OSCC in mice resembles very closely to human OSCC. The expression of RIPK-1, RIPK-3, MLKL and their respective phosphorylation was increased in OSCC tissues of cancer-bearing mice. In the analysis of the necroptosis pathway in human OSCC with the TCGA database, we found similar overexpression of RIPK-1 in human cancer, which correlated with the severity of cancer in terms of different cancer grades and stages. Pharmacological blockade of necroptosis with necrostatin-1 (NEC-1) reduced the progression and development of OSCC, characterized by reduced number and severity of tumour lesions, improved histology with reduced hyperplasia, dysplasia and invasive carcinoma. Immune profiling of blood, spleen and tumour tissues demonstrated suppressed expression of MDSCs (CD11b+Gr-1+) and M2-macrophages (CD11b+F4/80+CD206+), while M1-macrophages (CD11b+F4/80+MHCII+) were elevated in the treatment group. The ratio of M2/M1 was reduced in the treated group, suggesting the promotion of anti-tumour immune response. Expression of Arg-1, YM1/2, IL-10 and TGF-β was reduced in tumour tissues in the treated group.

In summary, blocking the necroptosis pathway alters the tumour microenvironment (TME) and inhibits the progression of OSCC. Targeting necroptosis could be an effective therapy for treating OSCC in a clinical setup.

Oral squamous cell carcinoma (OSCC) is characterized by dysregulation of multiple cell signaling pathways, including the necroptotic pathway. Recently, the incidence of OSCC is increasing among the young population (below the age of 40 years). These patients exhibit differences in the pathobiological characteristics and treatment response compared to the older cohorts. There is a notable lack of research exploring the role of necroptotic proteins in younger OSCC patients.

To investigate the expression of Mixed Lineage Kinase domain Like Pseudokinase (MLKL), a key necroptotic protein, in young and old patients with OSCC.

The study included sixty histopathologically confirmed cases of OSCC, categorized into two groups; Group I - 30 patients aged > 40 years and Group II - 30 patients aged ≤ 40 years. Each of these groups consisted of 10 cases each of well differentiated, moderately differentiated and poorly differentiated OSCC. The samples were evaluated for the MLKL gene expression using Real time PCR and the results were analyzed using the 2-ΔΔCT method.

The real-time PCR analysis showed a 31 % decrease in MLKL gene expression in the younger age group (Group II) compared to the older group. A decrease of 40 % in WDSCC, 67 % in MDSCC, and 38 % in PDSCC was observed in the younger group compared to the older age group.

Our findings suggest age-related differences in necroptotic cell death regulation through MLKL, with decreased MLKL expression observed in younger patients compared to older patients. Modulating necroptotic cell death pathways in OSCC can promote switching between different cell death pathways and provide effective therapeutic strategies.

The multifaceted roles and mechanisms of necroptosis in cancer cells remain incompletely understood. Here, we demonstrate that FGFR2 inhibition potently inhibits esophageal squamous cell carcinoma (ESCC) by inducing necroptosis in a RIP1/MLKL-dependent manner and show RIP3 is dispensable in this pathway. Notably, MST1 is identified as a necroptotic pathway component that interacts with RIP1 and MLKL to promote necroptosis by phosphorylating MLKL at Thr216. Additionally, FGFR2 inhibition induces Ser518 phosphorylation and triggers ubiquitin-mediated degradation of NF2, culminating in Hippo pathway suppression. Subsequently, YAP activation promotes RIP1 and MLKL transcriptional upregulation, further amplifying necroptosis. Intriguingly, IL-8 derived from necrotic cells stimulates peripheral surviving tumor cells to increase PD-L1 expression. Dual blockade of FGFR2/PD-L1 or FGFR2/IL-8-CXCR1/2 robustly impedes tumor growth in humanized mouse xenografts. Collectively, our findings delineate an alternative FGFR2-NF2-YAP signaling-dependent necroptotic pathway and shed light on the immunoregulatory role of FGFR2, offering promising avenues for combinatorial therapeutic strategies in clinical cancer management.

Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancers that has yet to benefit from immunotherapies. This is primarily a result of its characteristic 'cold' tumor microenvironment composed of cancer-associated fibroblasts (CAFs), a dense network of extracellular matrix and several immune cell types, the most abundant of which are the tumor-associated macrophages (TAMs). Advances in single-cell and spatial technologies have elucidated the vast functional heterogeneity of CAFs and TAMs, their symbiotic relationship and their cooperative role in the tumor microenvironment. In this Review, we provide an overview of the heterogeneity of CAFs and TAMs, how they establish an immunosuppressive microenvironment and their collaboration in the remodeling of the extracellular matrix. Finally, we examine why the impact of immunotherapy in PDAC has been limited and how a detailed molecular and spatial understanding of the combined role of CAFs and TAMs is paramount to the design of effective therapies.

Receptor-interacting protein kinase-3 is essential for the cell death pathway called necroptosis. Necroptosis is activated by the death receptor ligands and pattern recognition receptors of the innate immune system, leading to significant consequences in inflammation and in diseases, particularly cancer. Necroptosis is highly proinflammatory compared with other modes of cell death because cell membrane integrity is lost, resulting in releases of cytokines and damage-associated molecular patterns that potentiate inflammation and activate the immune system. We discuss various ways that necroptosis is triggered along with its potential role in cancer and therapy.

Breast cancer (BC) is the most common malignant tumor and the leading cause of cancer-related deaths among women worldwide. Great progress has been recently achieved in controlling breast cancer; however, mortality from breast cancer remains a substantial challenge, and new treatment mechanisms are being actively sought. Programmed cell death (PCD) is associated with the progression and treatment of many types of human cancers. PCD can be divided into multiple pathways including autophagy, apoptosis, mitotic catastrophe, necroptosis, ferroptosis, pyroptosis, and anoikis. Ubiquitination is a post-translational modification process in which ubiquitin, a 76-amino acid protein, is coupled to the lysine residues of other proteins. Ubiquitination is involved in many physiological events and promotes cancer development and progression. This review elaborates the role of ubiquitin-specific protease (USP) in programmed cell death, which is common in breast cancer cells, and lays the foundation for tumor diagnosis and targeted therapy.

