Cellular Oncology最新文献

{"title":"From benign neurofibromas to malignant peripheral nerve sheath tumors (MPNST): a gaming among multiple factors.","authors":"Yanan Yu, Chengjiang Wei, Minghui Yue, Cheng Zhang, Yixiao Wang, Zhichao Wang","doi":"10.1007/s13402-025-01054-9","DOIUrl":"10.1007/s13402-025-01054-9","url":null,"abstract":"<p><p>Almost all patients of Neurofibromatosis Type I (NF1) develop benign peripheral nerve tumors called neurofibromas, which are derived from neural crest Schwann cell lineage progenitors with biallelic NF1 gene mutations. More than 90% of NF1 patients develop dermal neurofibromas (DN), and 25-50% develop plexiform neurofibromas (PN). In 8-13% of individuals with NF1, PN can transform into malignant peripheral nerve sheath tumors (MPNSTs), a type of nerve soft tissue sarcoma that is the main cause of mortality of NF1 patients. In addition to arising from benign neurofibromas (50%), MPNSTs can also occur spontaneously (~40%) or following radiation therapy (~10%). Treatment for MPNST is limited to complete resection with negative margins. Still, the high recurrence of MPNST is a major concern. However, full resection of the pre-malignant lesions can largely reduce the recurrence and mortality of patients. So, early diagnosis and distinguishing malignancy from benign and premalignant lesions are particularly important. During the progression from benign neurofibromas to malignancy, a variety of changes including tumor morphology, genetic mutations, expression of multiple signaling pathways-related proteins and genome instability gradually occur. In this review, we detail these changes with the goals of identifying the histological and/or molecular signs of malignancy initiation, and an optimal therapeutic intervention window, to inhibit tumor progression and reduce the rate of mortality.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"841-857"},"PeriodicalIF":6.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143763039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibroblast-derived PI16 enhances tumor immune-suppressive microenvironment via inducing Tregs differentiation.","authors":"Daqin Suo, Lily Liang, Zengfei Xia, Ying Zhang, Tingting Zeng, Shuangjiang Li, Xin-Yuan Guan, Yan Li","doi":"10.1007/s13402-025-01090-5","DOIUrl":"https://doi.org/10.1007/s13402-025-01090-5","url":null,"abstract":"<p><strong>Purpose: </strong>Esophageal squamous cell carcinoma (ESCC) is aggressive with a poor prognosis. The tumor microenvironment (TME) significantly affects tumor progression and therapy resistance. Previous work has shown that fibroblasts in metastatic lymph nodes can confer cisplatin resistance to ESCC cells via PI16 (peptidase inhibitor 16). This study investigates the role of fibroblast-derived PI16 in the ESCC TME.</p><p><strong>Methods: </strong>Public single-cell RNA sequencing (scRNA-seq) data for ESCC were analyzed. A cell co-culture assay was performed to evaluate regulatory T cells (Tregs) differentiation from naïve CD4⁺ T cells. Immunoprecipitation and mass spectrometry examined PI16's mechanism in Treg differentiation. In vitro and in vivo assays were conducted to explore fibroblast-derived PI16's function. Additionally, multiplex fluorescent immunohistochemistry (mfIHC) was performed.</p><p><strong>Results: </strong>Analyses of the scRNA-seq dataset (GSE203115) reveal that fibroblasts can be classified into PI16 ⁺ and PI16^- subclusters based on PI16 expression levels. PI16 induces Treg differentiation from naïve CD4⁺ T cells through a DOCK2-dependent mechanism. Treatment with a DOCK2 inhibitor significantly inhibits PI16-induced Treg differentiation and increases Teff cell infiltration in vivo. Moreover, upregulation of PI16 in the tumor stroma is associated with poorer long-term survival outcomes in patients with ESCC.</p><p><strong>Conclusions: </strong>PI16⁺ fibroblasts promote the differentiation of Tregs from naïve CD4⁺ T cells through interaction with DOCK2. Upregulation of PI16 in the tumor stroma is associated with poorer long-term survival outcomes in patients with ESCC. Given the accumulating evidence on the therapeutic impact of targeting the TME, PI16⁺ fibroblasts emerge as a promising novel therapeutic target to overcome tumor immune suppression.