Cancer letters最新文献

{"title":"TAp73α drives cancer metastasis via PPI-mediated derepression of the neuronal HDAC2/REST-GABBR2 axis","authors":"Nico Murr ,&nbsp;Christin Richter ,&nbsp;Shailendra K. Gupta ,&nbsp;Elke Hammer ,&nbsp;Nares Trakooljul ,&nbsp;Anja Stoll ,&nbsp;Steffen Möller ,&nbsp;Lukas E. Neumann ,&nbsp;Brigitte M. Pützer ,&nbsp;Alf Spitschak","doi":"10.1016/j.canlet.2025.217867","DOIUrl":"10.1016/j.canlet.2025.217867","url":null,"abstract":"<div><div>Metastasis is the leading cause of death in patients with malignant melanoma, yet the molecular and transcriptional mechanisms remain elusive. This study reveals a crucial role of the p53 homolog, TAp73α, in promoting melanoma metastasis. Using multi-omics approaches combining transcriptomics, proteomics, cistromics and 3D modeling, we discovered a paradigm-shifting mechanism by which TAp73α binds directly to HDAC2, disassembles the HDAC2/REST repressor complex and aberrantly triggers activation of the neuronal receptor GABBR2 in cancer cells. TAp73α-induced derepression of GABBR2 expression leads to upregulation of EMT markers, promotes cancer cell invasiveness and proliferation, and correlates with poor survival outcomes. Our findings redefine the function of p73 in cancer pathogenesis and identify the TAp73α-HDAC2/REST-GABBR2 axis as a novel driver of melanoma progression. These insights could guide future strategies on melanoma treatment.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217867"},"PeriodicalIF":9.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual blockade of PD-1 and CTLA-4 generates long-lasting immunity against irradiated glioblastoma","authors":"Mara De Martino ,&nbsp;Camille Daviaud ,&nbsp;María Cecilia Lira ,&nbsp;Kayla Hernandez-Zirofsky ,&nbsp;Claire Vanpouille-Box","doi":"10.1016/j.canlet.2025.217856","DOIUrl":"10.1016/j.canlet.2025.217856","url":null,"abstract":"<div><div>Radiation therapy (RT) can release pro-inflammatory signals to jumpstart an anti-tumor immune response. However, glioblastoma (GBM) often recurs, suggesting that RT might not act as an immune adjuvant in this disease. A possible explanation for the lack of immune stimulation is the use of irradiation regimens that do not effectively stimulate anti-tumor immunity against GBM. Here, we tested the ability of various RT schedules to elicit type I interferon (IFN-I) response and explored its synergy with immunotherapy (IT) to trigger anti-tumor immunity against GBM. Using three murine GBM models, we show <em>in vitro</em> that single dose radiation ranging from 0Gy to 20Gy and fractionated radiation schedules (i.e. 3 daily fractions of 8Gy; 3 × 8Gy and 5 daily fractions of 6Gy; 5 × 6Gy) accumulates double stranded DNA and release IFN-I related cytokines in a dose-dependent fashion; with fractionated schedules being superior in triggering cancer-cell intrinsic IFN-I responses. Side-by-side comparison of various radiation regimen <em>in vivo</em> revealed that 5 × 6Gy better control GBM across the three GBM models tested. However, the addition of anti-PD1 or anti-CTLA4 to an immunogenic radiation schedule (i.e. 5 × 6Gy) did not prolong survival of irradiated mice. Surprisingly, only the dual blockade of PD-1 and CTLA4 promoted the expansion of proliferative T cells and conveyed immunological memory against irradiated GBM. Overall, this study demonstrates that an immunogenic radiation regimen is not sufficient to mount an anti-tumor immune response when combine with IT as monotherapy and highlights the need to combine an immunogenic irradiation with multiple IT to overcome immunosuppression of GBM.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217856"},"PeriodicalIF":9.