bims-flamet 2024-10-27 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024‒10‒27
34 papers selected by
Peio Azcoaga, Biodonostia HRI

Different subpopulations of macrophages, neutrophils, mast cells, and fibroblasts are involved in the control of tumor angiogenesis.
A new perspective on the therapeutic potential of tumor metastasis: targeting the metabolic interactions between TAMs and tumor cells.
Multifunctional ICG-SB@Lip-ZA Nanosystem Focuses on Remodeling the Inflammatory-Immunosuppressive Microenvironment After Photothermal Therapy to Potentiate Cancer Photothermal Immunotherapy.
The signature of extracellular vesicles in hypoxic breast cancer and their therapeutic engineering.
Crosstalk and communication of cancer-associated fibroblasts with natural killer and dendritic cells: New frontiers and unveiled opportunities for cancer immunotherapy.
Role of T Lymphocytes in Glioma Immune Microenvironment: Two Sides of a Coin.
Tumor-associated macrophages induce epithelial-mesenchymal transition and promote lung metastasis in breast cancer by activating the IL-6/STAT3/TGM2 axis.
Metabolic Reprogramming of Cancer-Associated Fibroblast in the Tumor Microenvironment: From Basics to Clinic.
Redefining the tumor microenvironment with emerging therapeutic strategies.
Computational dissection of the regulatory mechanisms of aberrant metabolism in remodeling the microenvironment of breast cancer.
Metabolic Reprogramming Induced by Aging Modifies the Tumor Microenvironment.
Unveiling the Role of Mechanical Microenvironment in Hepatocellular Carcinoma: Molecular Mechanisms and Implications for Therapeutic Strategies.
Excess Potassium Promotes Autophagy to Maintain the Immunosuppressive Capacity of Myeloid-Derived Suppressor Cells Independent of Arginase 1.
Spatial transcriptomics: a new frontier in accurate localization of breast cancer diagnosis and treatment.
Interactions and communications in the prostate tumour microenvironment: evolving towards effective cancer therapy.
FOXM1 derived from Triple negative breast cancer exosomes promotes cancer progression by activating IDO1 transcription in macrophages to suppress ferroptosis and induce M2 polarization of Tumor-associated macrophages.
Evolving strategies to overcome barriers in CAR-T cell therapy for acute myeloid leukemia.
Glucose impacts onto the reciprocal reprogramming between mammary adipocytes and cancer cells.
Targeted therapy approaches for epithelial-mesenchymal transition in triple negative breast cancer.
Tumor-associated macrophages and CD8+ T cells: dual players in the pathogenesis of HBV-related HCC.
AKAP12 positive fibroblast determines immunosuppressive contexture and immunotherapy response in patients with TNBC by promoting macrophage M2 polarization.
CXC chemokine receptor 4 - mediated immune modulation and tumor microenvironment heterogeneity in gastric cancer: Utilizing multi-omics approaches to identify potential therapeutic targets.
Microplastics: an often-overlooked issue in the transition from chronic inflammation to cancer.
Single-cell transcriptomics reveals tumor microenvironment changes and prognostic gene signatures in hepatocellular carcinoma.
Functional diversity and regulation of IL-9-producing T cells in cancer immunotherapy.
Dual roles of human endogenous retroviruses in cancer progression and antitumor immune response.
The potential of nanosystems in disrupting adenosine signaling pathways for tumor immunotherapy.
Intermittent Fasting and Fasting-mimicking Diet: Promising Strategies in Cancer Management.
Multifunctional role of the tumor associated monocytes/macrophages in the metastatic potential of inflammatory breast cancer.
Leukocyte immunoglobulin-like receptor B4: A keystone in immune modulation and therapeutic target in cancer and beyond.
SUMOylation regulates the aggressiveness of breast cancer-associated fibroblasts.
Mesoporous Microneedles Enabled Localized Controllable Delivery of Stimulator of Interferon Gene Agonist Nanoexosomes for FLASH Radioimmunotherapy against Breast Cancer.
LTBR acts as a novel immune checkpoint of tumor-associated macrophages for cancer immunotherapy.
Intratumoral microbiota: an emerging force in diagnosing and treating hepatocellular carcinoma.