Necroptosis, a non-apoptotic mode of programmed cell death, is characterized by the disintegration of the plasma membrane, ultimately leading to cell perforation and rupture. Recent studies have disclosed the mechanism of necroptosis and its intimate link with nanomaterials. Nanomedicine represents a novel approach in the development of therapeutic agents utilizing nanomaterials to treat a range of cancers with high efficacy. This article provides an overview of the primary mechanism behind necroptosis, the current research progress in nanomaterials, their potential use in various diseases-notably cancer, safety precautions, and prospects. The goal is to aid in the development of nanomaterials for cancer treatment.

Breast cancer is one of the most prevalent malignant tumors among women and ranks as the second leading cause of cancer-related deaths in females, primarily due to delays in diagnosis and shortcomings in treatment strategies. Consequently, there is a pressing need to identify reliable therapeutic targets and strategies. In recent years, the identification of effective biomarkers-particularly novel molecular therapeutic targets-has become a focal point in breast cancer research, aimed at predicting disease aggressiveness and monitoring treatment responses. Simultaneously, advancements in understanding the molecular mechanisms underlying cellular programmed death have opened new avenues for targeting kinase-regulated programmed cell death as a viable therapeutic strategy. This review summarizes the latest research progress regarding kinase-regulated programmed death (including apoptosis, pyroptosis, autophagy, necroptosis, and ferroptosis) in breast cancer treatment. It covers the key kinases involved in this mechanism, their roles in the onset and progression of breast cancer, and strategies for modulating these kinases through pharmacological interventions.

Biliary tract cancer (BTC) has greatly influenced patient survival for years. Nowadays, immunotherapy represents a promising breakthrough and proteomics is one of powerful technologies in biomarker research. We collected plasma and tissue samples from 37 patients with advanced BTC and 92 proteins were analyzed by proximity extension assay (PEA). Through linear mixed effect models, compared to partial response (PR) group, 8 proteins, IL7, ANGPT2, IL15, HO-1, CXCL1, CXCL5, IL33, and VEGFA, exhibited significantly higher expression in stable disease and progressive disease (SD_PD) group in response-effect analysis. It was also revealed that a subset of proteins increased over time, including PDCD1, TNFRSF4, DCN, CRTAM, VEGFR-2 and ADA in PR group and PDCD1, IL10, ADA, CD28, and PTN in SD_PD group. In interaction-effect analysis, HO-1, ANGPT2, IL15 were three significant differentially expressed proteins (DEPs). Receiver operating characteristic (ROC) analysis further demonstrated that HO-1, ANGPT2, IL15 showed high accuracy in patients with immune checkpoint blockade (ICB) treatment plus chemotherapy (AUC = 0.74). In addition, based on the obtained plasma and tissue samples, two nomogram models were constructed for predicting the prognosis of BTC by genome combined with proteomics. Collectively meaningful proteomic biomarkers are beneficial to evaluate the efficacy of immunotherapy, and these discovered biomarkers may be included in the scope of treatments' evaluation and improvement in future study.

Increasing evidence is showing that necroptosis has unique clinical significance in the occurrence and development of multiple diseases. Here, we systematically evaluate the role of necroptosis in clear cell renal cell carcinoma (ccRCC) and analyze its regulatory patterns.

First, we evaluated the expression and enrichment of necroptotic factors in ccRCC using gene set enrichment analysis (GSEA) and survival analysis in the expression profile from The Cancer Genome Atlas (TCGA) to demonstrate the overall mutation of necroptotic pathway genes. Then, we used unsupervised clustering to divide the samples into two subtypes related to necroptosis with significant differences in overall survival (OS) and subsequently detected the differentially expressed genes (DEGs) between them. Based on this, we constructed the necroptosis scoring system (NSS), which also performed outstandingly in hierarchical data. Finally, we analyzed the association between NSS and clinical parameters, immune infiltration, and the efficacy of immunotherapy containing immune checkpoint inhibitors (ICIs), and we suggested potential therapeutic strategies.

We screened 97 necroptosis-related genes and demonstrated that they were dysregulated in ccRCC. Using Cox analysis and least absolute shrinkage and selection operator (LASSO) regression, a prognostic prediction signature of seven genes was built. Receiver operating characteristic (ROC) curves and Kaplan-Meier (KM) analyses both showed that the model was accurate, and univariate/multivariate Cox analysis showed that as an independent prognostic factor, the higher the risk score, the poorer the survival outcome. Furthermore, the predicted scores based on the signature were observably associated with immune cell infiltration and the mutation of specific genes. In addition, the risk score could potentially predict patients' responsiveness to different chemotherapy regimens. Specifically, Nivolumab is more effective for patients with higher scores.

The necroptosis-related signature we constructed can accurately predict the prognosis of ccRCC patients and further provide clues for targeted, individualized therapy.

The role of the human microbiome in cancer has been extensively studied, focusing mainly on bacteria-host interactions and their impact on tumor development and treatment response. However, fungi, an immune-active component of the human microbiome, have received less attention regarding their roles in cancer. Recent studies have identified the widespread and specific colonization and distribution of fungi in multiple sites in patients across various cancer types. Importantly, host-fungal immune interactions significantly influence immune regulation within the tumor microenvironment. The rapid advancement of immune-checkpoint blockade (ICB)-based cancer immunotherapy creates an urgent need for effective biomarkers and synergistic therapeutic targets. Cancer-associated fungi and their associated antifungal immunity demonstrate significant potential and efficacy in enhancing cancer immunotherapy. This review summarizes and discusses the growing evidence of the functions and mechanisms of commensal and pathogenic cancer-associated fungi in cancer immunotherapy. Additionally, we emphasize the potential of fungi as predictive biomarkers and therapeutic targets in cancer immunotherapy.

