bims-tuchim 2021-06-20 papers

bims-tuchim

Biomed News

on Tumor-on-chip models

Issue of 2021–06–20
twelve papers selected by
Philipp Albrecht, Friedrich Schiller University

A Tumor-Penetrating Nanomedicine Improves the Chemoimmunotherapy of Pancreatic Cancer.
Delivery of Endothelial Cell-Laden Microgel Elicits Angiogenesis in Self-Assembling Ultrashort Peptide Hydrogels In Vitro.
3D Bioprinting-Based Vascularized Tissue Models Mimicking Tissue-Specific Architecture and Pathophysiology for in vitro Studies.
A novel organ-chip system emulates three-dimensional architecture of the human epithelia and the mechanical forces acting on it.
Chemo-Mechanistic multi-scale model of a three-dimensional tumor microenvironment to quantify chemotherapy response of cancer.
Engineering a 3D collective cancer invasion model with control over collagen fiber alignment.
Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance.
Organ-on-a-chip systems for vascular biology.
Establishment of a 3D model of tumor-driven angiogenesis to study the effects of anti-angiogenic drugs on pericyte recruitment.
Cell-type deconvolution analysis identifies cancer-associated myofibroblast component as a poor prognostic factor in multiple cancer types.
Metabolic reprogramming due to hypoxia in pancreatic cancer: Implications for tumor formation, immunity, and more.
Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells.

Small. 2021 Jun 18. e2101208

A Tumor-Penetrating Nanomedicine Improves the Chemoimmunotherapy of Pancreatic Cancer.

Qi-Song Tong, Wei-Min Miao, Hua Huang, Jia-Qi Luo, Rong Liu, Yong-Cong Huang, Dong-Kun Zhao, Song Shen, Jin-Zhi Du, Jun Wang.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a low survival rate. The therapeutic effect of chemotherapy and immunotherapy for PDAC is disappointing due to the presence of dense tumor stroma and immunosuppressive cells in the tumor microenvironment (TME). Herein, a tumor-penetrating nanoparticle is reported to modulate the deep microenvironment of PDAC for improved chemoimmunotherapy. The tumor pH-sensitive polymer is synthesized by conjugating N,N-dipentylethyl moieties and monomethoxylpoly(ethylene glycol) onto PAMAM dendrimer, into whose cavity a hydrophobic gemcitabine (Gem) prodrug is accommodated. They self-assemble into nanoparticles (denoted as SPN@Pro-Gem) with the size around 120 nm at neutral pH, but switch into small particles (≈8 nm) at tumor site to facilitate deep delivery of Gem into the tumor parenchyma. In addition to killing cancer cells that resided deeply in the tumor tissue, SPN@Pro-Gem could modulate the TME by reducing the abundance of tumor-associated macrophages and myeloid-derived suppressor cells as well as upregulating the expression level of PD-L1 of tumor cells. This collectively facilitates the infiltration of cytotoxic T cells into the tumors and renders checkpoint inhibitors more effective in previously unresponsive PDAC models. This study reveals a promising strategy for improving the chemoimmunotherapy of pancreatic cancer.

Keywords:  cancer chemoimmunotherapy; nanomedicine; pH-sensitive drug delivery; tumor penetration

DOI:  https://doi.org/10.1002/smll.202101208
ACS Appl Mater Interfaces. 2021 Jun 18.

Delivery of Endothelial Cell-Laden Microgel Elicits Angiogenesis in Self-Assembling Ultrashort Peptide Hydrogels In Vitro.

Gustavo Ramirez-Calderon, Hepi Hari Susapto, Charlotte A E Hauser.

