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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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VDAC2 enforces a mitochondrial checkpoint to cancer immunity

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Nature immunology 2025年 2025 May 19页

作者： Katia Cosentino Joost Verduijn Lorenzo Galluzzi Department of Biomedical Metabolic and Neural Sciences University of Modena and Reggio Emilia Modena Italy. katia.cosentino@unimore.it. Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA. Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA USA. deadoc80@***.

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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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Partial mitochondrial involvement in the antiproliferative and immunostimulatory effects of PT-112

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OncoImmunology 2025年第1期14卷 2507245页

作者： Soler-Agesta, Ruth Beltrán-Visiedo, Manuel Sato, Ai Yamazaki, Takahiro Guilbaud, Emma Yim, Christina Y. Congenie, Maria T. Ames, Tyler D. Anel, Alberto Galluzzi, Lorenzo Department of Radiation Oncology Weill Cornell Medical College New York NY United States Promontory Therapeutics New York NY United States Cancer Signaling and Microenvironment Program Fox Chase Cancer Center Philadelphia PA United States Biochemistry and Molecular and Cell Biology Aragón Health Research Institute (IIS-Aragón) University of Zaragoza Zaragoza Spain

PT-112 is a novel small molecule exhibiting promising clinical activity in patients with solid tumors. PT-112 kills malignant cells by inhibiting ribosome biogenesis while promoting the emission of immunostimulatory signals. Accordingly, PT-112 is an authentic immunogenic cell death (ICD) inducer and synergizes with immune checkpoint inhibitors in preclinical models of mammary and colorectal carcinoma. Moreover, PT-112 monotherapy has led to durable clinical responses, some of which persisting after treatment discontinuation. Mitochondrial outer membrane permeabilization (MOMP) regulates the cytotoxicity and immunogenicity of various anticancer agents. Here, we harnessed mouse mammary carcinoma TS/A cells to test whether genetic alterations affecting MOMP influence PT-112 activity. As previously demonstrated, PT-112 elicited robust antiproliferative and cytotoxic effects against TS/A cells, which were preceded by the ICD-associated exposure of calreticulin (CALR) on the cell surface, and accompanied by the release of HMGB1 in the culture supernatant. TS/A cells responding to PT-112 also exhibited eIF2α phosphorylation and cytosolic mtDNA accumulation, secreted type I IFN, and exposed MHC Class I molecules as well as the co-inhibitory ligand PD-L1 on their surface. Acute cytotoxicity and HMGB1 release caused by PT-112 in TS/A cells were influenced by MOMP competence. Conversely, PT-112 retained antiproliferative effects and its capacity to drive type I IFN secretion as well as CALR, MHC Class I and PD-L1 exposure on the cell surface irrespective of MOMP defects. These data indicate a partial involvement of MOMP in the mechanisms of action of PT-112, suggesting that PT-112 is active across various tumor types, including malignancies with MOMP defects. © 2025 The Author(s). Published with license by Taylor & Francis Group, LLC.

关键词： CD8+ cytotoxic T lymphocytes CGAS damage-associated molecular patterns immune checkpoint inhibitors mtDNA PD-1

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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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