Immunotherapy has transformed cancer treatment paradigms, but its effectiveness depends largely on the immunogenicity of the tumor. Unfortunately, the high resemblance of cancer to normal tissues makes most tumors immunologically 'cold', with a poor response to immunotherapy. Danger signals are critical for breaking immune tolerance and mobilizing robust, long-lasting antitumor immunity. Recent studies have identified inflammatory cell death modalities and their power in providing danger signals to trigger optimal tumor suppression. However, key mediators of inflammatory cell death are preferentially silenced during early tumor immunoediting. Strategies to rejuvenate inflammatory cell death hold great promise for broadening immunotherapy-responsive tumors. In this review, we examine how inflammatory cell death enhances tumor immunogenicity, how it is suppressed during immunoediting, and the potential of harnessing it for improved immunotherapy.

Cell death is critical in tumor biology. The common cancer therapies can cause cell death and alleviate tumor, while the cancer cells can develop a resistance to cell death and survive from the therapies. Thus, not only observing the alternative mechanisms of tumor cells resistant to cell death, but also understanding the intricate dynamics of cell death processes within the tumor microenvironment (TME), are essential for tailoring effective therapeutic strategies. High-throughput sequencing technologies have revolutionized cancer research by enabling comprehensive molecular profiling. Recent advances in single cell sequencing have unraveled the heterogeneity of TME components, shedding light on their complex interactions. In this review, we explored the interplay between cell death signaling and the TME, summarised the potential drugs inducing cell death in pre-clinical stage, reviewed some studies applying next-generation sequencing technologies in cancer death research, and discussed the future utilization of updated sequencing platforms in screening novel treatment methods targeted cell death. In conclusion, leveraging multi-omics technologies to dissect cell death signaling in the context of the TME holds great promise for advancing cancer research and therapy development.

Inositol phosphates (IPs) and inositol pyrophosphate play critical roles in many biological processes such as signaling molecules in pathways responsible for cellular functions involved in growth and maintenance. The biosynthesis of IPs is carried out by a family of inositol phosphate kinases. In mammals, Inositol tetrakisphosphate kinase-1 (ITPK1) phosphorylates inositol-1,3,4-trisphosphate (Ins(1,3,4)P3) and inositol-3,4,5,6-tetrakisphosphate (IP4), generating inositol-1,3,4,5,6-pentakisphosphate (IP5), which can be further phosphorylated to become inositol hexakisphosphate (IP6). ITPK1 also possesses phosphatase activity that can convert IP5 back to IP4; therefore, ITPK1 may serve as a regulatory step in IP6 production. IP6 utilization has been implicated in processes fundamental to cellular sustainability that are severely perturbed in many disease states including RNA editing, DNA repair, chromatin structure organization, and ubiquitin ligation. Therefore, ITPK1, with no known inhibitors in the literature, is a potential molecular target for modulating important processes in several human diseases. By independently coupling ITPK1 phosphatase and kinase activities to luciferase activity, we have developed and used biochemical high-throughput assays to discover eight ITPK1 inhibitors. Further analysis revealed that three of these leads inhibit ITPK1 in an ATP-competitive manner, with low micromolar to nanomolar affinities. We further demonstrate that the most potent ITPK1 inhibitor can regulate cellular ITPK1 activity. We determined the crystal structure of ITPK1 in complex with this inhibitor at a resolution of 2.25 Å. This work provides insight into the design of potential next-generation inhibitors.

The prognostic value of necroptosis-related microRNAs (miRNAs), which are important in tumorigenesis and development, remains unclear. Therefore, we aimed to screen prognostic necroptosis-related miRNAs in esophageal cancer (EC).

Nine necroptosis-related miRNA expression profiles and associated clinical data of EC patients were obtained from The Cancer Genome Atlas (TCGA) database. The relationships between necroptosis-related miRNAs and overall survival (OS) were determined via Cox regression model analysis. Target genes of the miRNAs were investigated in TargetScan, miRDB, and miRTarBase. The biological functions of these genes were evaluated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. For the most significant correlation between miR-425-5p expression and the survival of EC patients, the effect of miR-425-5p on necroptosis was explored in EC cells. The relationship between targeted gene expression and immune infiltration was also analyzed and validated.

Hsa-miR-425-5p, hsa-miR-500a-3p, hsa-miR-7-5p and hsa-miR-200a-5p were selected for the construction of a prognostic signature based on their correlation with the survival of EC patients. EC patients were divided into high- and low-risk groups according to the median value of the risk score. Patients in the high-risk group tended to have higher death rates than those in the low-risk group (P<0.05). The risk score was an independent prognostic indicator for the OS of EC patients [hazard ratio (HR) >1, P<0.05]. The prognostic model had good predictive efficiency. The genes targeted by necroptosis-related miRNAs were significantly enriched in apoptosis etc. The inhibition of miR-425-5p promoted necroptosis in EC cells by targeting branched chain amino acid transaminase 1 (BCAT1). The expression level of BCAT1 was significantly correlated with immune infiltration.

A necroptosis-related four-miRNA model was constructed successfully to predict the potential value of the four miRNAs in the prognosis of EC, which can be conducive to promoting the therapeutic effect on EC.

Given the limited efficacy of current first-line therapies, there is an urgent need to develop novel treatment strategies to improve the prognosis of patients with unresectable intrahepatic cholangiocarcinoma (uICC). This study aimed to evaluate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimens (HAIC-FO) plus anti-programmed death-(ligand) 1 immunotherapy [αPD-(L)1] antibody [HAIC+αPD-(L)1] compared to systemic chemotherapy (SYS) plus αPD-(L)1 antibody [SYS+αPD-(L)1] as a first-line treatment for patients with uICC.

In this retrospective study, treatment-naive uICC patients who were treated with HAIC+αPD-(L)1 or SYS+αPD-(L)1 were included. The clinical characteristics, therapeutic outcomes, and adverse events (AEs) of the patients in the two groups were compared. Propensity score matching (PSM) was performed to minimize biases between groups.

