In recent years, the development of chimeric antigen receptor (CAR) technology has greatly promoted the progress of cellular immunotherapy. Among them, CAR-T cell therapy has shown remarkable clinical effects in the treatment of hematological malignancies. However, this therapy still faces a series of challenges, including immunogenicity, toxic side effects, and insufficient maintenance of long-term efficacy. The latest research progress has extended CAR technology to mesenchymal stem cells (MSCs), and the resulting CAR-MSCs combine the precise targeting ability of CAR molecules with the inherent immunomodulatory, tissue homing, and regenerative repair properties of MSCs, providing a new therapeutic strategy for cancer and immune-related diseases. This review examines the engineering design, biological characteristics, and applications of CAR-MSCs in oncology and immune-related disorder therapy. Preclinical studies have shown their effectiveness against glioblastoma, Ewing sarcoma, acute myeloid leukemia, and lung cancer, as well as graft-versus-host disease, through TRAIL secretion, bispecific antibody production, and Treg induction. Despite promising results, significant hurdles persist in CAR-MSC manufacturing scalability, cell persistence, heterogeneous MSC tissue sourcing, and undefined application protocols, all of which are critical for clinical translation. We investigated corresponding strategies, including nonviral gene delivery, metabolic engineering, senescence-resistant MSC clones, and microenvironment-specific activation. Standardized production workflows incorporating rigorous quality control are essential for future applications. CAR-MSCs represent a paradigm shift in precision immunotherapy by providing dual therapeutic modalities for cancer and immune disorders. Fully unlocking their therapeutic potential will require interdisciplinary efforts to overcome biological and technical barriers while advancing combination therapies.
{"title":"Recent advances in CAR-MSCs: the new engine of cellular immunotherapy evolution.","authors":"Ying Chen,Jing Li,Yingying Ma,Jianjun Fang,Yang Yang,Lun Yan,Xi Zhang,Cheng Zhang","doi":"10.1186/s13045-025-01746-7","DOIUrl":"https://doi.org/10.1186/s13045-025-01746-7","url":null,"abstract":"In recent years, the development of chimeric antigen receptor (CAR) technology has greatly promoted the progress of cellular immunotherapy. Among them, CAR-T cell therapy has shown remarkable clinical effects in the treatment of hematological malignancies. However, this therapy still faces a series of challenges, including immunogenicity, toxic side effects, and insufficient maintenance of long-term efficacy. The latest research progress has extended CAR technology to mesenchymal stem cells (MSCs), and the resulting CAR-MSCs combine the precise targeting ability of CAR molecules with the inherent immunomodulatory, tissue homing, and regenerative repair properties of MSCs, providing a new therapeutic strategy for cancer and immune-related diseases. This review examines the engineering design, biological characteristics, and applications of CAR-MSCs in oncology and immune-related disorder therapy. Preclinical studies have shown their effectiveness against glioblastoma, Ewing sarcoma, acute myeloid leukemia, and lung cancer, as well as graft-versus-host disease, through TRAIL secretion, bispecific antibody production, and Treg induction. Despite promising results, significant hurdles persist in CAR-MSC manufacturing scalability, cell persistence, heterogeneous MSC tissue sourcing, and undefined application protocols, all of which are critical for clinical translation. We investigated corresponding strategies, including nonviral gene delivery, metabolic engineering, senescence-resistant MSC clones, and microenvironment-specific activation. Standardized production workflows incorporating rigorous quality control are essential for future applications. CAR-MSCs represent a paradigm shift in precision immunotherapy by providing dual therapeutic modalities for cancer and immune disorders. Fully unlocking their therapeutic potential will require interdisciplinary efforts to overcome biological and technical barriers while advancing combination therapies.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"69 1","pages":"92"},"PeriodicalIF":28.5,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145373950","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}
Pub Date : 2025-10-24DOI: 10.1186/s13045-025-01740-z
Zijian Zhang,Chao Cheng
Clonal hematopoiesis of indeterminate potential (CHIP) is a known risk factor for hematologic malignancies (HM), but its distribution and clinical implications across diverse ancestries remain poorly characterized. In this study, we investigated CHIP and its progression to HM in a large, racially diverse cohort from the All of Us Research Program, comprising 245,388 participants. We identified 10,446 CHIP driver mutations in 9,476 individuals. Our analysis revealed clear racial disparities in CHIP prevalence and mutational profiles: African American (AA) individuals had higher odds of CHIP and exhibited distinct mutation patterns compared to White American (WA) individuals. Consistent with prior studies, CHIP was associated with an increased risk of HM, particularly myeloid malignancies. Notably, ancestry influenced the subtype of myeloid malignancy observed; CHIP was more strongly linked to myeloproliferative neoplasms in AA individuals compared with WA individuals. These findings demonstrated significant racial differences in CHIP biology and HM progression, highlighting the need for ancestry-informed approaches to CHIP risk assessment and HM prevention.
