Experimental Hematology & Oncology最新文献

{"title":"Functional xenogeneic hematopoietic cells maintaining donor-dominant identity and immune tolerance enable therapy.","authors":"Shumin Xiong, Ren Zhou, Chuijin Wei, Xiaomin Wang, Yunhan Tang, Liaoliao Dong, Ping Yu, Duanqing Pei, Zhu Chen, Sai-Juan Chen, Lin Cheng","doi":"10.1186/s40164-026-00767-3","DOIUrl":"10.1186/s40164-026-00767-3","url":null,"abstract":"<p><strong>Background: </strong>The clinical supply of hematopoietic cells is severely constrained by the limitations of donor donation and inefficient in vitro generation. While generating these cells within interspecies chimeras presents a groundbreaking alternative, the fundamental biological properties and therapeutic potential of the resulting xenogeneic hematopoietic cells remain poorly characterized.</p><p><strong>Methods: </strong>We generated xenogeneic hematopoietic cells in rodent models via blastocyst complementation and bone marrow transplantation. A comprehensive comparative analysis of these cells was conducted using single-cell RNA sequencing and proteomics. Their functional efficacy was rigorously evaluated through reverse transplantation into a series of donor-species disease models, including hemorrhagic anemia, thalassemia, thrombocytopenia, and leukemia.</p><p><strong>Results: </strong>Bone marrow transplantation yielded significantly higher chimeric efficiency than blastocyst complementation. Xenogeneic hematopoietic cells, including red blood cells, platelets, and white blood cells, exhibited a transcriptional and proteomic profile that was dominantly donor-specific. Crucially, these cells did not elicit significant immune rejection upon reverse transfusion. Functionally, xenogeneic red blood cells rescued models of hemorrhagic anemia and thalassemia, platelets alleviated thrombocytopenia, and xenogeneic T cells engineered with a chimeric antigen receptor effectively suppressed leukemia progression. Furthermore, the implantation of xenogeneic hematopoietic cells partially reconstituted splenic morphology and function in immunodeficient recipients.</p><p><strong>Conclusion: </strong>Our study provides the first comprehensive functional validation of xenogeneic hematopoietic cells generated in interspecies bioreactors. We definitively show that these cells possess donor-like molecular identities, evade immune rejection, and serve as effective \"seed cells\" to rescue a wide spectrum of hematologic diseases. This work establishes a transformative paradigm for utilizing interspecies chimeras to overcome critical shortages in transfusion and cellular therapies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":" ","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13023125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147510606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel non-viral in vivo CAR-T therapies: latest updates from the 2025 ASH annual meeting.","authors":"Bin Xue, Yifan Liu, Aibin Liang, Wenjun Zhang","doi":"10.1186/s40164-026-00765-5","DOIUrl":"10.1186/s40164-026-00765-5","url":null,"abstract":"<p><p>The field of chimeric antigen receptor (CAR)-T cell therapy is undergoing a paradigm shift from complex ex vivo manufacturing to direct in vivo generation of CAR-T cells. This innovative approach leverages non-viral delivery platforms to reprogram a patient's own immune cells in situ, promising to overcome critical barriers of cost, scalability, and accessibility. The 2025 American Society of Hematology (ASH) Annual Meeting served as a showcase for groundbreaking preclinical data across a diverse array of non-viral technologies, including advanced lipid nanoparticles (LNPs), virus-like particles (VLPs), and polymeric nanoparticles. This correspondence summarizes the latest reports on these platforms, highlighting their potential to revolutionize the treatment of both autoimmune diseases and hematological malignancies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13003734/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147485125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA-based co-transfer of human CD8αβ with WT1-specific TCRαβ redirects tumor recognition by CD4 and γδ T-cells towards MHC class I-restricted WT1 epitopes and boosts CD8 T-cell responses with or without CD3 mRNA.","authors":"Diana Campillo-Davo, Donovan Flumens, Zwi N Berneman, Fumihiro Fujiki, Gils Roex, Maarten Versteven, Heleen H Van Acker, Viggo F I Van Tendeloo, Haruo Sugiyama, Sébastien Anguille, Eva Lion","doi":"10.1186/s40164-026-00764-6","DOIUrl":"10.1186/s40164-026-00764-6","url":null,"abstract":"<p><p>We