Front Med (Lausanne). 2024 ;11 1481609

Different subpopulations of macrophages, neutrophils, mast cells, and fibroblasts are involved in the control of tumor angiogenesis.

Domenico Ribatti.

  The tumor microenvironment comprises diverse cell types, including T and B lymphocytes, macrophages, dendritic cells, natural killer cells, myeloid-derived suppressor cells, neutrophils, eosinophils, mast cells, and fibroblasts. Cells in the tumor microenvironment can be either tumor-suppressive or tumor-supporting cells. In this review article, we analyze the double role played by tumor macrophages, tumor neutrophils, tumor mast cells, and tumor fibroblasts, in promoting angiogenesis during tumor progression. Different strategies to target the tumor microenvironment have been developed in this context, including the depletion of tumor-supporting cells, or their "re-education" as tumor-suppressor cells.

Keywords:  angiogenesis; fibroblasts; macrophages; mast cells; neutrophils; tumor progression

DOI:  https://doi.org/10.3389/fmed.2024.1481609
Int J Biol Sci. 2024 ;20(13): 5109-5126

A new perspective on the therapeutic potential of tumor metastasis: targeting the metabolic interactions between TAMs and tumor cells.

Xuan Zhao, Tong Ren, Sijin Li, Xu Wang, Rui Hou, Zhangchun Guan, Dan Liu, Junnian Zheng, Ming Shi.

  Tumor-associated macrophages (TAMs) undergo metabolic reprogramming, encompassing glucose, amino acid, fatty acid metabolism, tricarboxylic acid (TCA) cycle, purine metabolism, and autophagy, within the tumor microenvironment (TME). The metabolic interdependencies between TAMs and tumor cells critically influence macrophage recruitment, differentiation, M2 polarization, and secretion of epithelial-mesenchymal transition (EMT)-related factors, thereby activating intratumoral EMT pathways and enhancing tumor cell invasion and metastasis. Tumor cell metabolic alterations, including hypoxia, metabolite secretion, aerobic metabolism, and autophagy, affect the TME's metabolic landscape, driving macrophage recruitment, differentiation, M2 polarization, and metabolic reprogramming, ultimately facilitating EMT, invasion, and metastasis. Additionally, macrophages can induce tumor cell EMT by reprogramming their aerobic glycolysis. Recent experimental and clinical studies have focused on the metabolic interactions between macrophages and tumor cells to control metastasis and inhibit tumor progression. This review highlights the regulatory role of TAM-tumor cell metabolic codependencies in EMT, offering valuable insights for TAM-targeted therapies in highly metastatic tumors. Modulating the metabolic interplay between tumors and TAMs represents a promising therapeutic strategy for treating patients with metastatic cancers.

Keywords:  Epithelial-mesenchymal transition; Metabolism; Tumor cells; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.7150/ijbs.99680
Adv Healthc Mater. 2024 Oct 23. e2402211

Multifunctional ICG-SB@Lip-ZA Nanosystem Focuses on Remodeling the Inflammatory-Immunosuppressive Microenvironment After Photothermal Therapy to Potentiate Cancer Photothermal Immunotherapy.

Yi Cao, E Wen, Qiaoqi Chen, Xingsheng Li, Zhigang Wang.