{"title":"Racial disparities in clonal hematopoiesis and their impact on hematologic malignancies.","authors":"Zijian Zhang,Chao Cheng","doi":"10.1186/s13045-025-01740-z","DOIUrl":"https://doi.org/10.1186/s13045-025-01740-z","url":null,"abstract":"Clonal hematopoiesis of indeterminate potential (CHIP) is a known risk factor for hematologic malignancies (HM), but its distribution and clinical implications across diverse ancestries remain poorly characterized. In this study, we investigated CHIP and its progression to HM in a large, racially diverse cohort from the All of Us Research Program, comprising 245,388 participants. We identified 10,446 CHIP driver mutations in 9,476 individuals. Our analysis revealed clear racial disparities in CHIP prevalence and mutational profiles: African American (AA) individuals had higher odds of CHIP and exhibited distinct mutation patterns compared to White American (WA) individuals. Consistent with prior studies, CHIP was associated with an increased risk of HM, particularly myeloid malignancies. Notably, ancestry influenced the subtype of myeloid malignancy observed; CHIP was more strongly linked to myeloproliferative neoplasms in AA individuals compared with WA individuals. These findings demonstrated significant racial differences in CHIP biology and HM progression, highlighting the need for ancestry-informed approaches to CHIP risk assessment and HM prevention.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"28 1","pages":"88"},"PeriodicalIF":28.5,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357894","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}
Pub Date : 2025-10-24DOI: 10.1186/s13045-025-01741-y
Ashley Varkey,Manpreet Bariana,Mark Batistick,John Church,Elena Cassella,Shaina Anuncio,Shabnam Samimi,Alexander J Vallone,Zephyr Hameem,Sarvarinder Gill,James McCloskey,Yiming Chen,Ming Tan,Maher Albitar,Benjamin Tycko,Kar F Chow,Giuditta Mantile-Selvaggi,David S Siegel,Johannes L Zakrzewski
B cell maturation antigen (BCMA) has emerged as a prominent immunotherapeutic target in multiple myeloma (MM) due to its restricted expression on MM cells, plasma cells and mature B cells, with minimal presence in other normal tissues. In this study, we demonstrate through RNA sequencing and flow cytometry analyses of acute myeloid leukemia (AML) cell lines and primary patient samples that BCMA is also a relevant AML-associated antigen. Its robust surface expression on AML cells positions it as a promising candidate for targeted immunotherapy. Functionally, our findings indicate that BCMA in AML operates similarly to its role in MM - engaging the NF-kB pathway upon ligand binding, thereby activating gene expression programs that support leukemia cell survival and proliferation. We assessed several BCMA-targeted immunotherapeutic strategies, including bispecific T-cell engagers (TCE) and chimeric antigen receptor (CAR) transduced T-cells, NK-cells, and macrophages. We found that TCE treatment and BCMA CAR engineering markedly improved effector cell mediated cytotoxicity against AML cells, underscoring BCMA's potential as a viable therapeutic target in AML. Furthermore, BCMA- directed TCE therapy significantly augmented the anti-leukemic activity of adoptively transferred CD8+ T-cells in a human AML xenograft model. Taken together, these findings support BCMA as a novel immunotherapeutic target in AML. Leveraging existing BCMA-directed treatments developed for MM could enable rapid clinical translation and broaden immunotherapy options for patients with AML.
