Senescence-associated signature based on immunotherapy response sequencing reveals PPIL3 as target for bladder cancer treatment and prognosis prediction
BackgroundBladder cancer (Bca) remains a major genitourinary malignancy with unmet needs in immunotherapy optimization. Despite advancements in immune checkpoint inhibitors (ICIs), challenges persist, including low response rates and drug resistance. Emerging evidence links tumor cell senescence to...
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Frontiers Media S.A.
2025-06-01
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1613056/full |
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| author | Kaixuan Du Kaixuan Du Ning Kang Ning Kang Yuda Lin Yuda Lin Kaipeng Jia Kaipeng Jia Chong Shen Chong Shen Zhouliang Wu Zhouliang Wu Hailong Hu Hailong Hu |
| author_facet | Kaixuan Du Kaixuan Du Ning Kang Ning Kang Yuda Lin Yuda Lin Kaipeng Jia Kaipeng Jia Chong Shen Chong Shen Zhouliang Wu Zhouliang Wu Hailong Hu Hailong Hu |
| author_sort | Kaixuan Du |
| collection | DOAJ |
| description | BackgroundBladder cancer (Bca) remains a major genitourinary malignancy with unmet needs in immunotherapy optimization. Despite advancements in immune checkpoint inhibitors (ICIs), challenges persist, including low response rates and drug resistance. Emerging evidence links tumor cell senescence to immunotherapy efficacy, yet predictive biomarkers are lacking.MethodsWe integrated genomic sequencing of real-world Bca patients receiving low-dose paclitaxel combined with immunotherapy to identify differentially expressed genes (DEGs) between responders and non-responders. By intersecting DEGs with senescence-related gene sets (SRGs), we derived senescence-related DEGs (SRDEGs) and constructed a senescence-immunotherapy model (SIM) via TCGA-based multi-regression analysis.ResultsThe SIM, validated across three independent cohorts, demonstrated superior prognostic accuracy for overall survival (OS) compared to clinical parameters. High SIM scores correlated with immunosuppressive tumor microenvironments (TME). Drug sensitivity analysis revealed differential responses to cisplatin and paclitaxel between SIM subgroups. Critically, real-world validation confirmed SIM’s predictive power for immunotherapy response. Multi-omics profiling further highlighted PPIL3 as a hub gene driving senescence and suppressing proliferation. In vitro experiments showed elevated expression of PPIL3 facilitated the concentration of senescence markers (SA-β-gal) and inhabited tumor cell proliferation.ConclusionsThis study establishes SIM as a dual-purpose tool for survival prediction and immunotherapy stratification, and suggested that PPIL3 could be a therapeutic target to enhance the efficacy of Bca by regulating senescence. |
| format | Article |
| id | doaj-art-abea82d45d6540aaa3cf73f4415ae01c |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-abea82d45d6540aaa3cf73f4415ae01c2025-08-20T03:29:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.16130561613056Senescence-associated signature based on immunotherapy response sequencing reveals PPIL3 as target for bladder cancer treatment and prognosis predictionKaixuan Du0Kaixuan Du1Ning Kang2Ning Kang3Yuda Lin4Yuda Lin5Kaipeng Jia6Kaipeng Jia7Chong Shen8Chong Shen9Zhouliang Wu10Zhouliang Wu11Hailong Hu12Hailong Hu13Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin, ChinaTianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, ChinaDepartment of Urology, The Second Hospital of Tianjin Medical University, Tianjin, ChinaTianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, ChinaDepartment of Urology, The Second Hospital of Tianjin Medical University, Tianjin, ChinaTianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, ChinaDepartment of Urology, The Second Hospital of Tianjin Medical University, Tianjin, ChinaTianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, ChinaDepartment of Urology, The Second Hospital of Tianjin Medical University, Tianjin, ChinaTianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, ChinaDepartment of Urology, The Second Hospital of Tianjin Medical University, Tianjin, ChinaTianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, ChinaDepartment of Urology, The Second Hospital of Tianjin Medical University, Tianjin, ChinaTianjin Key Laboratory of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, ChinaBackgroundBladder cancer (Bca) remains a major genitourinary malignancy with unmet needs in immunotherapy optimization. Despite advancements in immune checkpoint inhibitors (ICIs), challenges persist, including low response rates and drug resistance. Emerging evidence links tumor cell senescence to immunotherapy efficacy, yet predictive biomarkers are lacking.MethodsWe integrated genomic sequencing of real-world Bca patients receiving low-dose paclitaxel combined with immunotherapy to identify differentially expressed genes (DEGs) between responders and non-responders. By intersecting DEGs with senescence-related gene sets (SRGs), we derived senescence-related DEGs (SRDEGs) and constructed a senescence-immunotherapy model (SIM) via TCGA-based multi-regression analysis.ResultsThe SIM, validated across three independent cohorts, demonstrated superior prognostic accuracy for overall survival (OS) compared to clinical parameters. High SIM scores correlated with immunosuppressive tumor microenvironments (TME). Drug sensitivity analysis revealed differential responses to cisplatin and paclitaxel between SIM subgroups. Critically, real-world validation confirmed SIM’s predictive power for immunotherapy response. Multi-omics profiling further highlighted PPIL3 as a hub gene driving senescence and suppressing proliferation. In vitro experiments showed elevated expression of PPIL3 facilitated the concentration of senescence markers (SA-β-gal) and inhabited tumor cell proliferation.ConclusionsThis study establishes SIM as a dual-purpose tool for survival prediction and immunotherapy stratification, and suggested that PPIL3 could be a therapeutic target to enhance the efficacy of Bca by regulating senescence.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1613056/fullsenescenceimmunotherapybladder cancerPPIL3therapeutic target |
| spellingShingle | Kaixuan Du Kaixuan Du Ning Kang Ning Kang Yuda Lin Yuda Lin Kaipeng Jia Kaipeng Jia Chong Shen Chong Shen Zhouliang Wu Zhouliang Wu Hailong Hu Hailong Hu Senescence-associated signature based on immunotherapy response sequencing reveals PPIL3 as target for bladder cancer treatment and prognosis prediction Frontiers in Immunology senescence immunotherapy bladder cancer PPIL3 therapeutic target |
| title | Senescence-associated signature based on immunotherapy response sequencing reveals PPIL3 as target for bladder cancer treatment and prognosis prediction |
| title_full | Senescence-associated signature based on immunotherapy response sequencing reveals PPIL3 as target for bladder cancer treatment and prognosis prediction |
| title_fullStr | Senescence-associated signature based on immunotherapy response sequencing reveals PPIL3 as target for bladder cancer treatment and prognosis prediction |
| title_full_unstemmed | Senescence-associated signature based on immunotherapy response sequencing reveals PPIL3 as target for bladder cancer treatment and prognosis prediction |
| title_short | Senescence-associated signature based on immunotherapy response sequencing reveals PPIL3 as target for bladder cancer treatment and prognosis prediction |
| title_sort | senescence associated signature based on immunotherapy response sequencing reveals ppil3 as target for bladder cancer treatment and prognosis prediction |
| topic | senescence immunotherapy bladder cancer PPIL3 therapeutic target |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1613056/full |
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