  Blood vessel generation is an essential process for tissue formation, regeneration, and repair. Notwithstanding, vascularized tissue fabrication in vitro remains a challenge, as current fabrication techniques and biomaterials lack translational potential in medicine. Naturally derived biomaterials harbor the risk of immunogenicity and pathogen transmission, while synthetic materials need functionalization or blending to improve their biocompatibility. In addition, the traditional top-down fabrication techniques do not recreate the native tissue microarchitecture. Self-assembling ultrashort peptides (SUPs) are promising chemically synthesized natural materials that self-assemble into three-dimensional nanofibrous hydrogels resembling the extracellular matrix (ECM). Here, we use a modular tissue-engineering approach, embedding SUP microgels loaded with human umbilical vein endothelial cells (HUVECs) into a 3D SUP hydrogel containing human dermal fibroblast neonatal (HDFn) cells to trigger angiogenesis. The SUPs IVFK and IVZK were used to fabricate microgels that gel in a water-in-oil emulsion using a microfluidic droplet generator chip. The fabricated SUP microgels are round structures that are 300-350 μm diameter in size and have ECM-like topography. In addition, they are stable enough to keep their original size and shape under cell culture conditions and long-term storage. When the SUP microgels were used as microcarriers for growing HUVECs and HDFn cells on the microgel surface, cell attachment, stretching, and proliferation could be demonstrated. Finally, we performed an angiogenesis assay in both SUP hydrogels using all SUP combinations between micro- and bulky hydrogels. Endothelial cells were able to migrate from the microgel to the surrounding area, showing angiogenesis features such as sprouting, branching, coalescence, and lumen formation. Although both SUP hydrogels support vascular network formation, IVFK outperformed IVZK in terms of vessel network extension and branching. Overall, these results demonstrated that cell-laden SUP microgels have great potential to be used as a microcarrier cell delivery system, encouraging us to study the angiogenesis process and to develop vascularized tissue-engineering therapies.

Keywords:  angiogenesis; flow focusing; hydrogel; microcarrier; microfluidics; microgel; self-assembling ultrashort peptide; vascularization

DOI:  https://doi.org/10.1021/acsami.1c03787
Front Bioeng Biotechnol. 2021 ;9 685507

3D Bioprinting-Based Vascularized Tissue Models Mimicking Tissue-Specific Architecture and Pathophysiology for in vitro Studies.

Dong Gyu Hwang, Yoo-Mi Choi, Jinah Jang.

  A wide variety of experimental models including 2D cell cultures, model organisms, and 3D in vitro models have been developed to understand pathophysiological phenomena and assess the safety and efficacy of potential therapeutics. In this sense, 3D in vitro models are an intermediate between 2D cell cultures and animal models, as they adequately reproduce 3D microenvironments and human physiology while also being controllable and reproducible. Particularly, recent advances in 3D in vitro biomimicry models, which can produce complex cell structures, shapes, and arrangements, can more similarly reflect in vivo conditions than 2D cell culture. Based on this, 3D bioprinting technology, which enables to place the desired materials in the desired locations, has been introduced to fabricate tissue models with high structural similarity to the native tissues. Therefore, this review discusses the recent developments in this field and the key features of various types of 3D-bioprinted tissues, particularly those associated with blood vessels or highly vascularized organs, such as the heart, liver, and kidney. Moreover, this review also summarizes the current state of the three categories: (1) chemical substance treatment, (2) 3D bioprinting of lesions, and (3) recapitulation of tumor microenvironments (TME) of 3D bioprinting-based disease models according to their disease modeling approach. Finally, we propose the future directions of 3D bioprinting approaches for the creation of more advanced in vitro biomimetic 3D tissues, as well as the translation of 3D bioprinted tissue models to clinical applications.

Keywords:  3D bioprinting; 3D in vitro tissue model; disease modeling; organ-organ crosstalk; vascularization

DOI:  https://doi.org/10.3389/fbioe.2021.685507
Biomaterials. 2021 Jun 06. pii: S0142-9612(21)00313-6. [Epub ahead of print]275 120957

A novel organ-chip system emulates three-dimensional architecture of the human epithelia and the mechanical forces acting on it.

Antonio Varone, Justin Ke Nguyen, Lian Leng, Riccardo Barrile, Josiah Sliz, Carolina Lucchesi, Norman Wen, Achille Gravanis, Geraldine A Hamilton, Katia Karalis, Christopher D Hinojosa.