{"title":"B cell maturation antigen is a novel target for immunotherapy of acute myeloid leukemia.","authors":"Ashley Varkey,Manpreet Bariana,Mark Batistick,John Church,Elena Cassella,Shaina Anuncio,Shabnam Samimi,Alexander J Vallone,Zephyr Hameem,Sarvarinder Gill,James McCloskey,Yiming Chen,Ming Tan,Maher Albitar,Benjamin Tycko,Kar F Chow,Giuditta Mantile-Selvaggi,David S Siegel,Johannes L Zakrzewski","doi":"10.1186/s13045-025-01741-y","DOIUrl":"https://doi.org/10.1186/s13045-025-01741-y","url":null,"abstract":"B cell maturation antigen (BCMA) has emerged as a prominent immunotherapeutic target in multiple myeloma (MM) due to its restricted expression on MM cells, plasma cells and mature B cells, with minimal presence in other normal tissues. In this study, we demonstrate through RNA sequencing and flow cytometry analyses of acute myeloid leukemia (AML) cell lines and primary patient samples that BCMA is also a relevant AML-associated antigen. Its robust surface expression on AML cells positions it as a promising candidate for targeted immunotherapy. Functionally, our findings indicate that BCMA in AML operates similarly to its role in MM - engaging the NF-kB pathway upon ligand binding, thereby activating gene expression programs that support leukemia cell survival and proliferation. We assessed several BCMA-targeted immunotherapeutic strategies, including bispecific T-cell engagers (TCE) and chimeric antigen receptor (CAR) transduced T-cells, NK-cells, and macrophages. We found that TCE treatment and BCMA CAR engineering markedly improved effector cell mediated cytotoxicity against AML cells, underscoring BCMA's potential as a viable therapeutic target in AML. Furthermore, BCMA- directed TCE therapy significantly augmented the anti-leukemic activity of adoptively transferred CD8+ T-cells in a human AML xenograft model. Taken together, these findings support BCMA as a novel immunotherapeutic target in AML. Leveraging existing BCMA-directed treatments developed for MM could enable rapid clinical translation and broaden immunotherapy options for patients with AML.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"13 1","pages":"89"},"PeriodicalIF":28.5,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357895","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}
Pub Date : 2025-10-24DOI: 10.1186/s13045-025-01745-8
Jingchao Su,Yifei Zeng,Zhuojin Song,Yinglu Liu,Kaixin Ou,Yuhan Wu,Minhong Huang,Yuhua Li,Sanfang Tu
Chimeric Antigen Receptor T (CAR-T) cell therapy has revolutionized cancer immunotherapy, particularly in hematological malignancies. However, the clinical application of autologous CAR-T cells faces significant high cost and manufacturing challenges. Universal allogeneic CAR-T cells, derived from healthy donors, represent a promising solution to these obstacles. These "off-the-shelf" therapies aim to reduce the complexity and cost of CAR-T production. Despite exciting advancements in genome-editing technologies and promising clinical trial data, significant challenges remain, including graft-versus-host disease (GVHD), Host-versus-graft reaction (HVGR), off-target effects, genotoxicity, and manufacturing scalability. To address these concerns, genome-editing technologies such as ZFNs, TALENs, Meganucleases, CRISPR systems, base editing, and prime editing are being employed. This review summarizes the progress of universal allogeneic CAR-T cell therapies, addresses the critical challenges, and discusses the future directions for their clinical implementation.
{"title":"Genome-edited allogeneic CAR-T cells: the next generation of cancer immunotherapies.","authors":"Jingchao Su,Yifei Zeng,Zhuojin Song,Yinglu Liu,Kaixin Ou,Yuhan Wu,Minhong Huang,Yuhua Li,Sanfang Tu","doi":"10.1186/s13045-025-01745-8","DOIUrl":"https://doi.org/10.1186/s13045-025-01745-8","url":null,"abstract":"Chimeric Antigen Receptor T (CAR-T) cell therapy has revolutionized cancer immunotherapy, particularly in hematological malignancies. However, the clinical application of autologous CAR-T cells faces significant high cost and manufacturing challenges. Universal allogeneic CAR-T cells, derived from healthy donors, represent a promising solution to these obstacles. These \"off-the-shelf\" therapies aim to reduce the complexity and cost of CAR-T production. Despite exciting advancements in genome-editing technologies and promising clinical trial data, significant challenges remain, including graft-versus-host disease (GVHD), Host-versus-graft reaction (HVGR), off-target effects, genotoxicity, and manufacturing scalability. To address these concerns, genome-editing technologies such as ZFNs, TALENs, Meganucleases, CRISPR systems, base editing, and prime editing are being employed. This review summarizes the progress of universal allogeneic CAR-T cell therapies, addresses the critical challenges, and discusses the future directions for their clinical implementation.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"73 1","pages":"90"},"PeriodicalIF":28.5,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357897","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}
Cluster of differentiation 47 (CD47) delivers an inhibitory signal that suppresses phagocytosis and prevents immune clearance of tumor cells by interacting with signal regulatory protein alpha (SIRPα) on myeloid cells. Although blockade of the CD47-SIRPα axis is a promising immunotherapeutic strategy, clinical development has been hindered by on-target toxicities (e.g., severe anemia) and insufficient potency. Herein we report a third generation CD47-SIRPα inhibitor HCB101, a rationally designed SIRPα-Fc fusion protein generated from a large-scale screening of a structure-guided SIRPα extracellular domain (ECD) mutant library and fused to a human IgG4 Fc. HCB101 demonstrates high-affinity binding to CD47, robustly promotes macrophage-mediated phagocytosis of tumor cells without affecting red blood cells and exhibits unique advantages over current CD47-targeting agents, including Hu5F9-G4, TTI-622, and ALX148. In multiple xenograft cancer models, HCB101 induced significant inhibition of tumor growth as a single agent and showed synergistic anti-tumor effects when combined with anti-HER2 or anti-EGFR monoclonal antibodies. Additionally, HCB101 treatment increased the M1/M2 macrophage ratio in the tumor microenvironment, suggesting repolarization of tumor-associated macrophages (TAMs) toward a pro-inflammatory phenotype. No dose-limiting toxicities or hematologic adverse effects were observed in murine or non-human primate studies.