evaluated the redirection of CD4, γδ and CD8 T-cells towards the Wilms' tumor protein (WT1) tumor-associated antigen, using a major histocompatibility complex (MHC) class I-restricted WT1-specific T-cell receptor (TCR) introduced via RNA-based engineering. We also studied whether co-transfection of TCR mRNA in combination with CD8αβ mRNA in CD4 and γδ T-cells or with CD8αβ and CD3γδεζ mRNAs in CD8 T-cells improves antigen-specific T-cell functional activity. We transfected primary human CD4 and CD8 T-cells following our in-house-developed protocol, in which electroporation with Dicer-substrate silencing RNA (DsiRNA) suppresses de novo expression of native TCR, followed by DsiRNA-resistant transgenic TCR mRNA transfection. This method allows minimal mispairing between native and introduced TCR chains. High frequencies of transgenic MHC class I-restricted WT1-specific TCR-positive cells were obtained in expanded CD4 and γδ T-cells. Only co-electroporation of CD8 mRNA led TCR mRNA-electroporated CD4 and γδ T-cells to MHC class I-restricted antigen-specific recognition of tumor cells. Co-electroporation of CD8 T-cells with WT1-specific TCR, CD8 and CD3 mRNAs also enhanced CD8 T-cell activation and antigen-specific recognition as compared to either TCR-engineered or TCR- and CD8-engineered cells. In summary, RNA electroporation is a fast and efficient method to engineer primary human CD8, CD4 and γδ T-cells for redirecting T-cell specificity. Transgenic CD8 expression in CD4 and γδ T-cells and co-electroporation of CD8 and CD3 mRNA in CD8 T-cells enable antigen recognition when T-cells are redirected with TCRs of low/intermediate avidity, showing the potential of TCR co-receptors to improve T-cell functional activity against tumor-associated antigens in adoptive TCR-T-cell therapies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13003731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147485187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prospects and advances of PROTAC in the treatment of hematologic malignancies.","authors":"Xinyang Wang, Ming Zhang, Heng Mei","doi":"10.1186/s40164-026-00759-3","DOIUrl":"10.1186/s40164-026-00759-3","url":null,"abstract":"<p><p>Over the past years, target protein degradation (TPD) has emerged as a hot topic in treating hematologic malignancies out of its strong ability to eliminate pathological proteins precisely. And as a flagship, Proteolysis-Targeting Chimeras (PROTACs) hijack the ubiquitin- proteasome system to catalytically degrade protein of interest (POI). Compared to small-molecule inhibitors (SMIs) and Chimeric antigen receptor T-cell (CAR-T) therapies, PROTACs exhibit distinct advantages in mechanism of action, toxicity profile, specificity, diversity of targets, and ability to overcome drug resistance. In this review, we comprehensively summarize PROTAC drugs that have entered clinical trials, with particular focus on eight candidates being developed for hematologic malignancies. We also classified 56 protein targets whose PROTACs are in pre-clinical stage into seven groups based on their functions, including \"epigenetic regulators\", \"kinases\", \"RNA regulators\", \"transcriptional regulators\", \"protein regulators\", and so on. In summary, this review synthesizes the current landscape of PROTAC therapeutics in hematologic malignancies and provides perspectives on future development directions.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":" ","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13003689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147472879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic and precise interventions for KRAS-mutant cancers.","authors":"JingHui Liang, JunXi Wu, Yuan Zhang, HongYu Wang, YiYang Zheng, Qing He","doi":"10.1186/s40164-026-00763-7","DOIUrl":"10.1186/s40164-026-00763-7","url":null,"abstract":"<p><p>KRAS is the most frequently altered oncogenic driver in human cancer. Its mutations drive the initiation and progression of many solid tumors. Clinical validation of covalent KRAS^G12C inhibitors marked a step change and renewed focus on allele-directed strategies and the circuits that regulate KRAS signaling. We summarize recent advances across KRAS structure and conformations, allelic heterogeneity, and roles in signaling, metabolic control, and immune microenvironment remodeling. For direct inhibition, we summarize allele-specific drugs for G12C, G12D and G12V, as well as conformation-selective broad-spectrum inhibitors, outlining design logic and therapeutic outlook. For indirect intervention, we analyze SHP2 and SOS1 inhibition, MEK blockade, metabolic targeting, and immunotherapy combinations, with the biological rationale for each pairing. We also analyze the genetic and phenotypic mechanisms underlying primary and acquired resistance, and discuss counterstrategies such as next-generation inhibitors, rational treatment sequencing, and circulating tumor DNA (ctDNA) monitoring. The KRAS therapeutic landscape is shifting toward conformation-aware, multimodal precision therapy and longitudinal disease management, which providing avenues for durable control of KRAS-mutant tumors.