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Impact of radiation therapy on the immunological tumor microenvironment

Cell Chemical Biology 2025年第5期32卷 678-693页

作者： Guilbaud, Emma Naulin, Flavie Meziani, Lydia Deutsch, Eric Galluzzi, Lorenzo Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA United States Department of Radiotherapy Gustave Roussy Cancer Campus Villejuif France INSERM RAMO-IT U1030 Villejuif France Faculty of Medicine University of Paris-Saclay Bicêtre Le Kremlin France

External beam radiation therapy (RT) is a cornerstone of modern cancer management, being utilized in both curative and palliative settings due to its safety, efficacy, and widespread availability. A primary biological effect of RT is DNA damage, which leads to significant cytostatic and cytotoxic effects. Importantly, malignant cells possess a limited capacity for DNA repair compared to normal cells, and when combined with irradiation techniques that minimize damage to healthy tissues, this creates an advantageous therapeutic window. However, the clinical effectiveness of RT also appears to involve both direct and indirect interactions between RT and non-transformed components of the tumoral ecosystem, particularly immune cells. In this review, we describe the molecular and cellular mechanisms by which irradiated cancer cells modify the immunological tumor microenvironment and how such changes ultimately impact tumor growth. © 2025 Elsevier Ltd

关键词： CD8+ cytotoxic T lymphocytes CGAS/STING signaling dendritic cells immune checkpoint inhibitors PD-1 tumor-associated macrophages

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A macrophage-neutrophil program drives mammary carcinogenesis

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Trends in cancer 2025年第5期11卷 427-429页

作者： Lukas Bolini Simon R V Knott Lorenzo Galluzzi Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA. Department of Biomedical Sciences Cedars-Sinai Medical Center Los Angeles CA USA. Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA. Electronic address: deadoc80@***.

The molecular and cellular pathways through which breast cancer evades immunosurveillance remain poorly understood. Recent data from Camargo et al. demonstrate that - on recruitment to the tumor microenvironment by ductal macrophages - a heterogeneous population of neutrophils can establish physical contacts with malignant cells within spatial niches that sustain mammary oncogenesis.

关键词： CCL3 MMTV-PyMT angiogenesis endothelial cells three Cs γδ T cells

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Novel metabolic routes to cancer immune evasion

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Trends in cancer 2025年

作者： Ayoub Jaa Aitziber Buque Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA. Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA. Electronic address: abuquemartinez@***.

The tumor microenvironment (TME) comprises heterogeneous cell types that closely interact with each other. Crosstalk among the TME components determines antitumor immune responses and their sensitivity to therapies such as immunotherapy. Recent studies published in cancer Cell by Tang et al. and Zhu et al. identify two novel metabolic adaptations that tumors use to facilitate immune evasion. These targetable mechanisms suggest new avenues to improve antitumor immune responses.

关键词： amino acids arginine breast cancer immunology metabolism tryptophan tumor microenvironment

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DACIT: Device for Axon - cancer Cell Interaction Testing in 2D & 3D

SSRN

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SSRN 2025年

作者： Velazquez-Quesada, Ines Alizadeh, Vahid Allison, Kara Belova, Elizaveta Kallogjerovic, Svetllana Hesketh, Natasha Zhang, Xiaotian Thomas, Gareth Tuzel, Erkan Gligorijevic, Bojana Temple University Hospital United States Bioengineering Department Temple University PhiladelphiaPA19122 United States Lewis Katz School of Medicine Temple University PhiladelphiaPA19140 United States Cancer Signaling and Microenvironment Program Fox Chase Cancer Center PhiladelphiaPA19111 United States Fels Cancer Institute for Personalized Medicine Lewis Katz School of Medicine Temple University PhiladelphiaPA19140 United States

There is increasing interest in studying the role of peripheral innervation in tumor growth and metastasis. However, in vitro studies of interactions between cancer cells and axonal projections are technically challenging. To address this, we have developed a microfluidic Device for Axon-cancer cell Interaction Testing in 2D and 3D (DACIT). We show that DACIT successfully separates neuronal soma from the axons and cancer cells into two compartments, which can be exposed to similar, or different growth conditions, depending on the experimental needs. We compare neoaxonogenesis using either the PC-12 cell line or primary embryonic or adult sensory neurons, demonstrating superior neurite growth in primary cells. Additionally, we show that DACIT can accommodate assessing growth and 3D invasion of tumor spheroids, due to its unique height profile. Hence, DACIT can be used to analyze cancer cell interactions with axons in most typical cell biology assays such as proliferation, invasion, and calcium activity which we demonstrate on examples of imaging transients in GCaMP6-labeled neurons, invadopodia assay, and 3D cancer spheroid invasion. © 2025, The Authors. All rights reserved.

