Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Beyond DNA damage: 3D tumor models and the integrin mechanobiology of radioresistance.","authors":"Nils Cordes","doi":"10.1186/s13046-026-03803-6","DOIUrl":"10.1186/s13046-026-03803-6","url":null,"abstract":"<p><p>Despite major advances in radiation delivery, clinical outcomes remain constrained by tumor biology rather than technology. Conventional radiobiology has relied on reductionist two-dimensional (2D) systems that fail to capture the spatial, mechanical, and multicellular organization of tumors. Three-dimensional (3D) tumor models now resolve radiation response as a mechanobiological process coordinated across the extracellular matrix (ECM), adhesion signaling, cytoskeleton, and nucleus. This review focuses on a specific and we argue, underappreciated intersection: how 3D models expose integrin-mediated mechanotransduction as a determinant of the DNA damage response (DDR) and therapy resistance epitomized by cell adhesion-mediated radioresistance (CAM-RR) - an organizing principle we frame as the ECM-integrin-nucleus axis. We first delineate which model classes resolve which layer of this biology, distinguishing effects of three-dimensional organization from those of defined ECM-integrin signaling, and we treat the underlying mechanobiology quantitatively rather than descriptively. We then develop a mechanistic framework linking ECM architecture and stiffness to integrin-RTK crosstalk, cytoskeletal tension, LINC-mediated force transfer, and chromatin-dependent DNA repair, in which radiosensitivity emerges as a property of tissue context. From a translational standpoint, 3D models enable functional, radiation-specific assessment of context-dependent radiosensitivity and of mechanically targeted radiosensitization, while their integration with quantitative imaging and computational approaches further supports biomarker-guided and adaptive treatment strategies. We close with testable predictions that this framework generates, intended to guide the next phase of biology-driven radiation oncology.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13439798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148680723","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":"PROTAC technology for sensitizing melanoma to immune checkpoint therapy.","authors":"Qiujun Zhou, Xiaowei Zhang, Chenlu Zhao, Difei Chen, Chen Chu, Xiaoliang Jin","doi":"10.1186/s13046-026-03799-z","DOIUrl":"https://doi.org/10.1186/s13046-026-03799-z","url":null,"abstract":"<p><p>Melanoma remains one of the most aggressive malignancies, with limited response to immune checkpoint inhibitors (ICIs) due to primary or acquired resistance. Proteolysis-targeting chimeras (PROTACs) have emerged as a novel therapeutic modality that induces selective degradation of target proteins via the ubiquitin-proteasome system, offering distinct advantages over conventional inhibitors. This review summarizes the design principles and molecular mechanisms of PROTACs, and highlights their emerging role in sensitizing melanoma to immunotherapy. Specifically, PROTACs can restore tumor antigen presentation, reprogram the immunosuppressive tumor microenvironment by targeting regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, and suppress key oncogenic signaling pathways. We also discuss combination strategies with PD-1/PD-L1 and CTLA-4 blockade, as well as current challenges including poor cell permeability, off-target effects, and acquired resistance. Finally, future perspectives on rational design, tissue-specific delivery systems, and clinical translation are addressed.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149301737","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":"Beyond conventional immune checkpoints: the LILRB axis as a dual regulator of tumor and immune cell states.","authors":"Alessandro Scagliotti, Ivan Depetro, Giorgia Tiberi, Paula Ariadna Diez-Villegas, Ermes Candiello, Paola Cappello","doi":"10.1186/s13046-026-03796-2","DOIUrl":"https://doi.org/10.1186/s13046-026-03796-2","url":null,"abstract":"<p><p>Immune checkpoint blockade targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/PD-L1 has transformed cancer therapy. However, limited response rates and frequent resistance highlight additional mechanisms of immune suppression within the tumor microenvironment (TME), particularly those driven by myeloid and innate immune compartments. The leukocyte immunoglobulin-like receptor B (LILRB) family has emerged as a central regulatory axis integrating immune and tumor cell-intrinsic programs. Beyond restraining immune activation, LILRB receptors reprogram myeloid cells toward tolerogenic states and, when expressed by tumor cells, directly sustain proliferation, metabolic adaptation, angiogenesis, and immune evasion. This dual functionality positions the LILRB axis as a system-level checkpoint linking immune suppression with tumor cell fitness. Here, we synthesize current knowledge on LILRB biology and discuss its implications for cancer immunotherapy, highlighting how targeting this pathway may overcome resistance to PD-1/PD-L1 blockade and enable more effective combination strategies aimed at reprogramming the tumor-immune ecosystem.