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":" ","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13003733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147456679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of ruxolitinib for graft-versus-host disease prophylaxis in patients with aplastic anemia undergoing PBSC-only allogeneic stem cell transplantation: a prospective phase II study.","authors":"Xiaoyu Zhang, Lulu Pan, Yanhong Zhao, Runzhi Ma, Lining Zhang, Ying Zhang, Gang Li, Weihua Zhai, Qiaoling Ma, Aiming Pang, Donglin Yang, Sizhou Feng, Ping Zhang, Yi He, Guoyou Qin, Erlie Jiang, Mingzhe Han","doi":"10.1186/s40164-026-00753-9","DOIUrl":"10.1186/s40164-026-00753-9","url":null,"abstract":"<p><strong>Background: </strong>While peripheral blood hematopoietic stem cell transplantation (PB-HSCT) supports rapid engraftment and reduces graft failure risk in aplastic anemia (AA) patients, it compromised higher risk of acute graft-versus-host disease (aGVHD), highlighting the need for more effective prophylactic strategies. This phase II clinical trial was designed to assess the efficacy and safety of ruxolitinib, a JAK1/2 inhibitor, as part of GVHD prophylaxis regimen following PB-HSCT.</p><p><strong>Methods: </strong>This open-label, single-arm, Phase II clinical trial (ClinicalTrials.gov: NCT05914714) enrolled patients with AA between June 2023 and December 2024. Ruxolitinib was initiated at the start of conditioning and continued for 3 months post-transplant at a dose of 5 mg twice daily. A historical control cohort receiving standard GVHD prophylaxis between January 2019 and May 2023 was included for comparison. To address baseline imbalances, propensity score-based inverse probability of treatment weighting (IPTW) was applied. The primary objective was the incidence of aGVHD six months after HSCT. Secondary endpoints included one-year overall survival (OS) and GVHD-free, failure-free survival (GFFS). Immune reconstitution-including T cells, B cells, NK cells-and levels of pro-inflammatory cytokines were also evaluated to explore potential mechanisms.</p><p><strong>Results: </strong>A total of 82 patients were enrolled (ruxolitinib group n = 46, historical control cohort n = 36). Comparative analysis showed that ruxolitinib significantly reduced the cumulative incidence of grade II-IV aGVHD (HR 0.24; p = 0.004) and severe aGVHD (0% vs 15.8%; p = 0.008) compared with the control group. At a median follow-up of 417 days (range: 112-725), the ruxolitinib group demonstrated significantly superior 1-year GFFS (91.6% vs. 72.1%; HR 0.23, weighted log-rank p = 0.012). Notably, the ruxolitinib group not only exhibited more rapid recovery of CD4 + Tregs at 3 months post-HSCT. Notably, but also suppressed proinflammatory cytokine levels during engraftment.</p><p><strong>Conclusions: </strong>The peri-transplantation addition of ruxolitinib to the standard GVHD prophylaxis regimen in PB-HSCT for AA patients has shown to be a safe and effective approach to reducing both the incidence of aGVHD, while improving patient outcomes. Our study suggests that ruxolitinib may offer a promising strategy for improving survival and immune recovery. Trial registration clinicaltrials.gov identifier: NCT05914714.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":" ","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12969854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147376453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo CAR-T engineering: insights from the 2025 ASH annual meeting.","authors":"Gelayol Asadi, Misagh Rajabinejad","doi":"10.1186/s40164-026-00762-8","DOIUrl":"10.1186/s40164-026-00762-8","url":null,"abstract":"<p><p>In vivo chimeric antigen receptor (CAR)-T engineering is a prominent field of research in cancer immunology, in which vectors are used to reprogram endogenous T-cells into CAR-T cells. Viral and nonviral platforms presented at the 67th Annual Meeting of the American Society of Hematology (ASH) offer precise T-cell targeting and efficient CAR expression. Preclinical models demonstrated robust generation of CAR-T cells, potent tumor clearance, and strong clinical translational potential. However, certain limitations remained to be addressed in future studies. This correspondence summarizes the key findings from the meeting, discusses current translational challenges, and highlights future directions.