{"title":"HCB101: a novel potent ligand-trap Fc-fusion protein targeting the CD47-SIRPα pathway with high safety and preclinical efficacy for hematological and solid tumors.","authors":"Jiin-Tarng Wang,Chi-Ling Tseng,Han-Fang Teng,Pan-Hsien Kuo,Yun-Chih Cheng,Yi-Jing Chen,Yi-Hsuan Lu,Chun-Chung Wang,Tsai-Kuei Shen,Hong-Fan Wang,Pei-Lun Tsai,Yu-Chen Wu,Chien-Hsin Ho,Wei-Tse Sun,Yen-Cheng Li,Yi-Hsuan Lee,Yu-Jiun Hung,Mingyi Chen,Zihai Li,Zong Sean Juo,Wenwu Zhai,Scott Shi-Kau Liu","doi":"10.1186/s13045-025-01742-x","DOIUrl":"https://doi.org/10.1186/s13045-025-01742-x","url":null,"abstract":"Cluster of differentiation 47 (CD47) delivers an inhibitory signal that suppresses phagocytosis and prevents immune clearance of tumor cells by interacting with signal regulatory protein alpha (SIRPα) on myeloid cells. Although blockade of the CD47-SIRPα axis is a promising immunotherapeutic strategy, clinical development has been hindered by on-target toxicities (e.g., severe anemia) and insufficient potency. Herein we report a third generation CD47-SIRPα inhibitor HCB101, a rationally designed SIRPα-Fc fusion protein generated from a large-scale screening of a structure-guided SIRPα extracellular domain (ECD) mutant library and fused to a human IgG4 Fc. HCB101 demonstrates high-affinity binding to CD47, robustly promotes macrophage-mediated phagocytosis of tumor cells without affecting red blood cells and exhibits unique advantages over current CD47-targeting agents, including Hu5F9-G4, TTI-622, and ALX148. In multiple xenograft cancer models, HCB101 induced significant inhibition of tumor growth as a single agent and showed synergistic anti-tumor effects when combined with anti-HER2 or anti-EGFR monoclonal antibodies. Additionally, HCB101 treatment increased the M1/M2 macrophage ratio in the tumor microenvironment, suggesting repolarization of tumor-associated macrophages (TAMs) toward a pro-inflammatory phenotype. No dose-limiting toxicities or hematologic adverse effects were observed in murine or non-human primate studies.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"68 1","pages":"87"},"PeriodicalIF":28.5,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351639","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}
Pub Date : 2025-10-13DOI: 10.1186/s13045-025-01736-9
Yan-Ruide Li,Xinyuan Shen,Yichen Zhu,Zhe Li,Ryan Hon,Yanxin Tian,Jie Huang,Annabel S Zhao,Nathan Y Ma,Catherine Zhang,David Lin,Karine Sargsyan,Yuan Yuan,Lili Yang
BACKGROUNDTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the lack of ER, PR, and HER2 expression. Its aggressive behavior, high degree of tumor heterogeneity, and immunosuppressive tumor microenvironment (TME) are associated with poor clinical outcomes, rapid disease progression, and limited therapeutic options. Although chimeric antigen receptor (CAR)-engineered T cell therapy has shown certain promise, its applicability in TNBC is hindered by antigen escape, TME-mediated suppression, and the logistical constraints of autologous cell production.METHODSIn this study, we employed hematopoietic stem and progenitor cell (HSPC) gene engineering and a feeder-free HSPC differentiation culture to generate allogeneic IL-15-enhanced, mesothelin-specific CAR-engineered invariant natural killer T (Allo15MCAR-NKT) cells.RESULTSThese cells demonstrated robust and multifaceted antitumor activity against TNBC, mediated by CAR- and NK receptor-dependent cytotoxicity, as well as selective targeting of CD1d+ TME immunosuppressive cells through their TCR. In both orthotopic and metastatic TNBC xenograft models, Allo15MCAR-NKT cells demonstrated potent antitumor activity, associated with robust effector and cytotoxic phenotypes, low exhaustion, and a favorable safety profile without inducing graft-versus-host disease.CONCLUSIONSTogether, these results support Allo15MCAR-NKT cells as a next-generation, off-the-shelf immunotherapy with strong therapeutic potential for TNBC, particularly in the context of metastasis, immune evasion, and treatment resistance.