  Successful translation of in vivo experimental data to human patients is an unmet need and a bottleneck in the development of effective therapeutics. Organ-on-Chip technology aims to address this need by leveraging recent significant advancements in microfabrication and biomaterials, which enable modeling of organs and their functionality. These microengineered chips offer researchers the possibility to recreate critical elements of native tissue architecture such as in vivo relevant tissue-tissue interface, air-liquid interface, and mechanical forces, including mechanical stretch and fluidic shear stress, which are crucial to recapitulate tissue level functions. Here, we present the development of a new, comprehensive 3D cell-culture system, where we combined our proprietary Organ-Chip technology with the advantages offered by three-dimensional organotypic culture. Leveraging microfabrication techniques, we engineered a flexible chip that consists of a chamber containing an organotypic epithelium, surrounded by two vacuum channels that can be actuated to stretch the hydrogel throughout its thickness. Furthermore, the ceiling of this chamber is a removable lid with a built-in microchannel that can be perfused with liquid or air and removed as needed for direct access to the tissue. The bottom part of this chamber is made from a porous flexible membrane which allows diffusive mass transport to and from the microfluidic channel positioned below the membrane. This additional microfluidic channel can be coated with endothelial cells to emulate a blood vessel and recapitulate endothelial interactions. Our results show that the Open-Top Chip design successfully addresses common challenges associated with the Organs-on-Chip technology, including the capability to incorporate a tissue-specific extracellular matrix gel seeded with primary stromal cells, to reproduce the architectural complexity of tissues by micropatterning the gel, and to extract the gel for H&E staining. We also provide proof-of-concept data on the feasibility of using the system with primary human skin and alveolar epithelial cells.

Keywords:  3D-organotypic cell based models; Hydrogel micropatterning; Microfluidic; Organs-on-Chips; Stretching; Stroma

DOI:  https://doi.org/10.1016/j.biomaterials.2021.120957
Biotechnol Bioeng. 2021 Jun 16.

Chemo-Mechanistic multi-scale model of a three-dimensional tumor microenvironment to quantify chemotherapy response of cancer.

Mohammad R Nikmaneshi, Bahar Firoozabadi, Aliasghar Mozafari.

  The exploring efficient chemotherapy would benefit from a deeper understanding of the tumor microenvironment (TME) and its role in tumor progression. Because in vivo experimental methods are unable to isolate or control individual factors of the TME, and in vitro models often cannot include all the contributing factors, some questions are best addressed with mathematical models of systems biology. In this work, we establish a multi-scale mathematical model of the tumor microenvironment to simulate three-dimensional tumor growth and angiogenesis and then implement the model for an array of chemotherapy approaches to elucidate the effect of TME conditions and drug scheduling on controlling tumor progression. Hyperglycemic condition as the most common disorder for cancer patients is considered to evaluate its impact on cancer response to chemotherapy. We show that combining anti-angiogenic and anti-cancer drugs improve the outcome of treatment and can decrease accumulation of drug in normal tissue and enhance drug delivery to the tumor. Our results demonstrate that although both concurrent and neoadjuvant combination therapies can increase intratumoral drug exposure and therapeutic accuracy, neoadjuvant therapy surpasses especially against hyperglycemia. Our model provides mechanistic explanations for clinical observations of tumor progression and response to treatment and establishes a computational framework for exploring better treatment strategies. This article is protected by copyright. All rights reserved.

Keywords:  IFP; chemotherapy; combination therapy; hyperglycemia; tumor microenvironment; vascular normalization

DOI:  https://doi.org/10.1002/bit.27863
Biomaterials. 2021 Jun 04. pii: S0142-9612(21)00278-7. [Epub ahead of print]275 120922

Engineering a 3D collective cancer invasion model with control over collagen fiber alignment.

Chia-Yi Su, Alice Burchett, Matthew Dunworth, Jong Seob Choi, Andrew J Ewald, Eun Hyun Ahn, Deok-Ho Kim.