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12947365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147304307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tertiary lymphoid structures correlate with reduced recurrence risk and enhanced antitumor immunity in esophageal squamous cell carcinoma with pathologic non-complete response to neoadjuvant chemoimmunotherapy.","authors":"Yang Wo, Tong Lu, Zijiang Yang, Xiongfei Li, Zheyi Wang, Yizhou Peng, Xuxia Shen, Feng Hou, Wenjie Jiao, Yihua Sun","doi":"10.1186/s40164-026-00748-6","DOIUrl":"10.1186/s40164-026-00748-6","url":null,"abstract":"<p><strong>Background: </strong>The majority of patients with locally advanced esophageal squamous cell carcinoma (ESCC) undergoing neoadjuvant chemoimmunotherapy (nCIT) failed to achieve pathologic complete response (pCR), had high risk of postoperative recurrence and lacked prognostic biomarkers. Tertiary lymphoid structures (TLS) are organized aggregates of immune cells and have the potential to regulate antitumor immune response. This study aimed to investigate the prognostic value and immune profile of TLS in non-pCR ESCC.</p><p><strong>Methods: </strong>We first analyzed clinicopathological features, recurrence events, and survival outcomes according to TLS status. Subsequently, based on the single-cell sequencing data, we analyzed the differences in the infiltration level, functional status and interaction mode of immune cells based on TLS status. The expression pattern of signature genes and the spatial localization of key immune cell subsets were verified through bulk RNA sequencing and multiplex immunohistochemistry.</p><p><strong>Results: </strong>The TLS(+) group demonstrated a lower likelihood of postoperative recurrence and superior survival rates relative to the TLS(-) group. The key immune cell subsets responsive to immunotherapy were enriched in the TLS(+) group, and the immune cells in the TLS(+) group showed a functional state of high activation and low exhaustion. Multiplex immunohistochemistry and cell-cell communication analysis suggested that tumor reactive T cells were spatially colocalized with B cells and antigen presenting cells in TLS and exhibited high interaction potential. In the TLS(+) group, we also identified precursor exhausted T cells and long-lived plasma cells with tumor reactivity and matured affinity. The presence of TLS correlated with enhanced synergistic interaction, activation and maturation of immune cells, suggesting a potential role in shaping in situ antitumor immunity.</p><p><strong>Conclusions: </strong>TLS status was the independent predictor of postoperative recurrence in non-pCR ESCC. TLS status correlated with the composition, functional state, and interaction patterns of immune cells. Specialized immune niches existed in non-pCR ESCC with TLS, potentially contributing to antitumor immune responses.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":" ","pages":""},"PeriodicalIF":13.5,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12947456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147283182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular background of Philadelphia chromosome dependent enhancement of cellular growth and tyrosine kinase inhibitor sensitivity.","authors":"Md Faruq Hossain, Lisa Hagenau, Lars R Jensen, Johannes Rhode, Thomas Sura, Manuela G Salazar, Ana Tzvetkova, Corinna Jensen, Stephanie Edwards, Heiko Dunkel, Stefan Simm, Josefine Radke, Andreas W Kuss","doi":"10.1186/s40164-026-00758-4","DOIUrl":"10.1186/s40164-026-00758-4","url":null,"abstract":"<p><p>The Philadelphia chromosome is the result of a balanced reciprocal translocation between the long arms of chromosomes 9 and 22, resulting in the fusion gene BCR-ABL1. Despite it being a hallmark of acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML) and mixed-phenotype acute leukemia, comparatively little is known about its effects, which can be directly attributed to its presence in cancer cells. To study this question, we created and characterized a Jurkat cell line carrying this alteration via a CRISPR/Cas9-based approach. Compared with wild-type Jurkat cells, BCR-ABL1 p190-expressing cells exhibited increased proliferation and increased sensitivity to tyrosine