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149301694","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":"Cancer therapy resistance converges on immune evasion: a unified framework from immunotherapy to targeted, endocrine, and DNA repair pathways.","authors":"Ha-Eun Jeong, Heesun Choi, Wan-Teck Lim, Su Bin Lim, Joon-Yong An","doi":"10.1186/s13046-026-03798-0","DOIUrl":"https://doi.org/10.1186/s13046-026-03798-0","url":null,"abstract":"<p><strong>Background: </strong>Cancer immunotherapy, including immune checkpoint inhibitors, chimeric antigen receptor T-cell (CAR-T) therapy, and bispecific antibodies, has transformed the treatment of advanced malignancies, yet primary and acquired resistance remain major barriers to durable benefit. Across these therapies, resistance reflects the failure of one or more of three shared requirements for effective antitumor immunity: tumor immune visibility, lost through defective antigen presentation and interferon signaling; immune access to tumor nests, restricted by stromal and vascular barriers; and effector cell function, undermined by suppressive myeloid and regulatory populations, metabolic restriction, and loss of tertiary lymphoid structures.</p><p><strong>Main body: </strong>In this review, we argue that resistance to targeted therapies, endocrine therapies, and PARP inhibitors should not be treated as a problem separate from immunotherapy resistance. Rather, these resistant states often converge on the same three axes that govern immunotherapy resistance (immune visibility, access, and effector function), yielding a unified framework across therapeutic classes. Using canonical immunotherapy resistance as a reference model, we examine how osimertinib resistance, androgen receptor (AR)-pathway-resistant states, and BRCA reversion-mediated PARP inhibitor resistance may remodel these same immune-evasion axes. Targeted therapy resistance provides the most complete case, with epithelial-mesenchymal transition, PD-L1 upregulation, STING suppression, and immune exclusion extending across all three axes. AR pathway reactivation shows plausible links to immune remodeling through direct MHC-I repression and myeloid reprogramming, although the clinical evidence base remains less mature. BRCA reversion illustrates a mechanistically suggestive dual-valence state in which restored DNA repair may diminish innate immune sensing while also generating computationally predicted junctional neopeptides whose immunogenicity remains to be validated.</p><p><strong>Conclusions: </strong>By reframing resistance as a new immune state that converges on the same three immune-evasion axes rather than a terminal event, this review shifts attention from why a therapy failed to which immune-evasion axis now predominates and how it might be countered. This perspective supports mechanism-matched combination therapy, adaptive molecular monitoring, and cautious exploitation of vulnerabilities generated by the resistant state itself. As an organizing model rather than a claim of uniform causality, the framework now requires prospective validation.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13711850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149289660","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":"U2 snRNP inhibition hampers pancreatic cancer cell viability by disrupting DNA repair proficiency and mitotic checkpoint integrity.","authors":"Valentina Panzeri, Marco Pieraccioli, Veronica Ruta, Maria Vittoria Manno, Cinzia Caggiano, Duaa Hartem, Alessia Riente, Giacomo Milletti, Giuseppe Quero, Sergio Alfieri, Juan Carlos López-Gil, Ana Galván-Del-Rey, Carmen Guerra, Giuseppe Maulucci, Claudio Sette","doi":"10.1186/s13046-026-03795-3","DOIUrl":"https://doi.org/10.1186/s13046-026-03795-3","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with remarkably poor prognosis. Splicing dysregulation is emerging as a hallmark and possible therapeutic target of PDAC.</p><p><strong>Methods: </strong>We performed high-throughput RNA sequencing analyses in PANC-1 cells treated with three drugs targeting the U2 small nuclear ribonucleoprotein (U2 snRNP): Pladienolide B, Thailanstatin A and Indisulam. The efficacy of splicing inhibitors, Talazoparib, Alisertib, AZD7762 and Barisertib, alone or in combination, was assessed in PDAC cells and patient-derived organoids (PDOs) by cell viability assays. RT-PCR, western blot and cell cycle assays were performed to evaluate the expression of DNA repair and mitotic genes and the execution of mitosis. PANC-1 cells were engineered to stably co-express GFP-tagged H2b histone and RFP-tagged β-tubulin by CRISPR/Cas-9 technology and used for time-lapse confocal microscopy and immunofluorescence analyses.