关键词： cancer cells

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Defeating kinases that promote tumorigenesis through non-catalytic functions with PROTACs - PIM kinase as an example

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Emerging Therapeutic Targets 2025年第4-5期29卷

作者： Pedro Torres-Ayuso John Brognard a Department of Cancer and Cellular Biology Lewis Katz School of Medicine Temple University Philadelphia PA USAb Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA c Laboratory of Cell and Developmental Signaling National Cancer Institute National Institutes of Health Frederick MD USA

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The role of RAC1 in resistance to targeted therapies in cancer

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Small GTPases 2024年第1期15卷 1-14页

作者： Cristina Uribe-Alvarez Jonathan Chernoff Cancer Signaling & Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA.

RAC1 is a small 21 kDa RHO GTPase that plays a pivotal role in regulating actin cytoskeletal dynamics and cell growth. Alterations in the activity of RAC1 are implicated in a range of diseases, including cancer. Increased RAC1 activity, due to overexpression and/or activating mutations, drives transcriptional upregulation, reactive oxygen species production, mesenchymal-to-epithelial transition, membrane ruffling, and uncontrolled cell proliferation, which are hallmarks of an oncogenic phenotype. While RAC1-activating mutations alone do not appear sufficient to transform cells, their combination with other common mutations, such as BRAF, NRAS, or NF1, have been linked to drug resistance and significantly worsen patient prognosis and hinder treatment responses. The precise mechanisms underlying drug resistance, and the regulation of splicing remain poorly understood. RAC1 is a challenging therapeutic target due to its ubiquitous presence and essential cellular functions. To date, there are no established standard treatments for cancers that harbour an additional RAC1 mutation or for RAC1-mediated drug resistance. Current experimental strategies aim to target RAC1 localization, its activators (. guanine nucleotide exchange factors) and downstream effectors. Regulating RAC1 expression by targeting epigenetic regulators, and direct targeting of RAC1 itself, may also be possible in the near future.

关键词： RAC1 RHO GTPases Signal transduction cancer drug resistance

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Challenges and Opportunities Modeling the Dynamic Tumor Matrisome

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Biomedical Engineering Frontiers 2023年第1期4卷 239-246页

作者： Shelly R.Peyton Manu O.Platt Edna Cukierman Department of Chemical Engineering University of Massachusetts AmherstAmherstMAUSA Coulter Department of Biomedical Engineering Georgia Institute of Technology and Emory UniversityAtlantaGAUSA Cancer Signaling&Microenvironment Program Marvin and Concetta Greenberg Pancreatic Cancer Institute.Fox Chase Cancer CenterTemple HealthPhiladelphiaPAUSA

We need novel strategies to target the complexity of cancer and,particularly,of metastatic *** an example of this complexity,certain tissues are particularly hospitable environments for metastases,whereas others do not contain fertile microenvironments to support cancer cell *** evidence that the extracellular matrix(ECM)of tissues is one of a host of factors necessary to support cancer cell growth at both primary and secondary tissue sites is *** on cancer metastasis has largely been focused on the molecular adaptations of tumor cells in various cytokine and growth factor environments on 2-dimensional tissue culture polystyrene *** imaging,conversely,has transformed our ability to watch,in real time,tumor cell invasion,intravasation,extravasation,and *** the interstitial ECM that supports all cells in the tumor microenvironment changes over time scales outside the possible window of typical intravital imaging,bioengineers are continuously developing both simple and sophisticated in vitro controlled environments to study tumor(and other)cell interactions with this *** this perspective,we focus on the cellular unit responsible for upholding the pathologic homeostasis of tumor-bearing organs,cancer-associated fibroblasts(CAFs),and their selfgenerated *** latter,together with tumoral and other cell secreted factors,constitute the“tumor matrisome”.We share the challenges and opportunities for modeling this dynamic CAF/ECM unit,the tools and techniques available,and how the tumor matrisome is remodeled(e.g.,via ECM proteases).We posit that increasing information on tumor matrisome dynamics may lead the field to alternative strategies for personalized medicine outside genomics.