  Prior to cancer cell invasion, the structure of the extracellular matrix (ECM) surrounding the tumor is remodeled, such that circumferentially oriented matrix fibers become radially aligned. This predisposed radially aligned matrix structure serves as a critical regulator of cancer invasion. However, a biomimetic 3D model recapitulating a tumor's behavioral response to these ECM structures is not yet available. In this study, we have developed a phase-specific, force-guided method to establish a 3D dual topographical tumor model in which each tumor spheroid/organoid is surrounded by radially aligned collagen I fibers on one side and circumferentially oriented fibers on the opposite side. A coaxial rotating cylinder system was employed to construct the dual fiber topography and to pre-seed tumor spheroids/organoids within a single device. This system enables the application of different force mechanisms in the nucleation and elongation phases of collagen fiber polymerization to guide fiber alignment. In the nucleation phase, fiber alignment is enhanced by a horizontal laminar Couette flow driven by the inner cylinder rotation. In the elongation phase, fiber growth is guided by a vertical gravitational force to form a large aligned collagen matrix gel (35 × 25 × 0.5 mm) embedded with >1000 tumor spheroids. The fibers above each tumor spheroid are radially aligned along the direction of gravitational force in contrast to the circumferentially oriented fibers beneath each tumor spheroid/organoid, where the presence of the tumor interferes with the gravity-induced fiber alignment. After tumor invasion, there are more disseminated multicellular clusters on the radially aligned side, compared to the side of the tumor spheroid/organoid facing circumferentially oriented fibers. These results indicate that our 3D dual topographical model recapitulates the preference of tumors to invade and disseminate along radially aligned fibers. We anticipate that this 3D dual topographical model will have broad utility to those studying collective tumor invasion and that it has the potential to identify cancer invasion-targeted therapeutic agents.

Keywords:  Aligned collagen fibers; Collective cell invasion; Couette flow; Extracellular matrix; Tumor dissemination; Tumor organoids

DOI:  https://doi.org/10.1016/j.biomaterials.2021.120922
Front Immunol. 2021 ;12 656364

Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance.

Khalil Khalaf, Doris Hana, Jadzia Tin-Tsen Chou, Chandpreet Singh, Andrzej Mackiewicz, Mariusz Kaczmarek.

  The tumor microenvironment (TME) is a complex and ever-changing "rogue organ" composed of its own blood supply, lymphatic and nervous systems, stroma, immune cells and extracellular matrix (ECM). These complex components, utilizing both benign and malignant cells, nurture the harsh, immunosuppressive and nutrient-deficient environment necessary for tumor cell growth, proliferation and phenotypic flexibility and variation. An important aspect of the TME is cellular crosstalk and cell-to-ECM communication. This interaction induces the release of soluble factors responsible for immune evasion and ECM remodeling, which further contribute to therapy resistance. Other aspects are the presence of exosomes contributed by both malignant and benign cells, circulating deregulated microRNAs and TME-specific metabolic patterns which further potentiate the progression and/or resistance to therapy. In addition to biochemical signaling, specific TME characteristics such as the hypoxic environment, metabolic derangements, and abnormal mechanical forces have been implicated in the development of treatment resistance. In this review, we will provide an overview of tumor microenvironmental composition, structure, and features that influence immune suppression and contribute to treatment resistance.

Keywords:  CAF; HIF - hypoxia inducible factor; MDSC (myeloid-derived suppressor cells); TGF - β1; TME (tumor microenvironment); Treg - regulatory T cell; microRNA (miR); tumor associated macrophage (TAM)

DOI:  https://doi.org/10.3389/fimmu.2021.656364
J Mol Cell Cardiol. 2021 Jun 09. pii: S0022-2828(21)00123-1. [Epub ahead of print]159 1-13

Organ-on-a-chip systems for vascular biology.

Christian J Mandrycky, Caitlin C Howard, Samuel G Rayner, Yu Jung Shin, Ying Zheng.