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipocytes promote cancer stemness properties in oral squamous cell carcinoma through C3/C3AR axis and sphingolipid metabolism","authors":"Tian Xu Qin ,&nbsp;Ying Ying Zhu ,&nbsp;Wai Hoe Ng ,&nbsp;Siew Kit Ng ,&nbsp;Min Fey Chek ,&nbsp;Kai Dun Tang","doi":"10.1016/j.canlet.2025.217848","DOIUrl":"10.1016/j.canlet.2025.217848","url":null,"abstract":"<div><div>There is convincing evidence that being overweight or having obesity is associated with an increased risk of developing oral squamous cell carcinoma (OSCC). Despite OSCC frequently spread to the cervical lymph nodes, where adipose tissue is the predominant tissue within the microenvironment, it is still largely unknown whether adipocytes could contribute to the formation of oral cancer stem cells (CSCs) niche during the oral carcinogenesis. Here, we report that adipocytes promote the CSCs phenotype of OSCC cells through the activation of complement C3 (C3). Subsequent clinical data analysis revealed that the elevated levels of C3 and its receptor C3AR are associated with aggressive features and shorter survival in human OSCC patients. Furthermore, C3 exists as an autocrine factor and through C3AR interaction regulates OSCC stemness and properties such as cell proliferation, migration and invasion. On the other hand, C3 and C3AR were found to be highly abundant in adipocytes upon co-cultured with OSCC cells, demonstrating its paracrine effect on adipocyte-CSCs interaction, which in turn promotes CSC properties and supports oral carcinogenesis. Intriguingly, the inhibition of functional C3/C3AR axis by sphingosine, a bioactive sphingolipid metabolite, resulted in the suppression of OSCC cells growth and adipocyte-promoted oral CSC self-renewal. In conclusion, our findings provide a novel insight into the mechanisms underlying the role of C3/C3AR axis in mediating the reciprocal interactions between adipocytes and OSCC cells, acting in an autocrine and paracrine manner, and specific inhibition of this interaction by sphingosine offers a potential targeted therapeutic approach for OSCC treatment.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217848"},"PeriodicalIF":9.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gobal crotonylome reveals that HNRNPC and its crotonylation promote p53-deficient tumor growth by stabilizing CCND1 and MCM3 mRNAs","authors":"Liangjie Sun ,&nbsp;Xiaolei Gao ,&nbsp;Meng Wang ,&nbsp;Yixin Zhang ,&nbsp;Ruiqing Sun ,&nbsp;Yang Chen ,&nbsp;Yan Bai ,&nbsp;Yi Li ,&nbsp;Lan Luo ,&nbsp;Chong Ding ,&nbsp;Yixiang Wang","doi":"10.1016/j.canlet.2025.217854","DOIUrl":"10.1016/j.canlet.2025.217854","url":null,"abstract":"<div><div>The role of p53 deficiency or mutation in regulating nonhistone protein crotonylation and its impact on cancer development remain unclear. The present study identified crotonylation as a therapeutic target in patients with p53 deficiency or mutation in colorectal cancer. Crotonylome analysis revealed that p53 deficiency upregulated heterogeneous nuclear ribonucleoprotein C (HNRNPC) and HNRNPC^K189Cr, promoting colorectal cancer cell proliferation by stabilizing CCND1 and MCM3 mRNAs through the MDM2/HDAC3 axis. Functional studies using HNRNPC^K189Q (activating mutation) and HNRNPC^K189R (inactivating mutation) confirmed the role of HNRNPC^K189Cr in tumor growth. HDAC3 was identified as a specific decrotonylase of HNRNPC^K189Cr. Sodium phytate, an HDAC3 agonist, effectively decrotonylated HNRNPC^K189Cr and, in combination with HNRNPC siRNA, significantly inhibited the <em>in vitro</em> and <em>in vivo</em> growth of HCT116 p53^−/− cells. An AOM/DSS-induced colorectal cancer model in K14-cre; p53 ^fl/fl mice validated the role of the p53/MDM2/HDAC3/HNRNPC^K189Cr axis in tumor progression. Additionally, the findings in the oral cancer cells WSU-HN6 and non-small lung cancer cells H1299 were in line with those in the HCT116 cells, suggesting that the p53/MDM2/HDAC3/HNRNPC^K189Cr regulatory mechanism plays a key role in a conserved manner. These findings revealed a novel mechanism by which p53 deficiency or mutation drives tumor progression via HNRNPC^K189Cr through MDM2/HDAC3 axis-mediated CCND1 and MCM3 mRNA stability. Targeting HNRNPC and its crotonylation with sodium phytate and HNRNPC <em>siRNA</em> offers a promising therapeutic strategy, potentially converting p53 from an “undruggable” target to a “druggable” target.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217854"},"PeriodicalIF":9.