{"title":"Targeting triple-negative breast cancer using cord-blood CD34⁺ HSPC-derived mesothelin-specific CAR-NKT cells with potent antitumor activity.","authors":"Yan-Ruide Li,Xinyuan Shen,Yichen Zhu,Zhe Li,Ryan Hon,Yanxin Tian,Jie Huang,Annabel S Zhao,Nathan Y Ma,Catherine Zhang,David Lin,Karine Sargsyan,Yuan Yuan,Lili Yang","doi":"10.1186/s13045-025-01736-9","DOIUrl":"https://doi.org/10.1186/s13045-025-01736-9","url":null,"abstract":"BACKGROUNDTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the lack of ER, PR, and HER2 expression. Its aggressive behavior, high degree of tumor heterogeneity, and immunosuppressive tumor microenvironment (TME) are associated with poor clinical outcomes, rapid disease progression, and limited therapeutic options. Although chimeric antigen receptor (CAR)-engineered T cell therapy has shown certain promise, its applicability in TNBC is hindered by antigen escape, TME-mediated suppression, and the logistical constraints of autologous cell production.METHODSIn this study, we employed hematopoietic stem and progenitor cell (HSPC) gene engineering and a feeder-free HSPC differentiation culture to generate allogeneic IL-15-enhanced, mesothelin-specific CAR-engineered invariant natural killer T (Allo15MCAR-NKT) cells.RESULTSThese cells demonstrated robust and multifaceted antitumor activity against TNBC, mediated by CAR- and NK receptor-dependent cytotoxicity, as well as selective targeting of CD1d+ TME immunosuppressive cells through their TCR. In both orthotopic and metastatic TNBC xenograft models, Allo15MCAR-NKT cells demonstrated potent antitumor activity, associated with robust effector and cytotoxic phenotypes, low exhaustion, and a favorable safety profile without inducing graft-versus-host disease.CONCLUSIONSTogether, these results support Allo15MCAR-NKT cells as a next-generation, off-the-shelf immunotherapy with strong therapeutic potential for TNBC, particularly in the context of metastasis, immune evasion, and treatment resistance.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"37 1","pages":"86"},"PeriodicalIF":28.5,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145277210","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}
Combination therapy is rapidly becoming the cornerstone of hepatocellular carcinoma (HCC) treatment. Immune checkpoint inhibitors (ICIs) have emerged as a central strategy in systemic therapy, yet their efficacy as monotherapies remains limited. Consequently, combinatorial approaches, such as ICIs-Tyrosine kinase inhibitors (TKIs), ICIs-chemotherapy, and dual ICI regimens, are gaining momentum. While clinical trials have established efficacy benchmarks, mechanistic insights remain scarce, partly due to the limitations of current preclinical models in mimicking the complex tumor microenvironment (TME). Given the substantial heterogeneity of HCC, spanning genetic, transcriptomic, and immunologic dimensions, treatment outcomes vary widely. Additional factors such as gut microbiota and epigenetic modifications further influence therapeutic response and resistance. Although PD-1, PD-L1, and CTLA-4 inhibitors are widely used, unresponsiveness is common. Novel targets such as LAG-3, TIM-3, TIGIT, and VISTA, as well as strategies to reprogram fibrotic and immunosuppressive TME, are under active investigation. Ultimately, translating basic insights into personalized therapy will depend on predictive biomarkers and integrated analyses that account for the complex interactions among tumor cells, the immune system, and the TME. This review synthesizes current knowledge and cellular mechanisms underpinning combination therapies, highlights therapeutic synergies, and discusses emerging directions for stratified treatment in HCC.