  Organ-on-a-chip (OOC) platforms involve the miniaturization of cell culture systems and enable a variety of novel experimental approaches. These range from modeling the independent effects of biophysical forces on cells to screening novel drugs in multi-organ microphysiological systems, all within microscale devices. As in living systems, the incorporation of vascular structure is a key feature common to almost all organ-on-a-chip systems. In this review we highlight recent advances in organ-on-a-chip technologies with a focus on the vasculature. We first present the developmental process of the blood vessels through which vascular cells assemble into networks and remodel to form complex vascular beds under flow. We then review self-assembled vascular models and flow systems for the study of vascular development and biology as well as pre-patterned vascular models for the generation of perfusable microvessels for modeling vascular and tissue function. We finally conclude with a perspective on developing future OOC approaches for studying different aspects of vascular biology. We highlight the fit for purpose selection of OOC models towards either simple but powerful testbeds for therapeutic development, or complex vasculature to accurately replicate human physiology for specific disease modeling and tissue regeneration.

Keywords:  Endothelial cells; Mechanotransduction; Microfluidics; Organ-on-a-chip; Organoids; Vascular biology

DOI:  https://doi.org/10.1016/j.yjmcc.2021.06.002
Biomater Sci. 2021 Jun 17.

Establishment of a 3D model of tumor-driven angiogenesis to study the effects of anti-angiogenic drugs on pericyte recruitment.

Yaqi Qiu, Ning Wang, Tingting Guo, Shoupei Liu, Xianglian Tang, Zhiyong Zhong, Qicong Chen, Haibin Wu, Xiajing Li, Jue Wang, Shuai Zhang, Yimeng Ou, Bailin Wang, Keqiang Ma, Weili Gu, Jie Cao, Honglin Chen, Yuyou Duan.

Hepatocellular carcinoma (HCC), as a well-vascularized tumor, has attracted increasing attention in antiangiogenic therapies. Notably, emerging studies reveal that the long-term administration of antiangiogenic drugs induces hypoxia in tumors. Pericytes, which play a vital role in vascular stabilization and maturation, have been documented to be associated with antiangiogenic drug-induced tumor hypoxia. However, the role of antiangiogenic agents in regulating pericyte behavior still remains elusive. In this study, by using immunostaining analysis, we first demonstrated that tumors obtained from HCC patients were highly angiogenic, in which vessels were irregularly covered by pericytes. Therefore, we established a new 3D model of tumor-driven angiogenesis by culturing endothelial cells, pericytes, cancer stem cells (CSCs) and mesenchymal stem cells (MSCs) with microcarriers in order to investigate the effects and mechanisms exerted by antiangiogenic agents on pericyte recruitment during tumor angiogenesis. Interestingly, microcarriers, as supporting matrices, enhanced the interactions between tumor cells and the extracellular matrix (ECM), promoted malignancy of tumor cells and increased tumor angiogenesis within the 3D model, as determined by qRT-PCR and immunostaining. More importantly, we showed that zoledronic acid (ZA) reversed the inhibited pericyte recruitment, which was induced by sorafenib (Sora) treatment, through fostering the expression and activation of ErbB1/ErbB2 and PDGFR-β in pericytes, in both an in vitro 3D model and an in vivo xenograft HCC mouse model. Hence, our model provides a more pathophysiologically relevant platform for the assessment of therapeutic effects of antiangiogenic compounds and identification of novel pharmacological targets, which might efficiently improve the benefits of antiangiogenic treatment for HCC patients.

DOI: https://doi.org/10.1039/d0bm02107e
Oncogene. 2021 Jun 17.

Cell-type deconvolution analysis identifies cancer-associated myofibroblast component as a poor prognostic factor in multiple cancer types.

Bingrui Li, Guangsheng Pei, Jun Yao, Qingqing Ding, Peilin Jia, Zhongming Zhao.