From January 2019 to January 2023, a total of 182 patients were enrolled; 147 patients were included in the HAIC+αPD-(L)1 group and 35 patients were included in the SYS+αPD-(L)1 group. After PSM, 61 and 26 patients were included in the HAIC+αPD-(L)1 and SYS+αPD-(L)1 groups, respectively. The HAIC+αPD-(L)1 group had longer median overall survival (mOS), median progression-free survival (mPFS), and median intrahepatic PFS (mIPFS) than did the SYS+αPD-(L)1 group (mOS: 14.5 vs. 10.5 months, P=0.02; mPFS: 10.4 vs. 6.4 months, P=0.02; mIPFS: 11.4 vs. 6.5 months, P<0.001). The overall incidence of AEs was comparable between the two groups, but the HAIC+αPD-(L)1 group had a lower incidence of grade 3-4 AEs related to anemia, leukopenia, weight loss, and fatigue.

HAIC+αPD-(L)1 had acceptable toxic effects and might improve outcomes compared to SYS+αPD-(L)1 as a first-line treatment for patients with uICC.

KRAS-dependent acinar-to-ductal metaplasia (ADM) is a fundamental step in the development of pancreatic ductal adenocarcinoma (PDAC), but the involvement of cell death pathways remains unclear. Here, we show that key regulators of programmed cell death (PCD) become upregulated during KRAS-driven ADM, thereby priming transdifferentiated cells to death. Using transgenic mice and primary cell and organoid cultures, we show that transforming growth factor (TGF)-β-activated kinase 1 (TAK1), a kinase regulating cell survival and inflammatory pathways, prevents the elimination of transdifferentiated cells through receptor-interacting protein kinase 1 (RIPK1)-mediated apoptosis and necroptosis, enabling PDAC development. Accordingly, pharmacological inhibition of TAK1 induces PCD in patient-derived PDAC organoids. Importantly, cell death induction via TAK1 inhibition does not appear to elicit an overt injury-associated inflammatory response. Collectively, these findings suggest that TAK1 supports cellular plasticity by suppressing spontaneous PCD activation during ADM, representing a promising pharmacological target for the prevention and treatment of PDAC.

The Damaraland mole-rat (DMR; Fukomys damarensis) is a long-lived (~ 20 years) Bathyergid rodent that diverged 26 million years ago from its close relative, the naked mole-rat (NMR). While the properties of NMR cultured fibroblasts have been extensively studied and have revealed several unusual features of this cancer-resistant, long-lived species, comparative DMR studies are extremely limited. We optimized conditions for successfully culturing primary DMR skin fibroblasts and also established immortalized DMR cells using simian virus 40 early region expression. Like NMRs, DMR fibroblasts are more resistant than mice to various cytotoxins including heavy metals, DNA-damaging agents, oxidative stressors, and proteasome inhibitors. DMR genome sequencing analyses revealed the presence of premature stop codons in the master regulator genes of necroptosis, an inflammatory programmed cell death-receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), although these mutations have different locations to those found in the NMR. DMR cells, like NMR cells, did not show significantly increased cell death in response to necroptosis induction. Our data suggest that both Bathyergid species require species-specific cell culture conditions for optimized growth, display similar resistance to cytotoxins, and show loss-of-function mutations abrogating the ability to employ necroptosis. These shared traits may contribute to their evolved adaptations to their subterranean lifestyle and prolonged longevity. These convergent insights and valuable resource may be pertinent to biomedical research.

Programmed cell death is a type of autonomic and orderly cell death mode controlled by genes that maintain homeostasis and growth. Tumor is a typical manifestation of an imbalance in environmental homeostasis in the human body. Currently, several tumor treatments are designed to trigger the death of tumor cells. Nasopharyngeal carcinoma is one of the most common malignant tumors in China. It displays obvious regional and ethnic differences in its incidence, being typically high in the south and low in the north of China. Nasopharyngeal carcinoma is currently considered to be a polygenic inherited disease and is often mediated by the interaction between multiple genes or between genes and the environment. Apoptosis has long been considered the key to tumor treatment, while other cell death pathways have often been overlooked. The current study provides an overview of the relationship among apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and nasopharyngeal carcinoma, and the regulatory pathways of nasopharyngeal carcinoma based on five cell death modes were synthesized from the view of molecule. We hope this review will help explore additional, novel programmed cell death targets for the treatment of nasopharyngeal carcinoma and thus promote in-depth research.

Strongyloides ratti is a helminth parasite that displays tissue-migrating and intestinal life stages. Myeloid C-type lectin receptors (CLRs) are pattern recognition receptors that recognize pathogen-derived ligands and initiate immune responses. To date, the role of CLRs in S. ratti infection has not been investigated. Here, we show that S. ratti-derived ligands are recognized by the CLR Macrophage inducible Ca2+-dependent lectin receptor (MINCLE). While MINCLE-deficiency did not affect initiation of a protective anti-S. ratti type 2 immunity, MINCLE-deficient mice had a transient advantage in intestinal immunity. Unravelling the underlying mechanism, we show that next to macrophages, dendritic cells and neutrophils, a fraction of eosinophils express MINCLE and expand during S. ratti infection. MINCLE-deficient eosinophils exhibited a more active phenotype and prolonged expansion in vivo and displayed increased capacity to reduce S. ratti motility and produce reactive oxygen species in vitro, compared to wild-type (WT) eosinophils. Depletion of eosinophils in S. ratti-infected mice after the tissue-migration phase elevated intestinal worm burden in MINCLE-deficient mice to the WT level. Thus, our findings establish a central contribution of eosinophils to parasite ejection from the intestine and suggest that S. ratti-triggered signalling via MINCLE interferes with eosinophil mediated ejection of S. ratti from the intestine.