{"title":"Combination immunotherapy in hepatocellular carcinoma: synergies among immune checkpoints, TKIs, and chemotherapy","authors":"Suoyi Dai, Yuhang Chen, Wenxun Cai, Shu Dong, Jiangang Zhao, Lianyu Chen, Chien-Shan Cheng","doi":"10.1186/s13045-025-01739-6","DOIUrl":"https://doi.org/10.1186/s13045-025-01739-6","url":null,"abstract":"Combination therapy is rapidly becoming the cornerstone of hepatocellular carcinoma (HCC) treatment. Immune checkpoint inhibitors (ICIs) have emerged as a central strategy in systemic therapy, yet their efficacy as monotherapies remains limited. Consequently, combinatorial approaches, such as ICIs-Tyrosine kinase inhibitors (TKIs), ICIs-chemotherapy, and dual ICI regimens, are gaining momentum. While clinical trials have established efficacy benchmarks, mechanistic insights remain scarce, partly due to the limitations of current preclinical models in mimicking the complex tumor microenvironment (TME). Given the substantial heterogeneity of HCC, spanning genetic, transcriptomic, and immunologic dimensions, treatment outcomes vary widely. Additional factors such as gut microbiota and epigenetic modifications further influence therapeutic response and resistance. Although PD-1, PD-L1, and CTLA-4 inhibitors are widely used, unresponsiveness is common. Novel targets such as LAG-3, TIM-3, TIGIT, and VISTA, as well as strategies to reprogram fibrotic and immunosuppressive TME, are under active investigation. Ultimately, translating basic insights into personalized therapy will depend on predictive biomarkers and integrated analyses that account for the complex interactions among tumor cells, the immune system, and the TME. This review synthesizes current knowledge and cellular mechanisms underpinning combination therapies, highlights therapeutic synergies, and discusses emerging directions for stratified treatment in HCC. ","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"42 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141544","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}
Cancer immunotherapy has revolutionized oncology by leveraging the immune system to combat tumors. Among various biomarkers, neoantigens and tumor mutational burden (TMB) have emerged as critical factors in tailoring personalized treatments. Neoantigens are tumor-specific peptides displayed on cancer cell surfaces, derived from somatic mutations. Recognized as "non-self" by the immune system, they trigger T-cell responses and enable therapies like personalized vaccines and adoptive T-cell transfer. Critically, neoantigen potential correlates with TMB, which quantifies the total somatic mutations within a tumor genome. A higher TMB generally correlates with a greater likelihood of generating immunogenic neoantigens, making it a predictive biomarker for the efficacy of immune checkpoint inhibitors (ICI). Progress in high-throughput sequencing, bioinformatics, and immuno-peptidomics has significantly enhanced the accuracy of neoantigen prediction, including assessments of major histocompatibility complex (MHC) binding affinity and T-cell receptor recognition. Clinically, neoantigen-based therapies have shown efficacy in early trials, with strategies such as mRNA vaccines demonstrating synergy with ICI by boosting T-cell activation and overcoming immune suppression. Combining neoantigen-based therapies with chemotherapy and radiotherapy harnesses synergistic mechanisms to enhance efficacy, overcome resistance, and emerge as a pivotal oncology research focus. The integration of TMB into clinical practice has received regulatory approval as a biomarker for stratifying patients for ICI therapies. Furthermore, advanced methodologies like liquid biopsy and single-cell technologies have streamlined TMB measurement, improving its predictive value for personalized immunotherapy. Collectively, neoantigens and TMB have optimized the evolution of precision immuno-oncology by providing frameworks that maximize therapeutic efficacy, overcome resistance mechanisms, and advance durable cancer remission.