  Achieving full eradication of residual tumors post photothermal therapy (PTT) hinges on the immune system's activation and response. Nevertheless, the resultant local inflammation attracts a significant influx of aberrant immune cells and fibroblasts, such as tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), following tumor PTT. This phenomenon exacerbates immune evasion and the persistence of residual tumor cells, culminating in tumor recurrence and advancement. To tackle this challenge, a combined therapeutic approach utilizing multifunctional ICG-SB@Lip-ZA nanosystem has been introduced. Indocyanine green (ICG) as a photothermal-transducer ablated tumor cells, zoledronic acid (ZA) depletes TAMs recruited by the inflammatory tumor microenvironment (mostly M2-like phenotype), SB-505124 affects CAFs proliferation in the tumor microenvironment (TME) by inhibiting the transforming growth factor-β （TGF-β） pathway, thereby removing physical barriers to T cell infiltration. In a breast cancer model, these immunomodulatory nanoliposomes markedly decrease the population of M2-like TAMs in the TME, eliminate physical barriers hindering T cell infiltration, reshape the inflammatory immune-suppressive tumor microenvironment, eventually leading to a rate of tumor eradication of 94%. This multifunctional ICG-SB@Lip-ZA nanosystem (including photothermal conversion, TAM depletion, and TGF-β pathway blockade) offers a promising strategy for mitigating the deteriorating tumor microenvironment following PTT and presents a more efficient approach for clinical photothermal-immune combination therapy.

Keywords:  cancer‐associated fibroblasts; inflammatory immune‐suppressive tumor microenvironment; nanomedicine; photothermal therapy; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/adhm.202402211
Cell Commun Signal. 2024 Oct 21. 22(1): 512

The signature of extracellular vesicles in hypoxic breast cancer and their therapeutic engineering.

Baiheng Zhu, Kehao Xiang, Tanghua Li, Xin Li, Fujun Shi.

  Breast cancer (BC) currently ranks second in the global cancer incidence rate. Hypoxia is a common phenomenon in BC. Under hypoxic conditions, cells in the tumor microenvironment (TME) secrete numerous extracellular vesicles (EVs) to achieve intercellular communication and alter the metabolism of primary and metastatic tumors that shape the TME. In addition, emerging studies have indicated that hypoxia can promote resistance to tumor treatment. Engineered EVs are expected to become carriers for cancer treatment due to their high biocompatibility, low immunogenicity, high drug delivery efficiency, and ease of modification. In this review, we summarize the mechanisms of EVs in the primary TME and distant metastasis of BC under hypoxic conditions. Additionally, we highlight the potential applications of engineered EVs in mitigating the malignant phenotypes of BC cells under hypoxia.

Keywords:  Breast cancer; Engineered EVs; Extracellular vesicles; Hypoxia; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-024-01870-w
Cancer Treat Rev. 2024 Oct 15. pii: S0305-7372(24)00171-3. [Epub ahead of print]131 102843

Crosstalk and communication of cancer-associated fibroblasts with natural killer and dendritic cells: New frontiers and unveiled opportunities for cancer immunotherapy.

Simone Ielpo, Francesca Barberini, Farnaz Dabbagh Moghaddam, Silvia Pesce, Chiara Cencioni, Francesco Spallotta, Adele De Ninno, Luca Businaro, Emanuela Marcenaro, Roberto Bei, Loredana Cifaldi, Giovanni Barillari, Ombretta Melaiu.

  Natural killer (NK) cells and dendritic cells (DCs) are critical mediators of anti-cancer immune responses. In addition to their individual roles, NK cells and DCs are involved in intercellular crosstalk which is essential for the initiation and coordination of adaptive immunity against cancer. However, NK cell and DC activity is often compromised in the tumor microenvironment (TME). Recently, much attention has been paid to one of the major components of the TME, the cancer-associated fibroblasts (CAFs), which not only contribute to extracellular matrix (ECM) deposition and tumor progression but also suppress immune cell functions. It is now well established that CAFs support T cell exclusion from tumor nests and regulate their cytotoxic activity. In contrast, little is currently known about their interaction with NK cells, and DCs. In this review, we describe the interaction of CAFs with NK cells and DCs, by secreting and expressing various mediators in the TME of adult solid tumors. We also provide a detailed overview of ongoing clinical studies evaluating the targeting of stromal factors alone or in combination with immunotherapy based on immune checkpoint inhibitors. Finally, we discuss currently available strategies for the selective depletion of detrimental CAFs and for a better understanding of their interaction with NK cells and DCs.

Keywords:  Cancer associated fibroblast (CAFs); Cell-cell interaction; Dendritic Cells; Immunotherapy; Natural Killer Cells; Solid tumors; Stromal Cell Therapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.ctrv.2024.102843
Biology (Basel). 2024 Oct 21. pii: 846. [Epub ahead of print]13(10):

Role of T Lymphocytes in Glioma Immune Microenvironment: Two Sides of a Coin.