In the evolving landscape of cancer treatment, the strategic manipulation of regulated cell death (RCD) pathways has emerged as a crucial component of effective anti-tumor immunity. Evidence suggests that tumor cells undergoing RCD can modify the immunogenicity of the tumor microenvironment (TME), potentially enhancing its ability to suppress cancer progression and metastasis. In this review, we first explore the mechanisms of apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, along with the crosstalk between these cell death modalities. We then discuss how these processes activate antigen-presenting cells, facilitate the cross-priming of CD8+ T cells, and trigger anti-tumor immune responses, highlighting the complex effects of novel forms of tumor cell death on TME and tumor biology. Furthermore, we summarize potential drugs and nanoparticles that can induce or inhibit these emerging RCD pathways and their therapeutic roles in cancer treatment. Finally, we put forward existing challenges and future prospects for targeting RCD in anti-cancer immunity. Overall, this review enhances our understanding of the molecular mechanisms and biological impacts of RCD-based therapies, providing new perspectives and strategies for cancer treatment.

Cell death mechanisms are broadly classified into accidental cell death (ACD) and regulated cell death (RCD). ACD such as necrosis, is an uncontrolled, accidental process, while RCD is tightly regulated by specific signaling pathways and molecular mechanisms. Tumor cells are characterized by their ability to evade cell death and sustain uncontrolled proliferation. The failure of programmed cell death is a key contributor to tumor initiation, progression, and resistance to cancer therapies. Traditionally, research has focused primarily on apoptosis as the dominant form of RCD in cancer. However, emerging evidence highlights the importance of other non-apoptotic forms of RCD, such as pyroptosis, ferroptosis, necroptosis, and parthanatos, in tumorigenesis and treatment response. These pathways are gaining attention for their potential roles in overcoming therapy resistance. In this review, we will discuss the recent advances in the study of non-apoptotic cell death pathways in malignant tumors and explore their therapeutic implications, offering insights into new targets for cancer treatment strategies.

Pancreatic cancer (PC) cannot currently be completely cured and has a poor prognosis. Necroptosis is a distinct form of regulated cell death that differs from both necrosis and apoptosis. Understanding the role of necroptosis during PC progression would open new avenues for targeted therapy.

The purpose of this study is to examine the impact of necroptosis on the progression of PC and related mechanisms.

RNA sequencing was performed to identify necroptosis-related genes that are differentially expressed in PC tissues. The biological functions of CHMP4C and its necroptosis effects were determined in vitro and in vivo. RNA immunoprecipitation, MeRIP-qPCR, Co-immunoprecipitation assays were conducted to evaluate the interaction among CHMP4C, YBX1 and caspase-8 mRNA. Extracellular vesicles were isolated using the differential ultracentrifugation method. The expression of CHMP4C, p-MLKL and CD117 were detected on a PC tissue microarray using multiplex immunofluorescence staining.

CHMP4C was significantly overexpressed in PC cells and tissues. It promoted cell growth and suppressed necroptosis of PC cells in both in vivo and in vitro settings. Mechanistically, CHMP4C interacted with YBX1 to mediate m5C modification of caspase-8 mRNA, resulting in increased caspase-8 expression and inhibition of RIPK1/RIPK3/MLKL pathway phosphorylation. Furthermore, CHMP4C promoted extracellular exocytosis of p-MLKL to further suppress necroptosis. Additionally, PC cells used CHMP4C within extracellular vesicles to recruit and stimulate mast cells (MCs), which in turn promoted PC cell proliferation. In PC tissues, the expression of CHMP4C showed a negative correlation with p-MLKL and a positive association with CD117. High expression levels of CHMP4C in patients were associated with poorer overall survival outcomes.

CHMP4C promotes PC progression by inhibiting necroptosis, which has potential as a biomarker and therapeutic target in PC.

Sepsis-associated acute kidney injury (SA-AKI) commonly occurs in critically ill patients and is closely associated with adverse outcomes. A comprehensive analysis of the current research landscape in SA-AKI can help uncover trends and key issues in this field. This study aims to provide a scientific basis for research directions and critical issues through bibliometric analysis.

We searched all articles on SA-AKI indexed in the SCI-Expanded of WoSCC up to May 7, 2024, and conducted bibliometric and visual analyses using bibliometric software CiteSpace and VOSviewer.

Over the past 20 years, there has been a steady increase in literature related to renal repair following AKI. China and the United States contribute over 60% of the publications, driving research in this field. The University of Pittsburgh is the most active academic institution, producing the highest number of publications. J. A. Kellum is both the most prolific and the most cited author in this area. "Shock" and "American Journal of Physiology-Renal Physiology" are the most popular journals, publishing the highest number of articles. Recent high-frequency keywords in this field include "septic AKI," "mitochondrial dysfunction," "inflammasome," "ferroptosis," and "macrophage." The terms "mitochondrial dysfunction," "inflammasome," "ferroptosis," and "macrophage" represent current research hotspots and potential targets in this area.

This is the first comprehensive bibliometric study to summarize the trends and advancements in SA-AKI research in recent years. These findings identify current research frontiers and hot topics, providing valuable insights for scholars studying SA-AKI.

As one of the most destructive and invasive cancers, pancreatic cancer exhibits complex tumor heterogeneity, which has been a major challenge for clinicians in terms of patient treatment and prognosis. The toll-like receptor (TLR) pathway is closely related to the immune microenvironment within various cancer tissues. To explore the development pattern of pancreatic cancer and find an ideal biomarker, our research has explored the mechanism of the TLR pathway in pancreatic cancer. We collected single-cell expression data from 57,024 cells and transcriptomic data from 945 pancreatic cancer patients, and conducted a series of analyses at both the single-cell and transcriptomic levels. By calculating the TLR pathway score, we clustered pancreatic cancer patients and conducted a series of analyses including metabolic pathways, immune microenvironment, drug sensitivity and so on. In the process of building prognostic models, we screened 33 core genes related to the prognosis of pancreatic cancer, and combined a series of machine learning algorithms to build the prognosis model of pancreatic cancer. We used single cell sequencing to clarify the complex intrinsic relationship between TLR pathway and pancreatic cancer. The strongest TLR signals were observed in macrophages and endothelial cells. With the occurrence of pancreatic cancer, the TLR signal of various cell types gradually increased, but with the increase of the malignant degree of ductal epithelial cells, the TLR signal gradually weakened. Cluster analysis showed that patients with the most active TLR pathway had severe dysregulation of immune microenvironment and the worst prognosis. Finally, we combined a series of machine learning algorithms to build a pancreatic cancer prognosis model that includes four genes (NT5E, TGFBI, ANLN, and FAM83A). The model showed strong performance in predicting the survival state of pancreatic cancer samples. We explored the important role of TLR pathway in pancreatic cancer and established and validated a new prognosis model for pancreatic cancer based on TLR-related genes.