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144689019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A diagnostic model based on transcriptomic analysis reveals inflammation as a potential prognosis factor for hepatoblastoma with hepatocellular carcinoma features.","authors":"Yuhua Shan, Min Zhang, Hongxiang Gao, Lei Zhang, Chenjie Xie, Jiquan Zhou, Liyuan Yang, Ji Ma, Qiuhui Pan, Zhen Zhang, Min Xu, Song Gu","doi":"10.1007/s13402-025-01077-2","DOIUrl":"https://doi.org/10.1007/s13402-025-01077-2","url":null,"abstract":"<p><strong>Introduction: </strong>Hepatoblastoma (HB) with hepatocellular carcinoma (HCC) features (HBHF) is a rare liver malignancy. Due to its rarity and diverse histological presentations, the prognosis of HBHF remains controversial, and diagnostic differentiation poses significant challenges. To enable more accurate outcome evaluation and targeted therapeutic strategies, rapid, comprehensive, and cost-effective methods are needed to complement histopathological evaluation.</p><p><strong>Methods: </strong>In this study, we conducted transcriptomic profiling on an HBHF cohort from our center and developed a machine-learning algorithm to quantify HCC-like expression features in HB tumors. Given overlapping histopathological and molecular charateristicss between HBHF and HCC, we further investigated shared risk factors associated with HBHF prognosis.</p><p><strong>Results: </strong>Significantly poorer outcomes in HBHF patients suggest fundamental biological distinctions from classical HB. Transcriptomic analysis revealed comparable somatic mutation profiles between HB and HBHF cohorts but identified inflammation activation, rather than specific mutations, as a key high-risk factor in HBHF. Clinical outcomes aligned with risk stratification generated by our quantification model.</p><p><strong>Conclusions: </strong>HBHF represents a distinct transitional entity between HB and HCC, exhibiting markedly worse clinical outcomes than HB. Our transcriptome-based computational model effectively discriminates HBHF and predicts its prognostic risk. Importantly, inflammatory activation emerges as a critical driver of tumor aggressiveness in this subtype.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S100A9 promotes resistance to anti-PD-1 immunotherapy in hepatocellular carcinoma by degrading PARP1 and activating the STAT3/PD-L1 pathway.","authors":"Xianwei Zhou, Chu Qiao, Xuehui Chu, Yajing Yang, Haoran Man, Jingxin Liu, Yunzheng Li, Zhu Xu, Huan Li, Xiaodong Shan, Zaowu Lian, Yanjun Lu, Weihong Wang, Decai Yu, Xitai Sun, Binghua Li","doi":"10.1007/s13402-025-01087-0","DOIUrl":"https://doi.org/10.1007/s13402-025-01087-0","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs), such as anti-programmed cell death protein-1 (PD-1) immunotherapy, have emerged as promising treatments for advanced hepatocellular carcinoma (HCC), significantly improving clinical outcomes. However, resistance to ICIs remains a major challenge, and the underlying mechanisms of this resistance are not yet fully understood. This study aimed to investigate the role of S100 calcium-binding protein A9 (S100A9) in mediating resistance to anti-PD-1 therapy.</p><p><strong>Approach and results: </strong>We conducted RNA sequencing (RNA-seq) on tumor samples from anti-PD-1 responders and non-responders in HCC patients. Differential expression analysis identified S100A9 as a potential driver gene of resistance to anti-PD-1 therapy. Subcutaneous tumor models and an orthotopic HCC model established via hydrodynamic transfection were utilized to evaluate the impact of S100A9 on the efficacy of PD-1 therapy. Our findings revealed that S100A9 promotes resistance to anti-PD-1 therapy in HCC. Mechanistically, S100A9 directly interacted with PARP1 and induced its degradation via the ubiquitin-proteasome pathway. This process increased STAT3 phosphorylation at Tyr705, thereby enhancing PD-L1 transcription. Notably, treatment with the S100A9 inhibitor Tasquinimod significantly improved the efficacy of anti-PD-1 therapy in HCC.</p><p><strong>Conclusions: </strong>Our study reveals that S100A9 facilitates immune evasion in HCC by enhancing PARP1 ubiquitination, STAT3 phosphorylation, and PD-L1 expression. Furthermore, combining S100A9 inhibitors with anti-PD-1 antibodies markedly enhances the therapeutic efficacy of ICIs in HCC. These findings highlight S100A9 as a potential therapeutic target for overcoming resistance to immunotherapy in HCC.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EGFR blockade confers sensitivity to pan-RAS inhibitors in KRAS-mutated cancers.","authors":"Junling Han, Bo Yu, Jianan Jing, Xiaoyu He, Yunfen Hua, Guotai Xu","doi":"10.1007/s13402-025-01075-4","DOIUrl":"https://doi.org/10.1007/s13402-025-01075-4","url":null,"abstract":"<p><strong>Introduction: </strong>KRAS is one of the most commonly occurring mutated oncogene in human cancers. Development of KRAS G12C or G12D inhibitors exhibit promising clinical activities, but patients harboring other hotspot KRAS mutations cannot benefit from those strategies. Recent development in pan-RAS inhibitors have broad therapeutic implications and merit clinical investigation. However, intrinsic and acquired drug resistance caused by tumor heterogeneity greatly limit the clinical application, posing a significant challenge in this field.