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[This corrects the article DOI: 10.3389/fimmu.2025.1726408.].

[This corrects the article DOI: 10.3389/fimmu.2023.1114103.].

Regulated cell death (RCD) is considered a critical pathway in cancer therapy, contributing to eliminating cancer cells and influencing treatment outcomes. The application of RCD in cancer treatment is marked by its potential in targeted therapy and immunotherapy. As a type of RCD, PANoptosis has emerged as a unique form of programmed cell death (PCD) characterized by features of pyroptosis, apoptosis, and necroptosis but cannot be fully explained by any of these pathways alone. It is regulated by a multi-protein complex called the PANoptosome. As a relatively new concept first described in 2019, PANoptosis has been shown to play a role in many diseases, including cancer, infection, and inflammation. This study reviews the application of PCD in cancer, particularly the emergence and implication of PANoptosis in developing therapeutic strategies for cancer. Studies have shown that the characterization of PANoptosis patterns in cancer can predict survival and response to immunotherapy and chemotherapy, highlighting the potential for PANoptosis to be used as a therapeutic target in cancer treatment. It also plays a role in limiting the spread of cancer cells. PANoptosis allows for the elimination of cancer cells by multiple cell death pathways and has the potential to address various challenges in cancer treatment, including drug resistance and immune evasion. Moreover, active investigation of the mechanisms and potential therapeutic agents that can induce PANoptosis in cancer cells is likely to yield effective cancer treatments and improve patient outcomes. Research on PANoptosis is still ongoing, but it is a rapidly evolving field with the potential to lead to new treatments for various diseases, including cancer.

The demise of cells in various ways enables the body to clear unwanted cells. Studies over the years revealed distinctive molecular mechanisms and functional consequences of several key cell death pathways. Currently, the most intensively investigated programmed cell death (PCD) includes apoptosis, necroptosis, pyroptosis, ferroptosis, PANoptosis, and autophagy, which has been discovered to play crucial roles in modulating the immunosuppressive tumor microenvironment (TME) and determining clinical outcomes of the cancer therapeutic approaches. PCD can play dual roles, either pro-tumor or anti-tumor, partly depending on the intracellular contents released during the process. PCD also regulates the enrichment of effector or regulatory immune cells, thus participating in fine-tuning the anti-tumor immunity in the TME. In this review, we focused primarily on apoptosis, necroptosis, pyroptosis, ferroptosis, PANoptosis, and autophagy, discussed the released molecular messengers participating in regulating their intricate crosstalk with the immune response in the TME, and explored the immunological consequence of PCD and its implications in future cancer therapy developments.

Zhaohui Chen,1,2,* Xueyuan Zhang,1,3,* Zhicheng Deng,1,2,* Jiali Luo,1,4 Chunyang Han,1,4 Yinlun Weng1,3,4 1Shenshan Medical Center, Memorial Hospital of Sun Yat-Sen University, Shanwei, Guangdong, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Cancer Pathogenesis and Precision Diagnosis and Treatment, Shenshan Medical Center, Memorial Hospital of Sun Yat-Sen University, Shanwei, Guangdong, People’s Republic of China; 3Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China; 4Department of Neurosurgery, Shenshan Medical Center, Memorial Hospital of Sun Yat-Sen University, Shanwei, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yinlun Weng, Email wengyl5@mail.sysu.edu.cnObjective: Primary intracerebral hemorrhage (ICH) is a severe stroke subtype characterized by high mortality and disability rates, largely attributable to secondary brain injury (SBI). While programmed cell death (PCD) pathways contribute to SBI, their mechanisms remain incompletely understood. This research investigated PANoptosis, a newly defined integrated PCD pathway, and its interactions with immune responses in ICH.Methods: The transcriptomic dataset GSE24265 was analyzed to identify differentially expressed genes (DEGs), which were intersected with a PANoptosis-related gene set. PANoptosis-related DEGs were analyzed through protein-protein interaction (PPI) networks, functional enrichment, and machine learning (LASSO and Random Forest) to identify signature genes. The diagnostic utility was evaluated using nomograms and receiver operating characteristic (ROC) curves. Immune interactions were assessed using CIBERSORT. Key findings were validated in clinical specimens using qRT-PCR and Western blot.Results: We identified 50 PANoptosis-related DEGs in ICH and derived five signature genes (AKR1C2, SLC2A14, FTL, TNFRSF12A, and SLC2A3) that were significantly upregulated and had high diagnostic accuracy. These genes were implicated in an inflammatory cell death hub, as their expression correlated with altered proportions of T follicular helper and T gamma delta cells, linking PANoptosis to immune dysregulation. Experimental validation confirmed the upregulation of mRNA levels of SLC2A3, SLC2A14, and TNFRSF12A in perihematomal tissues, along with increased protein levels of SLC2A3 and SLC2A14. Functional enrichment analysis linked these genes to HIF-1, NF-κB, and TNF signaling pathways in ICH PANoptosis.Conclusion: Our study identifies PANoptosis as a pathological hub connecting SBI and neuroinflammation in ICH, with five signature genes serving as key diagnostic biomarkers. Notably, SLC2A3 was significantly elevated in peripheral blood, highlighting its potential as a non-invasive plasma biomarker for ICH. These genes likely contribute to neuroinflammation through immune crosstalk and metabolic reprogramming, offering novel mechanistic insights and potential therapeutic targets for SBI post-ICH.Keywords: intracerebral hemorrhage, PANoptosis, machine learning, immune infiltration