Necroptosis, a recently identified mechanism of programmed cell death, exerts significant influence on various aspects of cancer biology, including tumor cell proliferation, stemness, metastasis, and immunosuppression. However, the role of necroptosis-related genes (NRGs) in Hepatocellular Carcinoma (HCC) remains elusive.

In this study, we assessed the mutation signature, copy number variation, and expression of 37 NRGs in HCC using the TCGA-LIHC dataset. We further validated our results using the ICGC-LIRI-JP dataset. To construct our prognostic model, we utilized the least absolute shrinkage and selection operator (LASSO), and evaluated the predictive efficacy of the NRGs-score using various machine learning algorithms, including K-M curves, time-ROC curves, univariate and multivariate Cox regression, and nomogram. In addition, we analyzed immune infiltration using the CIBERSOFT and ssGSEA algorithms, calculated the stemness index through the one-class logistic regression (OCLR) algorithm, and performed anti-cancer stem cells (CSCs) drug sensitivity analysis using oncoPredict. Finally, we validated the expression of the prognostic NRGs through qPCR both in vitro and in vivo.

About 18 out of 37 NRGs were found to be differentially expressed in HCC and correlated with clinical outcomes. To construct a prognostic model, six signature genes (ALDH2, EZH2, PGAM5, PLK1, SQSTM1, and TARDBP) were selected using LASSO analysis. These genes were then employed to categorize HCC patients into two subgroups based on NRGs-score (low vs. high). A high NRGs score was associated with a worse prognosis. Furthermore, univariate and multivariate Cox regression analyses were performed to confirm the NRGs-score as an independent risk factor. These analyses revealed strong associations between NRGs-score and critical factors, such as AFP, disease stage, and tumor grade in the HCC cohort. NRGs-score effectively predicted the 1-, 3-, and 5-year survival of HCC patients. Immune infiltration analysis further revealed that the expression of immune checkpoint molecules was significantly enhanced in the high NRGs-score group. Stemness analysis in the HCC cohort showed that NRGs-score was positively correlated with mRNA stemness index, and patients with high NRGs-score were sensitive to CSCs inhibitors. The findings from the external validation cohort provided confirmation that the NRGs-score presented a trait with universal applicability in accurately predicting the survival of HCC. Additionally, the six prognostic genes were consistently differentially expressed in both the HCC cell line and the mouse HCC model.

Our study demonstrated the pivotal role of NRGs in promoting stemness and immune suppression in HCC and established a robust model which could successfully predict HCC prognosis.

Necroptosis can promote antigen-specific immune responses, suggesting induced necroptosis as a therapeutic approach for cancer. Here we sought to determine the mechanism of immune activation but found the necroptosis mediators RIPK3 and MLKL dispensable for tumor growth in genetic and implantable models of breast or lung cancer. Surprisingly, inducing necroptosis within established breast tumors generates a myeloid suppressive microenvironment that inhibits T cell function, promotes tumor growth, and reduces survival. This was dependent upon the release of the nuclear alarmin interleukin-1α (IL-1α) by dying cells. Critically, IL-1α release occurs during chemotherapy and targeting this molecule reduces the immunosuppressive capacity of tumor myeloid cells and promotes CD8+ T cell recruitment and effector function. Neutralizing IL-1α enhances the efficacy of single agent paclitaxel or combination therapy with PD-1 blockade in preclinical models. Low IL1A levels correlates with positive patient outcome in several solid malignancies, particularly in patients treated with chemotherapy.

Triple-negative breast cancer (TNBC) is challenged by the low chemotherapy response and poor prognosis. Emerging evidence suggests that cytotoxic chemotherapy may lead to the pro-metastatic tumor microenvironment (TME) by eliciting pro-tumor extracellular vesicles (EVs) from cancer cells. However, the precise mechanisms and therapeutic approaches remain inadequately understood.

This study aims to determine whether XIAOPI formula (Chinese name XIAOPI San, XPS), a nationally sanctioned medication for mammary hyperplasia, can chemosensitize TNBC by remodeling the TME via modulating EV signaling, and exploring its underlying mechanisms.

Multiple methodologies, such as EV isolation, transmission electron microscope, flow cytometry, dual-luciferase reporter assays, co-immunoprecipitation and in vivo breast cancer xenograft, were employed to elucidate the effect and molecular mechanisms of XPS on paclitaxel-induced EV signaling (EV-dead) of TNBC.

XPS, at non-toxic concentrations, synergized with PTX to inhibit the invasion and chemoresistance of TNBC cells co-cultured with macrophages. Compared to EV-dead, XPS co-treatment-elicited EVs (EV-deadXPS) exhibited a decreased capacity to promote the invasion, chemoresistance and cancer stem cell subpopulation of the co-cultured TNBC cells. Mechanistically, XPS administration led to a reduction in CXCL1 cargo in EV-dead, and thereby attenuated its activation effect on macrophage polarization into M2 phenotype through the transcriptional downregulation of PD-L1 expression. Furthermore, XPS effectively reduced the number of EV-dead from TNBC cells by inhibiting CXCL1-mediated intraluminal vesicle (ILV) biogenesis in multivesicular bodies (MVBs). Moreover, molecular explorations revealed that XPS impaired ILV biogenesis by disrupting the RAB31/FLOT2 complex via suppressing the CXCL1/Myc signaling. Importantly, XPS significantly chemosensitized paclitaxel to inhibit TNBC growth and metastasis in vivo by suppressing EV-deadCXCL1-induced PD-L1 activation and M2 polarization of macrophages.