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear localization of YAP in pancreatic cancer: More players besides Hippo pathway","authors":"Yiping Xie ,&nbsp;Cheng Qin ,&nbsp;Xiangyu Zhang ,&nbsp;Zeru Li,&nbsp;Bangbo Zhao,&nbsp;Tianyu Li,&nbsp;Yutong Zhao,&nbsp;Yutong Yan,&nbsp;Haoyu Shi,&nbsp;Lirui Huang,&nbsp;Weibin Wang","doi":"10.1016/j.canlet.2025.217864","DOIUrl":"10.1016/j.canlet.2025.217864","url":null,"abstract":"<div><div>The Yes-associated protein (YAP) is a critical regulator of organ size and a key player in tumorigenesis, with its activity primarily governed by the Hippo signaling pathway. YAP mainly functions as a transcriptional co-activator, therefore its activity is closely related to its nuclear localization. Recent studies have shed light on mechanisms that regulate YAP's nuclear localization and activation, independent of the Hippo pathway. Beyond its role in development and tissue homeostasis, YAP's dysregulation is implicated in various cancers, including pancreatic cancer, one of the most lethal cancers. Activated YAP translocates to the nuclear of cancer cell, subsequently promotes expression of downstream genes involved in tumor growth, metastasis, and resistance to chemotherapy, etc. Moreover, YAP can also function as a transcription suppressor, indicating its context-dependent role in cancer. A thorough understanding of YAP regulation in pancreatic cancer could offer new insights for targeted therapy approaches. Here this review concludes recent findings on Hippo-independent regulation of YAP nuclear localization and the role of YAP in pancreatic cancer progression.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"629 ","pages":"Article 217864"},"PeriodicalIF":9.1,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic evolution of venetoclax resistance in acute myeloid leukemia unveiled by longitudinal single-cell RNA-seq","authors":"Huan Lu ,&nbsp;Huafeng Wang ,&nbsp;Qiwei Wang ,&nbsp;Deyu Huang ,&nbsp;Yingli Han ,&nbsp;Hui Wang ,&nbsp;Penglei Jiang ,&nbsp;Xinyue Qian ,&nbsp;Liping Mao ,&nbsp;Min Yang ,&nbsp;Hongyan Tong ,&nbsp;Jie Jin ,&nbsp;Pengxu Qian ,&nbsp;Hong-Hu Zhu","doi":"10.1016/j.canlet.2025.217853","DOIUrl":"10.1016/j.canlet.2025.217853","url":null,"abstract":"<div><div>Despite extensive investigation into venetoclax resistance mechanisms in acute myeloid leukemia (AML), the dynamics of bone marrow (BM) microenvironment remodeling during venetoclax-based therapies remain poorly characterized at single-cell resolution. Using paired single-cell RNA sequencing of BM specimens from AML patients undergoing DAV therapy (venetoclax/decitabine/cytarabine; pre- vs post-treatment), we systematically mapped therapy-induced transcriptional reprogramming, regulatory network alterations, and niche crosstalk across clinical response subgroups. Our analysis revealed two pivotal mechanisms governing therapeutic outcomes: First, pre-existing immune-activating niches marked by elevated HLA class I presentation synergized with therapy-enhanced CD8⁺ T cell cytotoxicity and reduced tumor-promoting stroma-leukemia interactions to facilitate favorable responses. Second, responder leukemic cells exhibited transposable element (TE)-associated type I interferon signaling upregulation. Primitive leukemic clones displayed <em>IMPDH2</em>-high states linked to <em>BCL2</em> inhibitor sensitivity, while resistant monocytic populations upregulated glycolysis and <em>MCL1</em> to bypass <em>BCL2</em> dependence. Leveraging these insights, we established a prognostic signature predicting patient responses to venetoclax-based therapies, validated in independent cohorts (Tumor Profiler, BeatAML2). High-risk patients identified by this signature demonstrated heightened sensitivity to <em>IGF-1R</em> inhibition. Functional validation in an established resistant cell line model confirmed that <em>IGF-1R</em> inhibition synergized with DAV by suppressing glucose uptake and differentiation. This study provides a comprehensive single-cell atlas of BM microenvironment evolution during venetoclax-based therapy, proposes a prognostic biomarker, and identifies a clinically actionable strategy to overcome therapeutic resistance in AML.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217853"},"PeriodicalIF":9.