Laiba Noor, Arun Upadhyay, Vibhuti Joshi.

  Glioma is known for its immunosuppressive microenvironment, which makes it challenging to target through immunotherapies. Immune cells like macrophages, microglia, myeloid-derived suppressor cells, and T lymphocytes are known to infiltrate the glioma tumor microenvironment and regulate immune response distinctively. Among the variety of immune cells, T lymphocytes have highly complex and multifaceted roles in the glioma immune landscape. T lymphocytes, which include CD4+ helper and CD8+ cytotoxic T cells, are known for their pivotal roles in anti-tumor responses. However, these cells may behave differently in the highly dynamic glioma microenvironment, for example, via an immune invasion mechanism enforced by tumor cells. Therefore, T lymphocytes play dual roles in glioma immunity, firstly by their anti-tumor responses, and secondly by exploiting gliomas to promote immune invasion. As an immunosuppression strategy, glioma induces T-cell exhaustion and suppression of effector T cells by regulatory T cells (Tregs) or by altering their signaling pathways. Further, the expression of immune checkpoint inhibitors on the glioma cell surface leads to T cell anergy and dysfunction. Overall, this dynamic interplay between T lymphocytes and glioma is crucial for designing more effective immunotherapies. The current review provides detailed knowledge on the roles of T lymphocytes in the glioma immune microenvironment and helps to explore novel therapeutic approaches to reinvigorate T lymphocytes.

Keywords:  T lymphocytes; glioma; immunomodulation; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3390/biology13100846
Int Immunopharmacol. 2024 Oct 18. pii: S1567-5769(24)01909-X. [Epub ahead of print]143(Pt 2): 113387

Tumor-associated macrophages induce epithelial-mesenchymal transition and promote lung metastasis in breast cancer by activating the IL-6/STAT3/TGM2 axis.

Yana Qi, Ranran Li, Mingyong Han.

  Breast cancer is one of the most common tumors in the world and metastasis is the major cause of tumor-related death. Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and often associated with cancer metastasis. Nevertheless, the mechanism by which TAMs regulate breast cancer metastasis remain unclear. In this study, we found that transglutaminase 2 (TGM2) could serve as a crucial target in the modulation of TAMs-induced epithelial-mesenchymal transition (EMT) and invasion of breast cancer cells. Further analysis revealed that IL-6 secreted from TAMs, which was capable of inducing TGM2 expression through the activation of the JAK/STAT3 signaling pathway. Subsequent luciferase reporter assays demonstrated that STAT3 binds to the TGM2 promoter region, thereby transcriptionally enhancing TGM2 expression. In conclusion, our current research has identified the IL-6/STAT3/TGM2 axis as a pivotal regulator in breast tumorigenesis caused by TAMs, presenting a novel target for the treatment of breast cancer.

Keywords:  Breast cancer; Epithelial-mesenchymal transition; Interleukin-6; Metastasis; TGM2; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.intimp.2024.113387
Clin Med Insights Oncol. 2024 ;18 11795549241287058

Metabolic Reprogramming of Cancer-Associated Fibroblast in the Tumor Microenvironment: From Basics to Clinic.

Lujia Zhou, Wenjie Zhang, Xiaoxue Hu, Daorong Wang, Dong Tang.

  Metabolic reprogramming occurs when tumor cells replenish themselves with nutrients required for growth to meet their metabolic needs. Cancer-associated fibroblasts (CAFs) are activated fibroblasts involved in building the c (TME) to promote tumor progression and metastasis. Metabolic reprogramming of CAFs can interact with cancer cells to generate metabolic crosstalk. Furthermore, CAF metabolic reprogramming has great potential as a new field of tumor treatment. This review summarizes the role of CAFs in TME and the mechanisms by which metabolic reprogramming of CAFs causes cancer progression and metastasis, demonstrating the great potential of CAF metabolic reprogramming in cancer chemotherapy and immunotherapy treatment. Furthermore, we provide an outlook for future CAF metabolic reprogramming for cancer treatment.