</p><p><strong>Results: </strong>Genes encoding for the U2 snRNP, which recognizes the 3' splice site, are upregulated in advanced PDAC. U2 snRNP-targeting drugs impair the DNA damage response (DDR) pathway in homologous recombination-proficient PDAC cells and PDOs, thus enhancing their sensitivity to PARP inhibitors. Genes whose splicing was disrupted by all three drugs are characterized by higher expression, more exon-intron junctions, weak 5' splice sites and atypical GC content. These features are enriched in mitotic genes (e.g. AURKA, AURKB, CHEK1), whose expression is strongly deregulated by splicing perturbation. Accordingly, splicing inhibition causes severe mitotic defects, leading to the accumulation of cells with misaligned condensed chromosomes on monopolar or bipolar spindles. Notably, high expression of AURKA, AURKB and CHEK1 correlates with poor prognosis in PDAC patients, whereas combined treatments with inhibitors of these mitotic kinases strongly impair the viability of PDAC cells and PDOs.</p><p><strong>Conclusions: </strong>These findings uncover gene features associated with sensitivity to splicing inhibitors in PDAC cells and suggest that the DDR and mitosis are biological processes highly sensitive to splicing perturbation.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660249/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149185796","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":"Cholesterol metabolism reprogramming: shaping tumor immunity and immunotherapy.","authors":"Jing-Wen Meng, Yue-Tao Tan, Shan-Mei Chen, Ting Li, Hui Wang","doi":"10.1186/s13046-026-03791-7","DOIUrl":"10.1186/s13046-026-03791-7","url":null,"abstract":"<p><p>Cholesterol, a vital biomolecule with essential physiological functions, undergoes frequent reprogramming of its metabolic pathways during tumorigenesis and progression. This reprogramming enables it to participate in immune regulation through multiple mechanisms. Accumulating evidence reveals the aberrant activation of cholesterol metabolic pathways across various malignancies. This dysregulation is characterized by enhanced synthesis, increased uptake, reduced efflux, and the accumulation of derivatives, such as cholesteryl esters and oxysterols. These alterations suggest that targeting cholesterol metabolism represents a promising strategy to enhance the efficacy of tumor immunotherapy. In cancer cells, reprogrammed cholesterol metabolism supports proliferation, stemness, and resistance to cell death, including ferroptosis and autophagy. Conversely, in immune cells, it modulates effector functions, polarization states, and the expression of immune checkpoints like PD-L1. Collectively, these effects shape an immunosuppressive tumor microenvironment that facilitates immune evasion. Furthermore, cholesterol metabolism intersects with critical oncogenic signaling pathways and is fine-tuned by non-coding RNAs, thereby further driving tumor progression and therapy resistance. This review systematically delineates the regulatory landscape of cholesterol homeostasis in both malignant and immune cells, highlighting its multifaceted impact on tumor immunity and therapeutic responses. A deeper understanding of cholesterol and its metabolite dynamics within the tumor microenvironment, as well as their crosstalk with other signaling networks, will not only aid in optimizing current immunotherapeutic approaches but also provide a crucial conceptual foundation for developing novel combination strategies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13711863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149276512","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":"ERK/GATAD2A/SAA1 axis drives osimertinib resistance via NF-κB and macrophage reprogramming in EGFR-mutated lung adenocarcinoma.","authors":"Junkan Zhu, Shencheng Ren, Tao Cheng, Guangyao Shan, Han Lin, Xiaolong Huang, Yunyi Bian, Lewei Duan, Yidu Hu, Yingting Wu, Dejun Zeng, Yongqiang Ao, Jiaqi Liang, Shuai Wang, Cheng Zhan","doi":"10.1186/s13046-026-03792-6","DOIUrl":"10.1186/s13046-026-03792-6","url":null,"abstract":"<p><strong>Background: </strong>Acquired resistance significantly limits the long-term clinical benefit of osimertinib in EGFR-mutant lung adenocarcinoma (LUAD). However, the early non-genetic adaptations and microenvironmental crosstalk that enable initial tumor survival remain poorly defined. This study aimed to elucidate the epigenetic-immune mechanisms driving osimertinib resistance and to identify novel actionable therapeutic targets.</p><p><strong>Methods: </strong>We integrated transcriptomic profiling and clinical cohort analyses to identify therapy-induced secreted factors during the evolution of EGFR-TKI resistance. The upstream regulatory mechanisms were characterized using ChIP, Co-IP, and dual-luciferase reporter assays. The dual functional roles of the identified factor, serum amyloid A1 (SAA1), in tumor-intrinsic signaling and macrophage polarization were investigated in vitro. Finally, the therapeutic efficacy of combining SAA1 neutralization with osimertinib was evaluated across patient-derived organoids, xenografts, and immunocompetent spontaneous lung tumor models.