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the VIP-VPAC Pathway in Melanoma Models Inhibits Tumor Growth and Liver Metastasis","authors":"Wenxi Wang ,&nbsp;Hua Yang ,&nbsp;Tenzin Passang ,&nbsp;Yiwen Li ,&nbsp;Hanwen Zhang ,&nbsp;Shayna E. Jankowski ,&nbsp;Fanyuan Zeng ,&nbsp;Shuhua Wang ,&nbsp;Po-Chih Hsu ,&nbsp;Jian-Ming Li ,&nbsp;Zihan Chen ,&nbsp;Gregory B. Lesinski ,&nbsp;Pia R. Mendoza ,&nbsp;Ying Li ,&nbsp;Cynthia R. Giver ,&nbsp;Hans E. Grossniklaus ,&nbsp;Edmund K. Waller","doi":"10.1016/j.canlet.2025.217855","DOIUrl":"10.1016/j.canlet.2025.217855","url":null,"abstract":"<div><div>Uveal melanoma (UVM) is resistant to immune checkpoint therapy and chemotherapy, resulting in high mortality rates, primarily due to liver metastases. While vasoactive intestinal peptide (VIP) signaling has been identified as an immune checkpoint and therapeutic target in pancreatic cancer, its role in melanoma remains unexplored. This study investigated the impact of a novel VIP receptor antagonist, ANT308, on melanoma cell behavior and tumor growth. Using both murine and human UVM/cutaneous melanoma cell lines, we examined the inhibition of VIP receptor signaling and its effects on cell migration and proliferation <em>in vitro</em>. Mechanistically, ANT308 downregulated melanoma cell adhesion molecule (MCAM) and N-cadherin expression at both the RNA and protein levels, as demonstrated by RNA sequencing and Western blot analyses. Knockdown of the VIP receptor VPAC2 in mouse and human melanoma cells produced similar effects on cell migration, proliferation, and MCAM protein expression, further implicating VIP-VPAC2 signaling in tumor progression. <em>In vivo</em> studies revealed that ANT308 treatment decreased MCAM expression in intraocular primary tumors, reduced the number and size of liver metastases following intraocular or subcutaneous melanoma injection, and showed a trend toward reduced tumor volume at the primary tumor site. In conclusion, our findings indicate that VIP receptor signaling promotes liver metastasis in melanoma, and targeting this pathway with VIP receptor antagonists may represent a novel therapeutic strategy for treating metastatic UVM.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217855"},"PeriodicalIF":9.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing neoadjuvant therapy with inetetamab for HER2-Positive breast cancer.","authors":"Wenbin Zhou, Qiang Ding","doi":"10.1016/j.canlet.2025.217852","DOIUrl":"10.1016/j.canlet.2025.217852","url":null,"abstract":"<p><p>HER2-positive breast cancer accounts for approximately 15 %-20 % of all breast cancer cases and is typically characterized by aggressive tumor biology, an elevated risk of recurrence, and poor long-term survival. Although HER2-targeted therapies such as trastuzumab and pertuzumab result in significantly improved clinical outcomes, the total pathological complete response (tpCR) rate remains suboptimal, particularly among hormone receptor (HR)-positive patients. Neoadjuvant therapy plays a critical role in facilitating tumor downstaging in locally advanced cases and provides a valuable opportunity to evaluate therapeutic efficacy and guide adjuvant treatment. Consequently, the development of novel anti-HER2 agents and combination strategies has become a major focus of ongoing researches. Inetetamab, a humanized monoclonal antibody targeting HER2 with an engineered Fc domain to enhance antibody-dependent cellular cytotoxicity, represents a promising candidate for improving treatment outcomes. In this issue of Cancer Letters, Zuo and colleagues present findings from a single-arm, multicenter phase II clinical trial investigating a neoadjuvant regimen combining inetetamab, pertuzumab, and nab-paclitaxel (TIP regimen) in patients with early-stage or locally advanced HER2-positive breast cancer. Through comprehensive evaluation of both efficacy and safety, the study demonstrates exceptional therapeutic potential of the TIP regimen, with a high tpCR rate observed in estrogen receptor (ER)-negative patients, indicating particular promise for this subgroup of HER2-positive breast cancer.