Keywords:  CAFs; Metabolic reprogramming; chemotherapy; immunotherapy; metastasis

DOI:  https://doi.org/10.1177/11795549241287058
Oncol Res. 2024 ;32(11): 1701-1708

Redefining the tumor microenvironment with emerging therapeutic strategies.

Suling Xu, Xiao Li, Wenxue Ma.

  The environment surrounding a tumor, known as the tumor microenvironment (TME), plays a role in how cancer progresses and responds to treatment. It poses both challenges and opportunities for improving cancer therapy. Recent progress in understanding the TME complexity and diversity has led to approaches for treating cancer. This perspective discusses the strategies for targeting the TME, such as adjusting networks using extracellular vesicles to deliver drugs and enhancing immune checkpoint inhibitors (ICIS) through combined treatments. Furthermore, it highlights adoptive cell transfer (ACT) therapies as an option for tumors. By studying how components of the TME interact and utilizing technologies like single-cell RNA sequencing and spatial transcriptomics, we can develop more precise and efficient treatments for cancer. This article emphasizes the need to reshape the TME to boost antitumor immunity and overcome resistance to therapy, providing guidance for research and clinical practices in precision oncology.

Keywords:  Adoptive cell transfer (ACT); Cancer immunotherapy; Cytokine targeting; Extracellular vesicles (EVs); Tumor microenvironment (TME)

DOI:  https://doi.org/10.32604/or.2024.055161
Yi Chuan. 2024 Oct;46(10): 871-885

Computational dissection of the regulatory mechanisms of aberrant metabolism in remodeling the microenvironment of breast cancer.

Yu-Xin Wan, Xin-Yu Zhu, Yu Zhao, Na Sun, Tian-Tong-Fei Jiang, Juan Xu.

  The composition of T cell subsets and tumor-specific T cell interactions within the tumor microenvironment (TME) contribute to the heterogeneity observed in breast cancer. Moreover, aberrant tumor metabolism is often intimately linked to dysregulated anti-tumor immune function of T cells. Identifying key metabolic genes that affect immune cell interactions thus holds promise for uncovering potential therapeutic targets in the treatment of breast cancer. This study leverages single-cell transcriptomic data from breast cancer to investigate tumor-specific T-cell subsets and their interacting subnetworks in the TME during cancer progression. We further assess the metabolic pathway activities of tumor-specifically activated T-cell subsets. The results reveal that metabolic pathways involved in insulin synthesis, secretion, degradation, as well as fructose catabolism, significantly influence multiple T cell interactions. By integrating the metabolic pathways that significantly up-regulate T cells in tumors and influence their interactions, we identify key abnormal metabolic genes associated with T-cell collaboration and further develop a breast cancer risk assessment model. Additionally, using gene expression profiles of prognosis-related genes significantly associated with aberrant metabolism and drug IC50 values, we predict targeted drugs, yielding potential candidates like GSK-J4 and PX-12. This study integrate the analysis of abnormal T-cell interactions and metabolic pathway abnormalities in the breast cancer TME, elucidating their roles in cancer progression and providing leads for novel breast cancer therapeutic strategies.

Keywords:  T-cell interactions; aberrant metabolism; breast cancer; microenvironmental remodelling

DOI:  https://doi.org/10.16288/j.yczz.24-167
Cells. 2024 Oct 17. pii: 1721. [Epub ahead of print]13(20):

Metabolic Reprogramming Induced by Aging Modifies the Tumor Microenvironment.

Xingyu Chen, Zihan Wang, Bo Zhu, Min Deng, Jiayue Qiu, Yunwen Feng, Ning Ding, Chen Huang.