</p><p><strong>Results: </strong>In this study, through CRISPR/Cas9 sgRNA screening using a human kinome sgRNA library, EGFR was discovered to correlate with the sensitivity of KRAS-mutated tumors to pan-RAS inhibitor RMC-7977. Through multiple in vitro cell proliferation or viability assays, EGFR loss or pharmacological EGFR inhibition significantly enhances the effectiveness of pan-RAS inhibitors in multiple KRAS^G12C or KRAS^G12D cancer cell lines, disregarding their cellular origins. Mechanistically, co-inhibition of EGFR and pan-RAS may further dampen the RTK-RAS-RAF-MEK-ERK pathway activation than either alone, thereby enhancing the anti-tumor activity of pan-RAS inhibitors. Strikingly, with the LL/2 syngeneic mice tumor model, the combination of pan-RAS inhibitors and EGFR inhibitors demonstrated more significant in vivo therapeutic efficacy compared to either single agent.</p><p><strong>Conclusion: </strong>In conclusion, this study employed high-throughput CRISPR/Cas9 sgRNA screening to identify the enhanced anti-cancer effects when combining EGFR inhibitors with pan-RAS inhibitors in multiple human KRAS-mutated cancer cell lines as well as a mouse syngeneic tumor model. This synergy underscores the potential for a combinational therapy strategy, leveraging EGFR and pan-RAS inhibitors to improve treatment outcomes for patients with KRAS-driven cancers.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell and bulk transcriptome analysis identifies B-cell subpopulations and associated cancer subtypes with distinct clinical and molecular characteristics.","authors":"Yin He, Li Zhao, Yufen Zheng, Xiaosheng Wang","doi":"10.1007/s13402-025-01082-5","DOIUrl":"https://doi.org/10.1007/s13402-025-01082-5","url":null,"abstract":"<p><strong>Backgroud: </strong>Previous studies have identified B cell subpopulations with pro- and anti-tumoral activities, while the clinical relevance of B cell subpopulations-specific markers in pan-cancer remains understudied.</p><p><strong>Methods: </strong>We integrated 14 scRNA-seq datasets (102,504 cells from 424 patients, 15 cancer types) to identify B cell subpopulations via unsupervised clustering. We characterized their functional dynamics and prognostic relevance through analyzing single-cell, bulk and spatial transcriptomic data. Moreover, using B cell subpopulations-specific gene signatures, we constructed models for predicting cancer prognosis and immunotherapy response.</p><p><strong>Results: </strong>We identified eight B cell subpopulations (b00-b07) which were classified into naive, plasma, memory, germinal center (GC), and cycling B cells. Trajectory analysis revealed b02-naive and b04-GC cells in early phases, evolving into b01- and b03-plasma/b05- and b06-memory/b07-cycling and b05-memory subpopulations. Anti-tumor responses were activated in early pseudotime, complement/immunoglobulin pathways peaked in mid-pseudotime, and energy metabolism increased in late-pseudotime. The enrichment of b07-cycling and b04-GC was negatively correlated with cancer prognosis, while b02-naive had a positive correlation. Spatial transcriptomic analysis showed clustered b00-b06 versus dispersed b07 cells, with b04-GC and b07-cycling cells distant from tertiary lymphoid structure cores. Based on the expression profiles of 1,047 B cell subpopulations-specific signatures, we identified three pan-cancer subtypes with distinct clinical and molecular characteristics. Using 13 B cell subpopulations-specific signatures, we constructed models to accurately predict cancer survival outcomes and immunotherapy response.</p><p><strong>Conclusions: </strong>Our study delineates eight B cell subpopulations with distinct prognostic relevance. Signature-based stratification and models underscore their clinical relevance in cancer outcomes and therapy response, advancing understanding of B cell heterogeneity in cancer.