Integrative analysis of immunogenic PANoptosis and experimental validation of cinobufagin-induced activation to enhance glioma immunotherapy
Abstract Background Glioma, particularly glioblastoma (GBM), is a highly aggressive tumor with limited responsiveness to immunotherapy. PANoptosis, a form of programmed cell death merging pyroptosis, apoptosis, and necroptosis, plays an important role in reshaping the tumor microenvironment (TME) an...
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| Format: | Article |
| Language: | English |
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BMC
2025-02-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03301-1 |
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| author | Yonghua Cai Heng Xiao Shuaishuai Xue Peng Li Zhengming Zhan Jie Lin Zibin Song Jun Liu Wei Xu Qixiong Zhou Songtao Qi Xi’an Zhang Ziyi Luo |
| author_facet | Yonghua Cai Heng Xiao Shuaishuai Xue Peng Li Zhengming Zhan Jie Lin Zibin Song Jun Liu Wei Xu Qixiong Zhou Songtao Qi Xi’an Zhang Ziyi Luo |
| author_sort | Yonghua Cai |
| collection | DOAJ |
| description | Abstract Background Glioma, particularly glioblastoma (GBM), is a highly aggressive tumor with limited responsiveness to immunotherapy. PANoptosis, a form of programmed cell death merging pyroptosis, apoptosis, and necroptosis, plays an important role in reshaping the tumor microenvironment (TME) and enhancing immunotherapy effectiveness. This study investigates PANoptosis dynamics in glioma and explores the therapeutic potential of its activation, particularly through natural compounds such as cinobufagin. Methods We comprehensively analyzed PANoptosis-related genes (PANoRGs) in multiple glioma cohorts, identifying different PANoptosis patterns and constructing the PANoptosis enrichment score (PANoScore) to evaluate its relationship with patient prognosis and immune activity. Cinobufagin, identified as a PANoptosis activator, was evaluated for its ability to induce PANoptosis and enhance anti-tumor immune responses both in vitro and in vivo GBM models. Results Our findings indicate that high PANoScore gliomas showed increased immune cell infiltration, particularly effector T cells, and enhanced sensitivity to immunotherapies. Cinobufagin effectively induced PANoptosis, leading to increased immunogenic cell death, facilitated tumor-associated microglia/macrophages (TAMs) polarization towards an M1-like phenotype while augmenting CD4+/CD8 + T cell infiltration and activation. Importantly, cinobufagin combined with anti-PD-1 therapy exhibited significant synergistic effects and prolonged survival in GBM models. Conclusions These findings highlight the therapeutic potential of PANoptosis-targeting agents, such as cinobufagin, in combination with immunotherapy, offering a promising approach to convert “cold” tumors into “hot” ones and improving glioma treatment outcomes. |
| format | Article |
| id | doaj-art-133c661ce76f44b787ec90c461011e10 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-133c661ce76f44b787ec90c461011e102025-02-09T12:59:50ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-02-0144112510.1186/s13046-025-03301-1Integrative analysis of immunogenic PANoptosis and experimental validation of cinobufagin-induced activation to enhance glioma immunotherapyYonghua Cai0Heng Xiao1Shuaishuai Xue2Peng Li3Zhengming Zhan4Jie Lin5Zibin Song6Jun Liu7Wei Xu8Qixiong Zhou9Songtao Qi10Xi’an Zhang11Ziyi Luo12Department of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical UniversityDepartment of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical UniversityDepartment of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical UniversityDepartment of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical UniversityDepartment of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical UniversityDepartment of Neurosurgery, Guangzhou Women and Children’s Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical UniversityNeurosurgery Center, Department of Functional Neurosurgery, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical UniversityDepartment of Neurosurgery, the 2nd affiliated hospital, Jiangxi Medical College, Nanchang UniversityDepartment of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical UniversityDepartment of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical UniversityDepartment of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical UniversityDepartment of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical UniversityDepartment of Neurosurgery, Institute of Brain Diseases, Nanfang Hospital, Southern Medical UniversityAbstract Background Glioma, particularly glioblastoma (GBM), is a highly aggressive tumor with limited responsiveness to immunotherapy. PANoptosis, a form of programmed cell death merging pyroptosis, apoptosis, and necroptosis, plays an important role in reshaping the tumor microenvironment (TME) and enhancing immunotherapy effectiveness. This study investigates PANoptosis dynamics in glioma and explores the therapeutic potential of its activation, particularly through natural compounds such as cinobufagin. Methods We comprehensively analyzed PANoptosis-related genes (PANoRGs) in multiple glioma cohorts, identifying different PANoptosis patterns and constructing the PANoptosis enrichment score (PANoScore) to evaluate its relationship with patient prognosis and immune activity. Cinobufagin, identified as a PANoptosis activator, was evaluated for its ability to induce PANoptosis and enhance anti-tumor immune responses both in vitro and in vivo GBM models. Results Our findings indicate that high PANoScore gliomas showed increased immune cell infiltration, particularly effector T cells, and enhanced sensitivity to immunotherapies. Cinobufagin effectively induced PANoptosis, leading to increased immunogenic cell death, facilitated tumor-associated microglia/macrophages (TAMs) polarization towards an M1-like phenotype while augmenting CD4+/CD8 + T cell infiltration and activation. Importantly, cinobufagin combined with anti-PD-1 therapy exhibited significant synergistic effects and prolonged survival in GBM models. Conclusions These findings highlight the therapeutic potential of PANoptosis-targeting agents, such as cinobufagin, in combination with immunotherapy, offering a promising approach to convert “cold” tumors into “hot” ones and improving glioma treatment outcomes.https://doi.org/10.1186/s13046-025-03301-1GliomaPANoptosisImmunotherapyCinobufaginTumor immune microenvironment |
| spellingShingle | Yonghua Cai Heng Xiao Shuaishuai Xue Peng Li Zhengming Zhan Jie Lin Zibin Song Jun Liu Wei Xu Qixiong Zhou Songtao Qi Xi’an Zhang Ziyi Luo Integrative analysis of immunogenic PANoptosis and experimental validation of cinobufagin-induced activation to enhance glioma immunotherapy Journal of Experimental & Clinical Cancer Research Glioma PANoptosis Immunotherapy Cinobufagin Tumor immune microenvironment |
| title | Integrative analysis of immunogenic PANoptosis and experimental validation of cinobufagin-induced activation to enhance glioma immunotherapy |
| title_full | Integrative analysis of immunogenic PANoptosis and experimental validation of cinobufagin-induced activation to enhance glioma immunotherapy |
| title_fullStr | Integrative analysis of immunogenic PANoptosis and experimental validation of cinobufagin-induced activation to enhance glioma immunotherapy |
| title_full_unstemmed | Integrative analysis of immunogenic PANoptosis and experimental validation of cinobufagin-induced activation to enhance glioma immunotherapy |
| title_short | Integrative analysis of immunogenic PANoptosis and experimental validation of cinobufagin-induced activation to enhance glioma immunotherapy |
| title_sort | integrative analysis of immunogenic panoptosis and experimental validation of cinobufagin induced activation to enhance glioma immunotherapy |
| topic | Glioma PANoptosis Immunotherapy Cinobufagin Tumor immune microenvironment |
| url | https://doi.org/10.1186/s13046-025-03301-1 |
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