  Aging is an important risk factor for tumorigenesis. Metabolic reprogramming is a hallmark of both aging and tumor initiation. However, the manner in which the crosstalk between aging and metabolic reprogramming affects the tumor microenvironment (TME) to promote tumorigenesis was poorly explored. We utilized a computational approach proposed by our previous work, MMP3C (Modeling Metabolic Plasticity by Pathway Pairwise Comparison), to characterize aging-related metabolic plasticity events using pan-cancer bulk RNA-seq data. Our analysis revealed a high degree of metabolically organized heterogeneity across 17 aging-related cancer types. In particular, a higher degree of several energy generation pathways, i.e., glycolysis and impaired oxidative phosphorylation, was observed in older patients. Similar phenomena were also found via single-cell RNA-seq analysis. Furthermore, those energy generation pathways were found to be weakened in activated T cells and macrophages, whereas they increased in exhausted T cells, immunosuppressive macrophages, and Tregs in older patients. It was suggested that aging-induced metabolic switches alter glucose utilization, thereby influencing immune function and resulting in the remodeling of the TME. This work offers new insights into the associations between tumor metabolism and the TME mediated by aging, linking with novel strategies for cancer therapy.

Keywords:  aging; glioma; metabolic plasticity; metabolic reprogramming; pan-cancer; scRNA sequencing analysis; tumor immune microenvironment

DOI:  https://doi.org/10.3390/cells13201721
Int J Biol Sci. 2024 ;20(13): 5239-5253

Unveiling the Role of Mechanical Microenvironment in Hepatocellular Carcinoma: Molecular Mechanisms and Implications for Therapeutic Strategies.

Jiachen Hong, Jiongjie Yu, Damiano Buratto, Wei Chen, Ruhong Zhou, Sunbin Ling, Xiao Xu.

  Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third leading cause of cancer deaths globally. More than 80% of HCC patients have a background of fibrosis or cirrhosis, which leads to changes in physical factors in tumor microenvironment (TME), such as increased stiffness, solid stress, fluid stresses and structural alterations in the extracellular matrix (ECM). In the past, the focus of cancer research has predominantly been on genetic and biochemical factors in the TME, and the critical role of physical factors has often been overlooked. Recent discoveries suggest these unique physical signals are converted into biochemical signals through a mechanotransduction process that influences the biological behavior of tumor cells and stromal cells. This process facilitates the occurrence and progression of tumors. This review delves into the alterations in the mechanical microenvironment during the progression of liver fibrosis to HCC, the signaling pathways activated by physical signals, and the effects on both tumor and mesenchymal stromal cells. Furthermore, this paper summarizes and discusses the therapeutic options for targeting the mechanical aspects of the TME, offering valuable insights for future research into novel therapeutic avenues against HCC and other solid tumors.

Keywords:  Extracellular matrix; Hepatocellular carcinoma; Mechanical microenvironment; Mechano-immunotherapy; Mechanosensors

DOI:  https://doi.org/10.7150/ijbs.102706
Cells. 2024 Oct 19. pii: 1736. [Epub ahead of print]13(20):

Excess Potassium Promotes Autophagy to Maintain the Immunosuppressive Capacity of Myeloid-Derived Suppressor Cells Independent of Arginase 1.

Ramesh Thylur Puttalingaiah, Matthew J Dean, Liqin Zheng, Phaethon Philbrook, Dorota Wyczechowska, Timothy Kayes, Luis Del Valle, Denise Danos, Maria Dulfary Sanchez-Pino.

  Potassium ions (K+) are critical electrolytes that regulate multiple functions in immune cells. Recent studies have shown that the elevated concentration of extracellular potassium in the tumor interstitial fluid limits T cell effector function and suppresses the anti-tumor capacity of tumor-associated macrophages (TAMs). The effect of excess potassium on the biology of myeloid-derived suppressor cells (MDSCs), another important immune cell component of the tumor microenvironment (TME), is unknown. Here, we present data showing that increased concentrations of potassium chloride (KCl), as the source of K+ ions, facilitate autophagy by increasing the expression of the autophagosome marker LC3β. Simultaneously, excess potassium ions significantly decrease the expression of arginase I (Arg I) and inducible nitric oxide synthase (iNOS) without reducing the ability of MDSCs to suppress T cell proliferation. Further investigation reveals that excess K+ ions decrease the expression of the transcription factor C/EBP-β and alter the expression of phosphorylated kinases. While excess K+ ions downregulated the expression levels of phospho-AMPKα (pAMPKα), it increased the levels of pAKT and pERK. Additionally, potassium increased mitochondrial respiration as measured by the oxygen consumption rate (OCR). Interestingly, all these alterations induced by K+ ions were abolished by the autophagy inhibitor 3-methyladenine (3-MA). Our results suggest that hyperosmotic stress caused by excess K+ ions regulate the mitochondrial respiration and signaling pathways in MDSCs to trigger the process of autophagy to support MDSCs' immunosuppressive function by mechanisms independent of Arg I and iNOS. Overall, our in vitro and ex vivo findings offer valuable insights into the adaptations of MDSCs within the K+ ion-rich TME, which has important implications for MDSCs-targeted therapies.