</p><p><strong>Results: </strong>We identified SAA1 as a critical therapy-induced secreted factor that progressively increases during the transition from drug tolerance to established resistance, which negatively correlates with clinical outcomes in patients receiving osimertinib. Mechanistically, osimertinib treatment suppressed the ERK-dependent phosphorylation of the transcriptional repressor GATAD2A at Ser114. This event destabilized the NuRD complex, thereby relieving the epigenetic transcriptional repression of SAA1. Secreted SAA1 promoted therapeutic resistance through dual mechanisms: activating the autocrine TLR4/NF-κB survival signaling in tumor cells and inducing the paracrine polarization of pro-tumorigenic SPP1⁺ macrophages. Therapeutically, targeted neutralization of SAA1 synergized robustly with osimertinib to reverse immunosuppressive remodeling and induce profound tumor regression in multiple preclinical models.</p><p><strong>Conclusions: </strong>Our findings define a novel therapy-induced ERK/GATAD2A/SAA1 epigenetic-immune axis that drives acquired resistance to osimertinib. SAA1 acts as a pivotal bridge between tumor-intrinsic survival adaptations and microenvironmental immune suppression, highlighting SAA1 neutralization as a tractable combinatorial strategy to enhance EGFR-TKI efficacy in LUAD.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13693122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149247326","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":"Transcriptional evidence of neuroendocrine cell plasticity beyond histological boundaries in lung neuroendocrine neoplasms: an in-silico analysis suggesting a progression model.","authors":"Giuseppe Pelosi, Mauro Papotti, Riccardo Papa, Eleonora Duregon, Maria Gemelli, Sergio Harari, Angelica Sonzogni, Alice Laffi, Tommaso De Pas, Chiara Catania, Barbara Bassani, Fiorenza Lotti, Antonino Bruno, Paola Muti, Fabrizio Bianchi","doi":"10.1186/s13046-026-03790-8","DOIUrl":"10.1186/s13046-026-03790-8","url":null,"abstract":"<p><p>Little is known as to whether there may be a patogenetic continuum among subsets of lung neuroendocrine neoplasms (NENs), including both neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). In this study, transcriptomic data from 205 pulmonary NETs and NECs were collected from four publicly available datasets and analyzed through supervised clustering of a curated 20-gene signature dealing with neuroendocrine differentiation, key oncogenic pathways, chromatin remodeling genes, and lineage-specific transcription factors. Two major clusters were identified, PNEN-A and PNEN-B. Compared to PNEN-A and independently of histological typing, PNEN-B demonstrated reduced neuroendocrine gene expression and increased activation of pulmonary epithelial cell lineages, such as glandular (club/AT2⁺), basal (ΔNp63⁺/p63⁺/CK5⁺), and tuft cell (POU2F3⁺) differentiation. PNEN-B tumors also exhibited features of inflamed but functionally constrained immune microenvironment, with increased expression of immunomodulatory neuropeptides (calcitonin, proopiomelanocortin, and gastrin-releasing peptide), alongside enrichment of T cell exhaustion markers. PNEN-B tumors significantly correlated with poor prognosis in a subset of cases. These findings reveal common transcriptional programs across the entire spectrum of pulmonary NENs, independent of histological typing. Attenuation of neuroendocrine differentiation, activation of alternative cell lineages, and modulation of microenvironment highlight subsets of tumors with potential pathogenetic and clinical implications.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13418738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148609519","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":"Tailored FcγR blockade enhances immune checkpoint therapy and overcomes resistance.","authors":"Robert J Oldham, Linda Mårtensson, Monika Semmrich, Niyaz Yoosuf, Petra Holmkvist, Lara V Graham, Martin C Taylor, Kirstie L S Cleary, Mona Yazdani, Josephine F Buckingham, Ali Roghanian, Ingrid Karlsson, Stephen A Beers, Ingrid Teige, Mark S Cragg, Björn Frendéus","doi":"10.1186/s13046-026-03785-5","DOIUrl":"10.1186/s13046-026-03785-5","url":null,"abstract":"<p><strong>Background: </strong>Fc-gamma receptors (FcγRs) regulate IgG antibody activity, and Fc-engineering is a proven method to improve the efficacy of tumor-targeting antibodies. Here, we explore tailored FcγR blockade to enhance the therapeutic efficacy and tolerability of immune checkpoint-blocking (ICB) antibodies.