关键词： invasion organs environments

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A retinoic acid:YAP1 signaling axis controls atrial lineage commitment

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Cell Reports 2025年第5期44卷 115687页

作者： Abraham, Elizabeth Kostina, Aleksandra Volmert, Brett Roule, Thomas Huang, Ling Yu, Jingting Williams, April E. Megill, Emily Douglas, Aidan Pericak, Olivia M. Morris, Alex Stronati, Eleonora Larrinaga-Zamanillo, Arantza Fueyo, Raquel Zubillaga, Mikel Andrake, Mark D. Akizu, Naiara Aguirre, Aitor Estaras, Conchi Department of Cardiovascular Sciences Aging + Cardiovascular Discovery Center Lewis Katz School of Medicine Temple University Philadelphia 19140 PA United States Institute for Quantitative Health Science and Engineering Division of Developmental and Stem Cell Biology Michigan State University East Lansing 48824 MI United States Department of Biomedical Engineering College of Engineering Michigan State University East Lansing 48824 MI United States Raymond G. Perelman Center for Cellular and Molecular Therapeutics The Children's Hospital of Philadelphia Philadelphia 19104 PA United States Integrative Genomics and Bioinformatics Core Salk Institute for Biological Studies La Jolla 92037 CA United States Department of Child and Adolescence Psychiatry The Children's Hospital of Philadelphia Philadelphia 19104 PA United States Department of Chemical and Systems Biology Stanford University School of Medicine Stanford 94305 CA United States Cancer Epigenetics Institute Fox Chase Cancer Center Philadelphia 19111 PA United States Molecular Modeling Facility Program in Cancer Signaling and Microenvironment Fox Chase Cancer Center Philadelphia 19111 PA United States

In cardiac progenitor cells (CPCs), retinoic acid (RA) signaling induces atrial lineage gene expression and acquisition of an atrial cell fate. To achieve this, RA coordinates a complex regulatory network of downstream effectors that is not fully identified. To address this gap, we applied a functional genomics approach (i.e., scRNA-seq and snATAC-seq) to untreated and RA-treated human embryonic stem cell (hESC)-derived CPCs. Unbiased analysis revealed that the Hippo effectors YAP1 and TEAD4 are integrated with the atrial transcription factor enhancer network and that YAP1 activates RA enhancers in CPCs. Furthermore, Yap1 deletion in mouse embryos compromises the expression of RA-induced genes, such as Nr2f2, in the CPCs of the second heart field. Accordingly, in hESC-derived patterned heart organoids, YAP1 regulates the formation of an atrial chamber but is dispensable for the formation of a ventricle. Overall, our findings revealed that YAP1 cooperates with RA signaling to induce atrial lineages during cardiogenesis. © 2025 The Author(s)

关键词： atrial differentiation cardiac enhancers cardiac progenitors chamber development CP: Developmental biology heart organoids NR2F2 retinoic acid signaling SHF TEAD4 YAP1

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Low-dose irradiation of the gut improves the efficacy of PD-L1 blockade in metastatic cancer patients

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cancer Cell 2025年第3期43卷 361-379.e10页

作者： Chen, Jianzhou Levy, Antonin Tian, Ai-Ling Huang, Xuehan Cai, Guoxin Fidelle, Marine Rauber, Conrad Ly, Pierre Pizzato, Eugénie Sitterle, Lisa Piccinno, Gianmarco Liu, Peng Durand, Sylvère Mao, Misha Zhao, Liwei Iebba, Valerio Felchle, Hannah Mallard de La Varende, Anne-Laure Fischer, Julius Clemens Thomas, Simon Greten, Tim F. Jones, Jennifer C. Monge, Cecilia Demaria, Sandra Formenti, Silvia Belluomini, Lorenzo Dionisi, Valeria Massard, Christophe Blanchard, Pierre Robert, Charlotte Quevrin, Clément Lopes, Eloise Clémenson, Céline Mondini, Michele Meziani, Lydia Zhan, Yizhou Zeng, Chengbing Cai, Qingxin Morel, Daphne Sun, Roger Laurent, Pierre-Antoine Mangoni, Monica Di Cataldo, Vanessa Arilli, Chiara Trommer, Maike Wegen, Simone Neppl, Sebastian Riechelmann, Rachel P. Camandaroba, Marcos P. Neto, Elson Santos Fournier, Pierre-Edouard Segata, Nicola Holicek, Peter Galluzzi, Lorenzo Buqué, Aitziber Alves Costa Silva, Carolina Derosa, Lisa Kroemer, Guido Chen, Chuangzhen Zitvogel, Laurence Deutsch, Eric Gustave Roussy Cancer Campus (GRCC) Clinicobiome Villejuif Cedex 94805 France Faculté de Médecine Université Paris-Saclay Kremlin-Bicêtre 94270 France Institut National de la Santé Et de la Recherche Médicale (INSERM) UMR 1015 Equipe Labellisée—Ligue Nationale contre le Cancer Villejuif 94805 France CICBT1428 Gustave Roussy Cancer Campus (GRCC) Villejuif 94805 France Department of Radiation Oncology Gustave Roussy Cancer Campus (GRCC) Villejuif 94805 France INSERM U1030 Radiothérapie Moléculaire et Innovations Thérapeutiques Gustave Roussy Cancer Campus (GRCC) Villejuif 94805 France Metabolomics and Cell Biology Platforms UMS AMMICa Gustave Roussy Cancer Campus Villejuif 94805 France Centre de Recherche des Cordeliers INSERM U1138 Équipe Labellisée – Ligue Nationale contre le Cancer Université Paris Cité Sorbonne Université Paris 75006 France Institut du Cancer Paris CARPEM Department of Biology Hôpital Européen Georges Pompidou AP-HP Paris 75015 France Department of Radiation Oncology Cancer Hospital of Shantou University Medical College Shantou 515031 China Department of Gastroenterology and Infectious Diseases University Hospital Heidelberg Heidelberg 69120 Germany Department of Computational Cellular and Integrative Biology University of Trento Trento 38123 Italy Department of Radiation Oncology Weill Cornell Medicine New York 10065 NY United States Drug Development Department (DITEP) Gustave Roussy Cancer Campus Villejuif 94805 France Department of Radiation Oncology Cyberknife and Radiotherapy Faculty of Medicine and University Hospital Cologne Cologne 50937 Germany Center for Integrated Oncology (CIO) Faculty of Medicine and University Hospital Cologne University of Cologne Cologne 50937 Germany Center for Molecular Medicine Cologne University of Cologne Cologne 50931 Germany Olivia Newton-John Cancer Wellness & Research Centre Austin Health Department of Radiation Oncology Heidelberg Melbourne 3084 VIC Australia Departme