Cancer-associated fibroblasts (CAFs) constitute a prominent component of the tumor microenvironment and play critical roles in cancer progression and drug resistance. Although recent studies indicate CAFs may consist of several CAF subtypes, the breadth of CAF heterogeneity and functional roles of CAF subtypes in cancer progression remain unclear. In this study, we implemented a cell-type deconvolutional approach to comprehensively characterize cell-type alternations across 18 cancer types from The Cancer Genome Atlas (TCGA). Pan-cancer survival analysis using deconvoluted CAF subtypes revealed myofibroblastic CAF (myCAF) composition as a poor prognostic factor in nine cancer types. Patients with higher myCAF compositions tend to have worse response to six antineoplastic drugs predicted by a lncRNA-based Elastic Net prediction model (LENP). In addition, integrative mutational analysis identified 14 and 413 genes associated with the differentiation degree of myCAF and inflammatory CAF (iCAF), respectively, with significant enrichment of genes involved in fibroblast and extracellular matrix (ECM)-related pathways. In summary, our findings systematically illustrated the complex roles of CAF subtypes in patient prognosis and drug response, and identified putative driver genes in CAF-subtype differentiation. These results provided novel therapeutic perspectives for targeting CAF subtypes in tumor microenvironment and arranging treatment scheme based on the CAF compositions in different cancer types.

DOI: https://doi.org/10.1038/s41388-021-01870-x
Biomed Pharmacother. 2021 Jun 10. pii: S0753-3322(21)00580-1. [Epub ahead of print]141 111798

Metabolic reprogramming due to hypoxia in pancreatic cancer: Implications for tumor formation, immunity, and more.

Xiadong Hao, Yidan Ren, Maoxiao Feng, Qin Wang, Yunshan Wang.

  Hypoxia is a common phenomenon in most malignant tumors, especially in pancreatic cancer (PC). Hypoxia is the result of unlimited tumor growth and plays an active role in promoting tumor survival, progression, and invasion. As the part of the hypoxia microenvironment in PC is gradually clarified, hypoxia is becoming a key determinant and an important therapeutic target of pancreatic cancer. To adapt to the severe hypoxia environment, cells have changed their metabolic phenotypes to maintain their survival and proliferation. Enhanced glycolysis is the most prominent feature of cancer cells' metabolic reprogramming in response to hypoxia. It provides the energy source for hypoxic cancer cells (although it provides less than oxidative phosphorylation) and produces metabolites that can be absorbed and utilized by normoxic cancer cells. In addition, the uptake of glutamine and fatty acids by hypoxic cancer cells is also increased, which is also conducive to tumor progression. Their metabolites are pooled in the hexosamine biosynthesis pathway (HBP). As a nutrition sensor, HBP, in turn, can coordinate glucose and glutamine metabolism. Its end product, UDP-GlcNAc, is the substrate of protein post-translational modification (PTM) involved in various signaling pathways supporting tumor progression. Adaptive metabolic changes of cancer cells promote their survival and affect tumor immune cells in the tumor microenvironment (TME), which contributes to tumor immunosuppressive microenvironment and induces tumor immunotherapy resistance. Here, we summarize the hypoxic microenvironment, its effect on metabolic reprogramming, and its contribution to immunotherapy resistance in pancreatic cancer.

Keywords:  Hypoxia; Immunosuppressive microenvironment; Metabolic reprogramming; Pancreatic cancer (PC)

DOI:  https://doi.org/10.1016/j.biopha.2021.111798
Nature. 2021 Jun 16.

Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells.

María Casanova-Acebes, Erica Dalla, Andrew M Leader, Jessica LeBerichel, Jovan Nikolic, Blanca M Morales, Markus Brown, Christie Chang, Leanna Troncoso, Steven T Chen, Ana Sastre-Perona, Matthew D Park, Alexandra Tabachnikova, Maxime Dhainaut, Pauline Hamon, Barbara Maier, Catherine M Sawai, Esperanza Agulló-Pascual, Markus Schober, Brian D Brown, Boris Reizis, Thomas Marron, Ephraim Kenigsberg, Christine Moussion, Philippe Benaroch, Julio A Aguirre-Ghiso, Miriam Merad.

Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment1,2. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis3-5, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions1. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial-mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8+ T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions.

DOI: https://doi.org/10.1038/s41586-021-03651-8