Keywords:  K+ ions, immunosuppression; MDSCs; arginase I; autophagy; potassium

DOI:  https://doi.org/10.3390/cells13201736
Front Immunol. 2024 ;15 1483595

Spatial transcriptomics: a new frontier in accurate localization of breast cancer diagnosis and treatment.

Yang Zhang, Shuhua Gong, Xiaofei Liu.

  Breast cancer is one of the most prevalent cancers in women globally. Its treatment and prognosis are significantly influenced by the tumor microenvironment and tumor heterogeneity. Precision therapy enhances treatment efficacy, reduces unwanted side effects, and maximizes patients' survival duration while improving their quality of life. Spatial transcriptomics is of significant importance for the precise treatment of breast cancer, playing a critical role in revealing the internal structural differences of tumors and the composition of the tumor microenvironment. It offers a novel perspective in studying the spatial structure and cell interactions within tumors, facilitating more effective personalized treatments for breast cancer. This article will summarize the latest findings in the diagnosis and treatment of breast cancer from the perspective of spatial transcriptomics, focusing on the revelation of the tumor microenvironment, identification of new therapeutic targets, enhancement of disease diagnostic accuracy, comprehension of tumor progression and metastasis, assessment of drug responses, creation of high-resolution maps of tumor cells, representation of tumor heterogeneity, and support for clinical decision-making, particularly in elucidating the tumor microenvironment, tumor heterogeneity, immunotherapy and their correlation with clinical outcomes.

Keywords:  breast cancer; immunotherapy; spatial transcriptomics; tumor heterogeneity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1483595
J Drug Target. 2024 Oct 24. 1-21

Interactions and communications in the prostate tumour microenvironment: evolving towards effective cancer therapy.

Qiang Dai, Yanling Peng, Peng He, Xiaojun Wu.

  Prostate cancer is one of the most common malignancies in men. The tumour microenvironment (TME) has a critical role in the initiation, progression, and metastasis of prostate cancer. TME contains various cell types, including cancer-associated fibroblasts (CAFs), endothelial cells, immune cells such as macrophages, lymphocytes B and T, natural killer (NK) cells, and other proteins such as extracellular matrix (ECM) components. The interactions and communications between these cells within the TME are crucial for the growth and response of various solid tumours, such as prostate cancer to different anticancer modalities. In this review article, we exemplify the various mechanisms by which the TME influences prostate cancer progression. The roles of different cells, cytokines, chemokines, and growth factors in modulating the immune response and prostate tumour growth will be discussed. The impact of these cells and factors and other ECM components on tumour cell invasion and metastasis will also be discussed. We explain how these interactions in TME can affect the response of prostate cancer to therapy. We also highlight the importance of understanding these interactions to develop novel therapeutic approaches for prostate cancer.

Keywords:  Prostate cancer; extracellular matrix; immune system; macrophages; tumor microenvironment

DOI:  https://doi.org/10.1080/1061186X.2024.2418344
Genes Genet Syst. 2024 Oct 18.

FOXM1 derived from Triple negative breast cancer exosomes promotes cancer progression by activating IDO1 transcription in macrophages to suppress ferroptosis and induce M2 polarization of Tumor-associated macrophages.

Tielin Wang, Yan Zhang, Hong Liu, Jian Wu.