</p><p><strong>Methods: </strong>Mechanistically matched murine surrogate and human lead FcγR-blocking and immune checkpoint-blocking antibodies were used to study whether tailored FcγR-blockade, targeting FcγRIIB selectively or all FcγRs, can enhance the efficacy and overcome resistance to immune checkpoint therapy in vivo and in vitro. Mechanistic studies were performed with clinical reagents, including ipilimumab, nivolumab, pembrolizumab, and human FcγRIIB-selective (BI-1607) and pan-FcγR-blocking (BI-1206) antibodies, using human cells and transgenic animals with clinically relevant expression of immune checkpoint receptors.</p><p><strong>Results: </strong>We demonstrate that FcγRIIB-selective and pan-FcγR-blocking antibodies increase the in vivo efficacy of αCTLA-4 and αPD-1 antibodies, respectively. FcγRIIB-selective antibody enhancement of αCTLA-4 was associated with increased intratumoral Treg depletion, myeloid reprogramming, interferon-γ and CXCL10-induction, and increased activated effector CD8⁺ T cells, correlating with higher activating-to-inhibitory (A:I) FcγR engagement ratios. Conversely, pan-FcγR blockade protected αPD-1-coated T cells from macrophage phagocytosis, increasing intratumoral activated CD8⁺ T cells by decreasing activating and inhibitory FcγRs.</p><p><strong>Conclusions: </strong>Our studies provide in vivo proof of concept that tailored FcγR blockade enhances immune checkpoint therapy and overcomes resistance through mechanistically distinct pathways. Clinical trials with tailored human FcγRIIB-blocking antibodies are ongoing.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13418441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148609596","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":"Unraveling the use of vaccine therapy in HER2-positive breast cancer: a comprehensive review of current state and future perspectives.","authors":"Aldo Caltavituro, Claudia Martinelli, Michela Palleschi, Miriam Pirolo, Vincenza Cantile, Roberto Buonaiuto, Carmine De Angelis, Fabio Puglisi, Lucia Del Mastro, Grazia Arpino, Mario Giuliano, Michelino De Laurentiis","doi":"10.1186/s13046-026-03789-1","DOIUrl":"10.1186/s13046-026-03789-1","url":null,"abstract":"<p><strong>Background: </strong>Despite significant advances in early detection and therapeutic strategies, breast cancer (BC) continues to pose a major public health challenge. The treatment of HER2-positive (HER2 +) BC has evolved substantially over recent years with the advent of monoclonal antibodies (mAbs), small-molecule tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates (ADCs). Clinical progress has been significantly accelerated by a deeper understanding of the immune-regulatory properties of this subtype and its interactions with the tumor microenvironment. Despite the availability of effective HER2-targeted therapies, approximately one-third of patients develops resistance, highlighting the need for novel and more durable treatment strategies. Indeed, while current treatments have shown promising efficacy by promoting a \"passive immune response,\" they are associated with the emergence of resistant clones. Conversely, vaccine-based therapies are designed to elicit a durable \"active immune response\" by presenting tumor-associated antigens that stimulate the host immune system to recognize and eliminate malignant cells. This approach has the potential to generate long-lasting immunological memory, preventing recurrence, disease progression, and the emergence of immune-evasive tumor variants.</p><p><strong>Main body: </strong>This review provides a comprehensive overview of cancer vaccines strategies for HER2 + BC with emphasis on their mechanisms, advantages, limitations, and their current developmental status. We explore diverse delivery platforms, including peptide/protein-based, nucleic acid, and cell-based vaccines. The clinical utility of these strategies is assessed across different disease settings: from prevention and interception in pre-invasive lesions, to the (neo)adjuvant treatment of early-stage BC and the management of advanced metastatic disease. While advanced-stage BC often presents an immunosuppressive tumor microenvironment that hinders vaccine efficacy, early-stage disease offers a more favorable immunological milieu for inducing robust and durable T-cell responses. Furthermore, we discuss emerging innovations such as neoantigen discovery, next-generation adjuvants (e.g., TLR and STING agonists), and novel combinatorial approaches with checkpoint inhibitors to overcome immune evasion.</p><p><strong>Conclusion: </strong>Although most BC vaccines remain under clinical investigation, they represent a promising frontier for achieving disease control and the coming decade is expected to yield pivotal insights into their clinical utility and therapeutic potential.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"45 1","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149247329","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}