kinase inhibitors (TKIs). By integrating gene expression, DNA methylation and protein expression data generated by next-generation sequencing (NGS) and mass spectrometry analyses, we identified a number of pathways as well as individual proteins that are altered in association with BCR-ABL1 p190. Among the deregulated proteins, we identified known cancer proteins, such as the tumor suppressors ASS1 and ABI3, which were downregulated in our model, or specifically upregulated TRBC1. Particularly noteworthy is the downregulation of CYP51A1, which is known to confer TKI resistance under normal circumstances, and therefore directly associated with increased TKI sensitivity in BCR-ABL1 p190-positive cells. Another interesting feature is SPART, whose abundance was increased despite strong promoter hypermethylation, indicating that some transcriptional changes in BCR-ABL1 p190-carrying cells occur independently of promoter methylation and reflect broader regulatory effects of the fusion.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"15 1","pages":"26"},"PeriodicalIF":13.5,"publicationDate":"2026-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12922320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146226127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-intrinsic PD-L1 drives lung cancer progression in response to TLR stimulation by promoting autophagy through the TRAF6-BECN1 signaling axis.","authors":"Yoolim Sung, Ha-Jeong Lee, Mi-Jeong Kim, Ji Hye Shin, Ji Young Kim, Yeeun Kang, Chaeeun Lee, Duk-Hwan Kim, Jae-Hyuck Shim, Tae Jin Kim, Eunyoung Chun, Ki-Young Lee","doi":"10.1186/s40164-026-00761-9","DOIUrl":"10.1186/s40164-026-00761-9","url":null,"abstract":"<p><strong>Background: </strong>Programmed death-ligand 1 (PD-L1, CD274) is well known for its immunosuppressive function within the tumor microenvironment; however, its tumor cell-intrinsic roles remain incompletely characterized. Emerging evidence suggests that PD-L1 may regulate oncogenic processes beyond immune evasion. This study aimed to define the intrinsic functions of PD-L1 in non-small cell lung cancer (NSCLC), with a focus on autophagy and metastasis-related signaling pathways.</p><p><strong>Methods: </strong>Integrated transcriptomic analyses of patient-derived NSCLC specimens were performed to evaluate associations between CD274 expression and oncogenic gene signatures. CRISPR-Cas9-mediated knockout and plasmid-driven overexpression of PD-L1 were conducted in H460 and A549 cell lines to assess proliferation, migration, clonogenicity, and 3D spheroid growth. Molecular interactions among PD-L1, TRAF6, and BECN1 were examined through immunoprecipitation and ubiquitination assays. Autophagy induction was evaluated by LC3 lipidation and autophagosome formation under Toll-like receptor (TLR) stimulation. The functional relevance of PD-L1 in metastasis was further assessed using xenograft models.</p><p><strong>Results: </strong>Clinical transcriptomic analyses demonstrated that CD274 upregulation correlates with enrichment of cancer progression, proliferation, and autophagy-associated gene sets in NSCLC. PD-L1 knockout markedly reduced cell proliferation, migration, clonogenicity, and 3D spheroid formation, whereas its overexpression enhanced these oncogenic phenotypes. Mechanistically, PD-L1 physically interacted with TRAF6 and BECN1, promoting TRAF6-dependent BECN1 ubiquitination and TLR-induced autophagy. PD-L1 depletion suppressed TLR-driven LC3 lipidation, autophagosome formation, and epithelial-mesenchymal transition (EMT), while PD-L1 overexpression augmented autophagy and EMT responses. In vivo, PD-L1-deficient lung cancer cells displayed diminished tumor growth and reduced metastatic potential in xenograft models.</p><p><strong>Conclusions: </strong>This study identifies PD-L1 as a previously unrecognized intrinsic driver of NSCLC progression through activation of the TLR-TRAF6-BECN1 autophagy axis and promotion of EMT. Beyond its canonical role in immune evasion, PD-L1 functions as a dual-regulator of tumorigenesis by coordinating autophagy-dependent oncogenic processes. These findings provide novel mechanistic insight and support the therapeutic rationale for targeting PD-L1 not only as an immune checkpoint but also as a key modulator of cancer cell-intrinsic signaling in NSCLC.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":" ","pages":"28"},"PeriodicalIF":13.5,"publicationDate":"2026-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12922217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146206855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}