This pioneering study not only sheds novel light on EV-deadCXCL1 as a potential therapeutic target to suppress TNBC chemoresistance and metastasis, but also provides XPS as a promising adjuvant formula to chemosensitize TNBC by remodeling EV-deadCXCL1-mediated immunosuppressive TME.

Sturgeon has a long lifespan and slow evolutionary rate due to their powerful endogenous antioxidant system. This work aimed to assess the in vitro and in vivo antioxidant activity of sturgeon extracts from both muscle and roe. The extraction process without enzyme hydrolysis is not only simple, but also can produce extracts with better free radicals scavenging abilities than enzymatic hydrolysates in both cellular and in vivo experiments. Moreover, in mouse models with liver injury and immunosuppression treatment, the sturgeon extracts demonstrated strong hepatoprotective and immune-enhancing functions, comparable to vitamin C and ginseng extract supplements, which were attributed to abundant antioxidant peptides of the extracts. The 15 isolated peptides exhibited diverse free radical scavenging ability. Therefore, the sturgeon extracts showed high potential to be applied in food and biomedical industries.

The Macrophage-inducible C-type lectin (Mincle) is a pattern-recognition receptor (PRR), which has shown much promise as a molecular target for the development of TH1/TH17-skewing vaccine adjuvants. In 2009, the first non-proteinaceous Mincle ligands, trehalose dimycolate (TDM) and trehalose dibehenate (TDB), were identified. This prompted a search for other Mincle agonists and the exploration of Mincle agonists as vaccine adjuvants for both preventative and therapeutic (anti-cancer) vaccines. In this review, we discuss those classes of Mincle agonists that have been explored for their adjuvant potential. These Mincle agonists have been used as stand-alone adjuvants or in combination with other pathogen-associated molecular patterns (PAMPs) or immunomodulatory agents. We will also highlight recently identified Mincle ligands with hitherto unknown adjuvanticity. Conjugate vaccines that contain covalently linked adjuvants and/or adjuvant-antigen combinations are also presented, as well as the different formulations (e.g., oil-in-water emulsions, liposomes, and particulate delivery systems) that have been used for the codelivery of antigens and adjuvants. Insofar the reader is presented with a thorough review of the potential of Mincle-mediated vaccine adjuvants, including historical context, present-day research and clinical trials, and outstanding research questions, such as the role of ligand presentation and Mincle clustering, which, if better understood, will aid in the development of the much-needed TH1/TH17-skewing vaccine adjuvants.

Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant widely utilized in industrial manufacturing and daily life, leading to significant environmental accumulation and various public health issues. This study aims to characterize spliceosome-associated protein 130 (SAP130) as a key mediator of crosstalk between hepatocytes and macrophages, elucidating its role in PFOS-induced liver inflammation. The data demonstrate that PFOS exposure induces ferroptosis in mouse liver and AML12 cells. During ferroptosis, SAP130 is released from injured hepatocytes into the microenvironment, binding to macrophage-inducible C-type lectin (Mincle) and activating the Mincle/Syk signaling pathway in macrophages, ultimately promoting M1 polarization and exacerbating liver injury. Treatment with the ferroptosis inhibitor Ferrostatin-1 reduces SAP130 release, inhibits Mincle/Syk signaling activation, and mitigates inflammatory response. Furthermore, siSAP130 suppresses the activation of the Mincle signaling pathway and M1 polarization in BMDM cells. Conversely, treatment with the ferroptosis agonist Erastin enhances paracrine secretion of SAP130 and exacerbates inflammation. These findings emphasize the significance of hepatocyte-macrophage crosstalk as a critical pathway for PFOS-induced liver injury in mice while highlighting SAP130 as a pivotal regulator of ferroptosis and inflammation, thereby elucidating the potential mechanism of PFOS-induced liver injury.

Tumor-associated macrophages (TAMs) play a pivotal role in sculpting the tumor microenvironment and influencing cancer progression, particularly through their interactions with various forms of regulated cell death (RCD), including apoptosis, pyroptosis, ferroptosis, and necroptosis. This review examines the interplay between TAMs and these RCD pathways, exploring the mechanisms through which they interact to promote tumor growth and advancement. We examine the underlying mechanisms of these intricate interactions, emphasizing their importance in cancer progression and treatment. Moreover, we present potential therapeutic strategies for targeting TAMs and manipulating RCD to enhance anti-tumor responses. These strategies encompass reprogramming TAMs, inhibiting their recruitment, and selectively eliminating them to enhance anti-tumor functions, alongside modulating RCD pathways to amplify immune responses. These insights offer a novel perspective on tumor biology and provide a foundation for the development of more efficacious cancer therapies.

U2AF homology motif kinase 1 (UHMK1) is a newly discovered molecule that may have multiple functions. Recent studies have revealed that UHMK1 had aberrant expression in many tumors and was associated with tumor progression. However, UHMK1 was rarely reported in oral squamous cell carcinoma (OSCC).

In this study, Western blot, quantitative real-time polymerase chain reaction (PCR), and immunohistochemistry were used to detect the expression of UHMK1 in OSCC and peritumoral non-neoplastic tissues. Then, its relationship with clinicopathologic parameters was analyzed. The Kaplan-Meier method and Cox regression model were used to analyze the effects of UHMK1 expression on the prognosis and survival of OSCC patients.

Our results showed that UHMK1 had higher expression in OSCC tissues compared with in peritumoral non-neoplastic tissues, and its high expression was associated with high TNM stage and lymph node metastasis. High UHMK1 expression was related to short overall and disease-free survival times. Moreover, UHMK1 expression was identified as an independent prognostic factor that influences overall and disease-free survival of OSCC patients.

High expression of UHMK1 is associated with the poor prognosis of patients, and it can be used as a potential prognostic molecule for OSCC.