{"title":"The role of neoantigens and tumor mutational burden in cancer immunotherapy: advances, mechanisms, and perspectives","authors":"Shengbo Sun, Lanchun Liu, Jingkang Zhang, Liting Sun, Wenlong Shu, Zhengyang Yang, Hongwei Yao, Zhongtao Zhang","doi":"10.1186/s13045-025-01732-z","DOIUrl":"https://doi.org/10.1186/s13045-025-01732-z","url":null,"abstract":"Cancer immunotherapy has revolutionized oncology by leveraging the immune system to combat tumors. Among various biomarkers, neoantigens and tumor mutational burden (TMB) have emerged as critical factors in tailoring personalized treatments. Neoantigens are tumor-specific peptides displayed on cancer cell surfaces, derived from somatic mutations. Recognized as \"non-self\" by the immune system, they trigger T-cell responses and enable therapies like personalized vaccines and adoptive T-cell transfer. Critically, neoantigen potential correlates with TMB, which quantifies the total somatic mutations within a tumor genome. A higher TMB generally correlates with a greater likelihood of generating immunogenic neoantigens, making it a predictive biomarker for the efficacy of immune checkpoint inhibitors (ICI). Progress in high-throughput sequencing, bioinformatics, and immuno-peptidomics has significantly enhanced the accuracy of neoantigen prediction, including assessments of major histocompatibility complex (MHC) binding affinity and T-cell receptor recognition. Clinically, neoantigen-based therapies have shown efficacy in early trials, with strategies such as mRNA vaccines demonstrating synergy with ICI by boosting T-cell activation and overcoming immune suppression. Combining neoantigen-based therapies with chemotherapy and radiotherapy harnesses synergistic mechanisms to enhance efficacy, overcome resistance, and emerge as a pivotal oncology research focus. The integration of TMB into clinical practice has received regulatory approval as a biomarker for stratifying patients for ICI therapies. Furthermore, advanced methodologies like liquid biopsy and single-cell technologies have streamlined TMB measurement, improving its predictive value for personalized immunotherapy. Collectively, neoantigens and TMB have optimized the evolution of precision immuno-oncology by providing frameworks that maximize therapeutic efficacy, overcome resistance mechanisms, and advance durable cancer remission.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"31 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928246","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}
Pub Date : 2025-09-01DOI: 10.1186/s13045-025-01738-7
Juanjuan Shang, Mei Ding, Xiangxiang Zhou
S-palmitoylation, one reversible post-translational modification (PTM) involving the binding of palmitate to proteins, influences protein stability, localization and interactions. Through S-palmitoylation, proteins can be targeted to specific cellular compartments, form functional complexes, and participate in intricate signaling cascades. Organized and reversible S-palmitoylation process achieves remarkable roles in the precise orchestration of biological activities, including cell signaling, membrane trafficking, synaptic transmission and cellular immunity. S-palmitoylation has been implicated in the pathogenesis of diverse disorders including cancers, cardiovascular diseases, metabolic diseases, immunological diseases, infection diseases, nervous system and mental diseases. Altered S-palmitoylation of proteins changes the oncogenic function, synaptic localization, enzymatic activity and signaling transduction, potentially contributing to disease progression. Understanding and targeting S-palmitoylation pathways hold promise for therapeutic interventions in associated diseases. Collectively, S-palmitoylation is a key regulatory mechanism with significant implications for disease pathogenesis. Investigating the role of S-palmitoylation provides insights into diagnostic markers and potential therapeutic targets, highlighting the importance of ongoing research in understanding the broader implications of S-palmitoylation in health and disease.
s -棕榈酰化是一种可逆的翻译后修饰（PTM），涉及棕榈酸酯与蛋白质的结合，影响蛋白质的稳定性、定位和相互作用。通过s -棕榈酰化，蛋白质可以靶向特定的细胞区室，形成功能复合物，并参与复杂的信号级联反应。有组织的可逆s -棕榈酰化过程在细胞信号传导、膜运输、突触传递和细胞免疫等生物活动的精确协调中发挥着重要作用。s -棕榈酰化与多种疾病的发病机制有关，包括癌症、心血管疾病、代谢疾病、免疫疾病、传染病、神经系统疾病和精神疾病。s -棕榈酰化蛋白的改变改变了致癌功能、突触定位、酶活性和信号转导，可能导致疾病进展。理解和靶向s -棕榈酰化途径为相关疾病的治疗干预带来了希望。总的来说，s -棕榈酰化是一个关键的调控机制，对疾病的发病机制具有重要意义。研究s -棕榈酰化的作用提供了对诊断标记物和潜在治疗靶点的见解，强调了正在进行的研究在理解s -棕榈酰化在健康和疾病中的更广泛含义方面的重要性。