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217852"},"PeriodicalIF":9.1,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CHD4 drives gastric cancer metastasis via MYH9/GSK3β/β-catenin axis and WNT/EMT pathway activation","authors":"Yuntao Shi ,&nbsp;Zidan Zhao ,&nbsp;Shangbo Zhou ,&nbsp;Ziwen Zhou ,&nbsp;Zhangsen Huang ,&nbsp;Zhijun Zhou ,&nbsp;Changhua Zhang","doi":"10.1016/j.canlet.2025.217813","DOIUrl":"10.1016/j.canlet.2025.217813","url":null,"abstract":"<div><div>Gastric cancer (GC) metastasis remains a significant cause of cancer-related mortality, yet the molecular mechanisms underlying this process have not been fully elucidated. CHD4, a chromatin remodeling factor, has been associated with oncogenic processes, but its precise role in GC metastasis has not been defined. In this study, we identify CHD4 as a critical regulator of GC metastasis through the MYH9/GSK3β/β-catenin axis and the activation of the WNT pathway and epithelial–mesenchymal transition (EMT). Clinically, CHD4 was significantly overexpressed in GC tissues and strongly correlated with advanced disease stages and poor prognosis. Mechanistically, CHD4 interacted with MYH9 via its ATPase domain and promoted the nuclear-to-cytoplasmic translocation of MYH9, thereby enabling MYH9 to orchestrate inhibitory phosphorylation and ubiquitination-dependent degradation of GSK3β. This, in turn, stabilized β-catenin, leading to its nuclear accumulation and activation of downstream WNT target genes, such as Cyclin D1, along with the induction of EMT. Functionally, suppression of CHD4 expression inhibited GC cell migration, invasion, and metastasis in vivo, while MYH9 restoration reversed these effects. Collectively, these findings establish CHD4 as a key regulator of GC metastasis through the MYH9/GSK3β/β-catenin axis and underscore its potential as a therapeutic target for inhibiting GC progression.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217813"},"PeriodicalIF":9.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144242000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transarterial chemoembolization combined with intra-arterial infusion of sintilimab and bevacizumab for advanced hepatocellular carcinoma: a phase 2 study","authors":"Mao-Yuan Mu ,&nbsp;Zi-Xiong Chen ,&nbsp;Yu-Zhe Cao ,&nbsp;Xiao-Bo Fu ,&nbsp;Li-Jie Qiu ,&nbsp;Han Qi ,&nbsp;Fei Gao","doi":"10.1016/j.canlet.2025.217851","DOIUrl":"10.1016/j.canlet.2025.217851","url":null,"abstract":"<div><div>Transarterial chemoembolization (TACE) is an effective locoregional treatment for unresectable hepatocellular carcinoma (HCC). Arterial administration can enhance local drug concentrations while reducing systemic toxicity. The potential synergistic effects of combining locoregional treatments with systemic therapy in advanced HCC warrant further investigation. This phase 2 study (NCT04796025) aimed to evaluate the efficacy and safety of TACE combined with intra-arterial infusion of sintilimab and bevacizumab in patients with advanced HCC. Eligible patients received TACE on demand plus intra-arterial infusion of sintilimab and bevacizumab for four cycles. Maintenance therapy included intravenous administration of sintilimab and bevacizumab until disease progression or unacceptable side effects. The primary outcome was the objective response rate (ORR) based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). A total of 34 patients (median age, 53 years [IQR 45–59]; 33 men) were enrolled. With a median follow-up of 10.3 months (IQR 5.8–15.6), our results showed a favorable ORR of 70.6 %. The median PFS was calculated as 6.0 months (95 % CI 4.8 - not reached), and the median OS was 12.2 months (95 % CI 9.3 - not reached). Common treatment-related adverse events (any grade) included elevated alanine transaminase (17.6 %), abdominal pain (14.7 %), elevated aspartate aminotransferase (11.8 %), and hypertension (11.8 %). Grade 3 adverse events included hypertension (2.9 %) and gastrointestinal hemorrhage (8.8 %). No serious treatment-related adverse events were observed. TACE combined with sintilimab and bevacizumab has demonstrated a favorable ORR and promising efficacy in advanced HCC, with manageable side effects.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217851"},"PeriodicalIF":9.1,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144230151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}