Pancreatic cancer is a highly lethal malignancy, and its diagnosis and treatment continue to pose significant challenges. Despite advancements in surgical and comprehensive treatment methods, the five-year survival rate remains below 12 %. With the rapid development of microbiome science, the gut and oral microbiota, which are readily accessible and can be sampled non-invasively, have emerged as a novel area of interest in pancreatic cancer research. Dysbiosis in these microbial communities can induce persistent inflammatory responses and affect the host's immune system, promoting cancer development and impacting the efficacy of treatments like chemotherapy and immunotherapy. This review provides an up-to-date overview of the roles of both gut and oral microbiota in the onset, progression, diagnosis, and treatment of pancreatic cancer. It analyzes the potential of utilizing these microbiomes as biomarkers and therapeutic targets from a clinical application perspective. Furthermore, it discusses future research directions aimed at harnessing these insights to advance the diagnosis and treatment strategies for pancreatic cancer. By focusing on the microbiome's role in clinical and translational medicine, this review offers insights into improving pancreatic cancer diagnosis and treatment outcomes.

PANoptosis is a cell death pathway involved in pyroptosis, apoptosis and necrosis, and plays a key role in the development of malignant tumors. However, the molecular signature of PANoptosis in colorectal cancer (CRC) prognosis has not been thoroughly explored. The present study aimed to develop a novel prognostic model based on PANoptosis-related genes in CRC.

We initially included transcriptome data of 404 CRC samples from The Cancer Genome Atlas (TCGA) cohort and identified differentially expressed genes related to PANoptosis. We then employed Cox, least absolute shrinkage and selection operator (LASSO) regression, and Random Forest methods to determine the prognostic value and constructed a PANoptosis prognostic model, followed by the validation on both internal (TCGA) and external datasets [Nanjing Colorectal Cancer (NJCRC) and Gene Expression Omnibus (GEO), n=635]. We performed immune infiltration analysis and gene set enrichment analysis to reveal biological processes and pathways against differential risk score. Ultimately, we carried out drug sensitivity analysis to predict the response of CRC patients to diverse treatment strategies.

We constructed a predictive model based on four PANoptosis-related genes (TIMP1, CDKN2A, CAMK2B, and TLR3), with a high performance [area under the curve (AUC)1-year =0.702, AUC3-year =0.725, AUC5-year =0.668] and being an independent prognostic factor in predicting the prognosis of CRC patients. Notably, colorectal tumor with high PANoptosis risk score performed higher levels of macrophage infiltration and immune scores, but a greater reduction of Tumor Microenvironment Score (TMEscore) and DNA replication. Particularly, patients in high-risk group exhibited higher sensitivity to fluorouracil, oxaliplatin and lapatinib compared to the low-risk group.

This study highlights the prognostic potential of PANoptosis-related features in CRC, demonstrating their role as key biomarkers significantly associated with patient survival and aiding in the identification of high-risk patients, thereby advancing immunotherapy approaches.

This study aimed to investigate the molecular links and mechanisms between Crohn's disease (CD) and colorectal cancer (CRC).

This study used the Gene Expression Omnibus (GEO) database to identify Differentially expressed genes (DEGs) in CD (GSE112366) and CRC (GSE110224), analyzed by 'edgeR' and 'limma'. The Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes explored DEG functions, and the Search Tool for the Retrieval of Interacting Genes (STRING) informed the protein-protein interaction network construction visualized in Cytoscape (version 3.7.2). Cyto-Hubba identified key genes, whose biomarker potential for CD and CRC was evaluated.

The study discovered 61 DEGs, with 44 up- and 17 down-regulated, linked to immune responses and signaling pathways. CXCL1, highly expressed in colon cancer, correlated with better prognosis and lower staging. It also showed associations with immune infiltration and checkpoint molecules, suggesting a role in cancer progression and retreat.

CXCL1 may play a role in the development of colorectal cancer from inflammatory bowel disease.

From its earliest characterization, it has been recognized that there is a role for regulated (programmed) cell death in cancer. As our understanding of the different types of programmed cell death processes and their molecular control has advanced, so have the technologies that allow us to manipulate these processes to, for example, fight against cancer. In this review, we describe the roles of the different forms of regulated cell death in the development of cancer as well as their potential therapeutic exploitation. In that vein, we explore the development and use of BH3-mimetics, a unique class of drugs that can directly activate the apoptotic cell death machinery to treat cancer. Finally, we address key challenges that face the field to improve the use of these therapeutics and the efforts that are being undertaken to do so.

Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related deaths, constituting 75%-85 % of all primary liver cancers. The objective of this study was to develop a necroptosis-related gene signature using single-cell and bulk RNA sequencing to predict HCC patient prognoses.

A total of 25 key necroptosis regulators were identified from previous literature. We evaluated the necroptosis scores of different cell types using single-cell sequencing data from HCC and analyzed 168 necroptosis-related genes. The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset served as the training set for establishing a novel necroptosis-related gene risk signature, employing univariate and multivariate Cox regression analyses. Additionally, the study examined the model's relevance in immunity and immunotherapy, and predicted chemosensitivity in HCC patients based on the gene signature. The key genes were validated by the biological experiments.

Compared to other cell types, hepatoma cells displayed the lowest necroptosis scores. A new six-gene necroptosis-related signature (S100A11, MAGEC2, MAGEA6, CTP2C9, SOX4, AKR1B10) was developed using the TCGA database and validated in the ICGC database. Patients in the high-risk category had poorer prognoses, with the risk score serving as an independent prognostic indicator beyond other clinical factors. These high-risk patients also exhibited greater immune infiltration but demonstrated a weaker anti-tumor response due to elevated expression of immune checkpoints. Pathways involving hypoxia, glycolysis, and P53, as well as the frequency of P53 somatic mutations, were notably heightened in the high-risk group. Additionally, the six genes in the model showed significantly different mRNA expression in hepatoma cell lines compared to normal hepatocytes, with the role of MAGEA6 in liver cancer being elucidated through critical experiments.

This study successfully developed a six-gene necroptosis-related signature to predict prognoses in HCC patients. It further explored the roles of necroptosis in hepatoma cells and the tumor microenvironment.