The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8⁺ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential. © 2025 The Author(s)

关键词： bile acids cancer Christensenella minuta dendritic cells gut microbiota metabolomics radiotherapy tumor immunosurveillance

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A novel anti-FGFR1 monoclonal antibody OM-RCA-01 exhibits potent antitumor activity and enhances the efficacy of immune checkpoint inhibitors in lung cancer models

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Immuno-Oncology and Technology 2024年 23卷 100725-100725页

作者： Tsimafeyeu, I. Makhov, P. Ovcharenko, D. Smith, J. Khochenkova, Y. Olshanskaya, A. Khochenkov, D. Bureau for Cancer Research - BUCARE New York Program in Cancer Signaling and Microenvironment Fox Chase Cancer Center Philadelphia Altogen Labs Austin United States N.N. Blokhin National Medical Research Center of Oncology Moscow Clinical Oncology Hospital No. 1 Moscow Center for Medicinal Chemistry Togliatti State University Togliatti Russian Federation

Background: Fibroblast growth factor receptor 1 (FGFR1) plays a crucial role in carcinogenesis. Exploring the combination of the novel humanized monoclonal anti-FGFR1 antibody OM-RCA-01 and immunotherapy was intriguing due to involvement of FGFR1 in mechanisms of resistance to checkpoint inhibitors. Materials and methods: Lung cancer A549, exhibiting distinct levels of FGFR1 expression, were cultured in basic FGF medium with OM-RCA-01 supplementation. The efficacy of antibody monotherapy was validated in a lung cancer xenograft study. To investigate whether OM-RCA-01 could enhance the efficacy of immunotherapy in vitro and in vivo, mixed lymphocyte reaction/Staphylococcal enterotoxin B assays and FGFR1/programmed death-ligand 1-positive patient-derived xenograft model were established. Results: The antibody effectively suppressed receptor phosphorylation, resulting in inhibited cell proliferation. OM-RCA-01 led to a substantial delay in tumor growth compared to non-specific immunoglobulin G in a xenograft study. The median tumor volume was 1048.5 mm³ and 2174 mm³ in the study and vehicle groups, respectively, representing a twofold difference in favor of the anti-FGFR1 antibody. In vitro, the combination of nivolumab and OM-RCA-01 resulted in higher levels of interferon gamma and interleukin-2 release compared with nivolumab alone. In vivo, pembrolizumab in combination with OM-RCA-01 produced a greater inhibitory effect on tumor growth compared with vehicle and pembrolizumab alone. The curve plateaued, indicating minimal tumor growth from day 16 onwards in the combination group. The OM-RCA-01 demonstrated no toxicity, even at therapeutic doses or higher doses. Conclusions: Our preclinical studies demonstrate that OM-RCA-01 exhibits robust activity with minimal toxicity. Combining an anti-FGFR1 antibody with a checkpoint inhibitor may enhance the efficacy of both drugs. However, further studies are needed to elucidate the mechanism of this inter

关键词： anti-FGFR1 monoclonal antibody fibroblast growth factor receptor 1 immune checkpoint inhibitors immunotargeted therapy

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