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactylation: the regulatory code of cellular life activity and a barometer of diseases.","authors":"Xuebing Xu, Xuming Wu, Dandan Jin, Jie Ji, Tong Wu, Mengxiang Huang, Junpeng Zhao, Zihan Shi, Lirong Zhou, XuYang He, Yuxuan Huang, Shihai Xuan, Mingbing Xiao, Xiaolei Cao","doi":"10.1007/s13402-025-01083-4","DOIUrl":"https://doi.org/10.1007/s13402-025-01083-4","url":null,"abstract":"<p><p>Lactylation is a novel post-translational modification of proteins, which has attracted extensive attention since its discovery. Lactylation takes lactate, a common metabolite, as its substrate and mediates the modification under the action of lactyltransferases. Although lactylation modification was initially found to undergo in histones, subsequent studies have shown that this novel modification is not limited to specific protein classes, and can undergo in both histone and non-histone proteins. Lactylation has been proved to play an important regulatory role in a variety of diseases, including tumors, metabolic disorders, cardiovascular diseases, and neurodegenerative diseases. Given the tumor properties of its substrate lactate, lactylation has been most extensively studied in tumors, and as a result, we have gained a deeper understanding of the potential molecular mechanisms and regulatory roles of lactylation in tumors. In this paper, we will summarize the regulatory and functional mechanisms of lactylation, explain the cellular processes in which lactylation is involved and its association with various diseases, and look forward to the future clinical application of lactylation.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy of CDK4/6 Inhibition in colorectal cancer and the role of p16 expression in predicting drug resistance.","authors":"Julia S Schneider, Najib Ben Khaled, Liangtao Ye, Ralf Wimmer, Linda Hammann, Alexander Weich, Christoph Suppan, Ujjwal M Mahajan, Andreas Jung, Jörg Kumbrink, Gerald Denk, Monika Rau, Volker Kunzmann, Solveig Kuss, Jens Neuman, Julia Mayerle, Andreas Geier, Heike M Hermanns, Enrico N De Toni, Florian P Reiter","doi":"10.1007/s13402-025-01080-7","DOIUrl":"https://doi.org/10.1007/s13402-025-01080-7","url":null,"abstract":"<p><strong>Introduction: </strong>Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. The use of sequential polychemotherapies has improved the survival of patients with advanced metastatic disease. However, the survival rates achieved are low, and chemotherapy-related side effects are significant. Therefore, new, efficient, and tolerable therapies are urgently needed. In this study, we investigate the efficacy of pharmacological cyclin D-dependent kinase (CDK) 4/6 inhibition and explore the relevance of p16 as predictors of susceptibility to CDK 4/6 therapy.</p><p><strong>Materials and methods: </strong>CDK 4/6 inhibitors were evaluated in native and FOLFOX- or ribociclib-resistant CRC, hepatocellular carcinoma (HCC), and breast cancer (BC) cell lines using viability, colony formation, and flow cytometry (FC)-based assays. Western blotting was employed to assess the expression of Rb and members of the INK4 family. SiRNA-based knockdown of CDK4/6 was utilized to gain insights into mechanisms of action or resistance. Tissue from 185 CRC patients was examined for the expression of p16 and its relevance for progression-free and overall survival. The prognostic relevance of cyclin-dependent kinase inhibitor 2 A (CDKN2A) mRNA expression data was derived from The Cancer Genome Atlas (TCGA) data.</p><p><strong>Results: </strong>Ribociclib demonstrates significant antitumoral effects in various CRC, HCC, and BC cell lines, similar to two other approved CDK4/6 inhibitors (palbociclib and abemaciclib). Ribociclib-resistant cell lines (Hep-3B, HCC-1937, and BT-549) exhibited higher p16 expression compared to ribociclib-sensitive cell lines. In ribociclib-sensitive cell lines, CDK4/6 inhibition led to G1 phase arrest, whereas resistant cells did not exhibit such effects. A similar phenotype could be observed upon dual siRNA based CDK4/6 knockdown in ribociclib-sensitive HuH-7 and ribociclib-resistant Hep-3B cell lines. All CRC cell lines tested showed sensitivity to ribociclib, including the FOLFOX-resistant SW620 cell line. Low mRNA expression of CDKN2A (p16) was associated with favorable prognosis in CRC patients. No prognostic significance was found for p16 protein expression in an early-stage CRC cohort (n = 185).</p><p><strong>Conclusion: </strong>Ribociclib demonstrates significant antitumoral effects across a large panel of cancer cell lines and chemoresistant models, especially in CRC. Resistance towards ribociclib is associated with high p16 expression, which is a negative prognostic marker for patients with CRC. Our findings underscore p16 as a promising biomarker for predicting ribociclib responsiveness and emphasize the need for further mechanistic studies and combination therapy approaches to overcome resistance in p16^high patients.