Soner Kocak University of Health Sciences, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, Department of Orthopaedic and Traumatology, Istanbul, TurkeyCorrespondence: Soner Kocak, University of Health Sciences, Istanbul Kanuni Sultan Suleyman Training and Research Hospital, Department of Orthopaedic and Traumatology, Istanbul, Turkey, Tel + 90 212 404 15 00 ; +90 507 344 00 01, Email dr.sonerkocak@gmail.com

PANoptosis, a new research hotspot at the moment, is a cell death pattern in which pyroptosis, apoptosis, and necroptosis all occur in the same cell population. In essence, PANoptosis is a highly coordinated and dynamically balanced programmed inflammatory cell death pathway that combines the main features of pyroptosis, apoptosis, and necroptosis. Many variables, such as infection, injury, or self-defect, may be involved in the occurrence of PANoptosis, with the assembly and activation of the PANoptosome being the most critical. PANoptosis has been linked to the development of multiple systemic diseases in the human body, including infectious diseases, cancer, neurodegenerative diseases, and inflammatory diseases. Therefore, it is necessary to clarify the process of occurrence, the regulatory mechanism of PANoptosis, and its relation to diseases. In this paper, we summarized the differences and relations between PANoptosis and the three types of programmed cell death, and emphatically expounded molecular mechanism and regulatory patterns of PANoptosis, with the expectation of facilitating the application of PANoptosis regulation in disease treatment.

Programmed cell death plays crucial roles in organismal development and host defense. Recent studies have highlighted mechanistic overlaps and extensive, multifaceted crosstalk between pyroptosis, apoptosis, and necroptosis, three programmed cell death pathways traditionally considered autonomous. The growing body of evidence, in conjunction with the identification of molecules controlling the concomitant activation of all three pathways by pathological triggers, has led to the development of the concept of PANoptosis. During PANoptosis, inflammatory cell death occurs through the collective activation of pyroptosis, apoptosis, and necroptosis, which can circumvent pathogen-mediated inhibition of individual death pathways. Many of the molecular details of this emerging pathway are unclear. Here, we describe the activation of PANoptosis by bacterial and viral triggers and report protein interactions that reveal the formation of a PANoptosome complex. Infection of macrophages with influenza A virus, vesicular stomatitis virus, , or serovar Typhimurium resulted in robust cell death and the hallmarks of PANoptosis activation. Combined deletion of the PANoptotic components caspase-1 (CASP1), CASP11, receptor-interacting serine/threonine-protein kinase 3 (RIPK3), and CASP8 largely protected macrophages from cell death induced by these pathogens, while deletion of individual components provided reduced or no protection. Further, molecules from the pyroptotic, apoptotic, and necroptotic cell death pathways interacted to form a single molecular complex that we have termed the PANoptosome. Overall, our study identifies pathogens capable of activating PANoptosis and the formation of a PANoptosome complex.

Programmed cell death is regulated by evolutionarily conserved pathways that play critical roles in development and the immune response. A newly recognized pathway for proinflammatory programmed cell death called PANoptosis is controlled by a recently identified cytoplasmic multimeric protein complex named the PANoptosome. The PANoptosome can engage, in parallel, three key modes of programmed cell death-pyroptosis, apoptosis, and necroptosis. The PANoptosome components have been implicated in a wide array of human diseases including autoinflammatory diseases, neurodegenerative diseases, cancer, microbial infections, and metabolic diseases. Here, we review putative components of the PANoptosome and present a phylogenetic analysis of their molecular domains and interaction motifs that support complex assembly. We also discuss genetic data that suggest PANoptosis is coordinated by scaffolding and catalytic functions of the complex components and propose mechanistic models for PANoptosome assembly. Overall, this review presents potential mechanisms governing PANoptosis based on evolutionary analysis of the PANoptosome components.

[This corrects the article DOI: 10.3389/fimmu.2023.1247131.].