{"title":"Recent advances in S-palmitoylation and its emerging roles in human diseases","authors":"Juanjuan Shang, Mei Ding, Xiangxiang Zhou","doi":"10.1186/s13045-025-01738-7","DOIUrl":"https://doi.org/10.1186/s13045-025-01738-7","url":null,"abstract":"S-palmitoylation, one reversible post-translational modification (PTM) involving the binding of palmitate to proteins, influences protein stability, localization and interactions. Through S-palmitoylation, proteins can be targeted to specific cellular compartments, form functional complexes, and participate in intricate signaling cascades. Organized and reversible S-palmitoylation process achieves remarkable roles in the precise orchestration of biological activities, including cell signaling, membrane trafficking, synaptic transmission and cellular immunity. S-palmitoylation has been implicated in the pathogenesis of diverse disorders including cancers, cardiovascular diseases, metabolic diseases, immunological diseases, infection diseases, nervous system and mental diseases. Altered S-palmitoylation of proteins changes the oncogenic function, synaptic localization, enzymatic activity and signaling transduction, potentially contributing to disease progression. Understanding and targeting S-palmitoylation pathways hold promise for therapeutic interventions in associated diseases. Collectively, S-palmitoylation is a key regulatory mechanism with significant implications for disease pathogenesis. Investigating the role of S-palmitoylation provides insights into diagnostic markers and potential therapeutic targets, highlighting the importance of ongoing research in understanding the broader implications of S-palmitoylation in health and disease.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"13 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928247","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}
Pub Date : 2025-08-29DOI: 10.1186/s13045-025-01737-8
Ning Jiang, Zhaoyi Yang, Huilei Miao, Shujun Xing, Shuhang Wang, Ning Li
While chimeric antigen receptor (CAR) T cell therapy is highly effective for hematological malignancies, its widespread use is limited by complex, patient-specific manufacturing. Universal CAR-T (UCAR-T) cells, derived from allogeneic donors, offer a potential "off-the-shelf" solution. However, their clinical translation hinges on overcoming two key immunological barriers: graft-versus-host disease (GvHD) and host-versus-graft rejection (HvGR), which compromise safety and therapeutic persistence. This review summarizes recent advances in UCAR-T cell engineering and clinical strategies designed to improve both safety and efficacy. We discuss gene-editing technologies—such as CRISPR/Cas9 and base editors—used to prevent GvHD by ablating the T cell receptor (TCR) and to evade HvGR by disrupting human leukocyte antigen (HLA) expression. We also explore the development of UCAR-T products from alternative cell sources with low intrinsic alloreactivity, such as γδ T cells. Furthermore, we detail multifaceted approaches to augment UCAR-T cell function and persistence, from the perspectives of enhancing intrinsic functions, reshaping the tumor microenvironment (TME) and overcoming tumor heterogeneity. Finally, we analyze recent clinical trial outcomes, which show promising efficacy in hematological malignancies but highlight ongoing challenges in solid tumors. The continued integration of sophisticated cellular engineering with innovative clinical strategies—such as enhanced lymphodepletion, combination therapies, and alternative administration routes—will be essential to realize the full potential of UCAR-T as a widely accessible and potent cell therapy.
{"title":"Recent advances in universal chimeric antigen receptor T cell therapy","authors":"Ning Jiang, Zhaoyi Yang, Huilei Miao, Shujun Xing, Shuhang Wang, Ning Li","doi":"10.1186/s13045-025-01737-8","DOIUrl":"https://doi.org/10.1186/s13045-025-01737-8","url":null,"abstract":"While chimeric antigen receptor (CAR) T cell therapy is highly effective for hematological malignancies, its widespread use is limited by complex, patient-specific manufacturing. Universal CAR-T (UCAR-T) cells, derived from allogeneic donors, offer a potential \"off-the-shelf\" solution. However, their clinical translation hinges on overcoming two key immunological barriers: graft-versus-host disease (GvHD) and host-versus-graft rejection (HvGR), which compromise safety and therapeutic persistence. This review summarizes recent advances in UCAR-T cell engineering and clinical strategies designed to improve both safety and efficacy. We discuss gene-editing technologies—such as CRISPR/Cas9 and base editors—used to prevent GvHD by ablating the T cell receptor (TCR) and to evade HvGR by disrupting human leukocyte antigen (HLA) expression. We also explore the development of UCAR-T products from alternative cell sources with low intrinsic alloreactivity, such as γδ T cells. Furthermore, we detail multifaceted approaches to augment UCAR-T cell function and persistence, from the perspectives of enhancing intrinsic functions, reshaping the tumor microenvironment (TME) and overcoming tumor heterogeneity. Finally, we analyze recent clinical trial outcomes, which show promising efficacy in hematological malignancies but highlight ongoing challenges in solid tumors. The continued integration of sophisticated cellular engineering with innovative clinical strategies—such as enhanced lymphodepletion, combination therapies, and alternative administration routes—will be essential to realize the full potential of UCAR-T as a widely accessible and potent cell therapy.","PeriodicalId":16023,"journal":{"name":"Journal of Hematology & Oncology","volume":"29 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144919390","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}
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