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OTUD1 downregulates PD-L1 expression by deubiquitinating STAT3 and promotes the immune response in CcRCC.","authors":"Huaiyuan Liang, Xinlin Liu, Wanyang Guo, Wei Xiong, Da Ren, Wentao Liu","doi":"10.1007/s13402-025-01079-0","DOIUrl":"https://doi.org/10.1007/s13402-025-01079-0","url":null,"abstract":"<p><strong>Background: </strong>Clear cell renal cell carcinoma (ccRCC) is the most common malignant tumor of the urinary system and has the highest mortality rate. In addition to surgical tumor reduction, systemic drug therapy is the most important treatment method for metastatic renal cancer. In recent years, immunotherapeutic drugs represented by PD-1 antibodies have been used in the treatment of metastatic ccRCC and achieved good therapeutic effects. However, due to the occurrence of immune escape, only about 50-60% of patients with advanced renal cancer can significantly benefit from immunotherapy. The mechanism of immune escape is extremely complex and has not been clarified. We intend to delve into the driving mechanisms of immune evasion in ccRCC and explore potential targets for intervention.</p><p><strong>Methods: </strong>In this study, we analyzed the expression of OTUD1 and related pathways in ccRCC through TCGA, GEO dataset, and cBioPortal web tool. At the same time, a mouse model of allogeneic transplanted clear cell renal cell carcinoma was constructed, and the effect of OTUD1 on anti-PD1 antibody therapy was discussed. Experiments such as co-IP, flow cytometry, and RNA-seq analysis were used to investigate the mechanism by which OTUD1 regulates immunity through STAT3.</p><p><strong>Results: </strong>This study reveals that OTUD1 suppresses PD-L1 expression and enhances antitumor immunity in clear cell renal cell carcinoma (ccRCC) by deubiquitinating and stabilizing STAT3, thereby inhibiting its nuclear translocation and transcriptional activity. As a key regulator of the JAK-STAT pathway, OTUD1 disrupts PD-1/PD-L1-mediated immune evasion, offering a potential therapeutic strategy to improve immunotherapy responses in ccRCC. These findings highlight the OTUD1-STAT3-PD-L1 axis as a novel mechanism for overcoming immune checkpoint resistance.</p><p><strong>Conclusion: </strong>Overall, we demonstrate that OTUD1 interacts with STAT3 and deubiquitinates, inhibits its nuclear translocation and activity, and ultimately inhibits immune evasion of ccRCC by downregulating PD-L1.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":6.6,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thymidine kinase 1 indicates resistance to immune checkpoint plus tyrosine kinase inhibition in renal cell carcinoma.","authors":"Jiajun Wang, Xianglai Xu, Ying Wang, Yanjun Zhu","doi":"10.1007/s13402-025-01048-7","DOIUrl":"10.1007/s13402-025-01048-7","url":null,"abstract":"<p><strong>Purpose: </strong>Immune checkpoint plus tyrosine kinase inhibition (IO + TKI) has emerged as the first-line therapy in metastatic renal cell carcinoma (RCC), but no biomarker can predict its efficacy. Thymidine kinase 1 (TK1) is closely associated with immune evasion in tumors.</p><p><strong>Methods: </strong>Metastatic RCC patients treated by IO + TKI were enrolled from two cohorts (ZS-MRCC, n = 45; Javelin-101, n = 726). High-risk localized RCC were also enrolled (ZS-HRRCC, n = 40). TK1 was assessed by RNA-sequencing in all cohorts, and the immune contexture was assessed by flow cytometry and immunohistochemistry.</p><p><strong>Results: </strong>Higher TK1 expression was found in patients resistant to IO + TKI therapy (p = 0.025). High-TK1 group showed poor progression-free survival (PFS) in both the ZS-MRCC cohort (P = 0.008) and the Javelin-101 cohort (P = 0.036). By multivariate Cox regression, high-TK1 was determined as an independent factor for poor PFS (hazard ratio (HR) = 3.855, P = 0.002). High-TK1 expression was associated with decreased granzyme B⁺ CD8⁺ T cells (ρ=-0.22, P = 0.18), increased PD1⁺ CD4⁺ T cells (ρ = 0.33, P = 0.04), increased PDL1⁺ macrophages (ρ = 0.45, P < 0.001), and increased regulatory T cells (ρ = 0.35, P = 0.03). A novel random forest (RF) risk score was built by machine learning based on TK1 and immunologic parameters. Combined IO + TKI therapy surpassed sunitinib monotherapy in the low RF risk score group (HR = 0.158, P < 0.001), but was inferior to sunitinib in the high RF risk score group (HR, 2.195, P < 0.001).</p><p><strong>Conclusion: </strong>High-TK1 expression could be a potential indicator for therapeutic resistance, poor PFS and immune evasion in metastatic RCC under IO + TKI therapy. The novel RF risk score may help stratify patients for IO + TKI therapy.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":"775-787"},"PeriodicalIF":6.6,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}