  To explore the oncogenic mechanism of FOXM1 in the tumor microenvironment (TME) regarding triple negative breast cancer (TNBC) promotion. The mRNA and protein levels of target genes in TNBC cells and their exosomes were detected by RT-qPCR and western blot. Co-culture models of TNBC cells and THP-1/M0 macrophages was established to detect the impact of co-culture on FOXM1 expression and macrophage polarization direction. The bioinformatics website was used to predict the binding sites between the FOXM1 and IDO1 promoter, which were further validated using dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. Finally, after erastin-induced ferroptosis, Cell Counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and other experiments were conducted to investigate whether the FOXM1/IDO1 axis regulates M2 macrophage polarization through ferroptosis. It was found that FOXM1 was highly expressed in exosomes derived from TNBC cells, and TNBC cells upregulated FOXM1 expression in THP-1 cells through exosomes to promote M2 macrophage polarization. Furthermore, FOXM1 upregulated IDO1 in M2-type TAMs by regulating transcription. Lastly, FOXM1/IDO1 inhibited ferroptosis, promoting M2 macrophage polarization, thereby advancing TNBC progression. In conclusions, FOXM1 derived from TNBC cell-derived exosomes activated IDO1 transcription in TAMs to inhibit ferroptosis, promoting TAMs' M2 polarization and exerting carcinogenic effects.

Keywords:  FOXM1; IDO1; M2 macrophage polarization; TNBC; exosomes

DOI:  https://doi.org/10.1266/ggs.24-00079
Expert Rev Hematol. 2024 Oct 23.

Evolving strategies to overcome barriers in CAR-T cell therapy for acute myeloid leukemia.

Chanukya K Colonne, Erik L Kimble, Cameron J Turtle.

  INTRODUCTION: Acute myeloid leukemia (AML) is a complex and heterogeneous disease characterized by an aggressive clinical course and limited efficacious treatment options in the relapsed/refractory (R/R) setting. Chimeric antigen receptor (CAR)-modified T (CAR-T) cell immunotherapy is an investigational treatment strategy for R/R AML that has shown some promise. However, obstacles to successful CAR-T cell immunotherapy for AML remain.AREAS COVERED: In analyses of clinical trials of CAR-T cell therapy for R/R AML, complete responses without measurable residual disease have been reported, but the durability of those responses remains unclear. Significant barriers to successful CAR-T cell therapy in AML include the scarcity of suitable tumor-target antigens (TTA), inherent T cell functional deficits, and the immunoinhibitory and hostile tumor microenvironment (TME). This review will focus on these barriers to successful CAR-T cell therapy in AML, and discuss scientific advancements and evolving strategies to overcome them.
EXPERT OPINION: Achieving durable remissions in R/R AML will likely require a multifaceted approach that integrates advancements in TTA selection, enhancement of the intrinsic quality of CAR-T cells, and development of strategies to overcome inhibitory mechanisms in the AML TME.

Keywords:  AML; CAR-T cells; T cell fitness; acute myeloid leukemia; chimeric antigen receptor; immunotherapy; tumor antigen; tumor microenvironment

DOI:  https://doi.org/10.1080/17474086.2024.2420614
Sci Rep. 2024 10 21. 14(1): 24674

Glucose impacts onto the reciprocal reprogramming between mammary adipocytes and cancer cells.

Maria Rosaria Ambrosio, Michiel Adriaens, Kasper Derks, Teresa Migliaccio, Valerio Costa, Domenico Liguoro, Simona Cataldi, Vittoria D'Esposito, Giovanni Maneli, Rita Bassolino, Simone Di Paola, Marinella Pirozzi, Fabrizio Schonauer, Francesco D'Andrea, Francesco Beguinot, Ilja Arts, Pietro Formisano.

  An established hallmark of cancer cells is metabolic reprogramming, largely consisting in the exacerbated glucose uptake. Adipocytes in the tumor microenvironment contribute toward breast cancer (BC) progression and are highly responsive to metabolic fluctuations. Metabolic conditions characterizing obesity and/or diabetes associate with increased BC incidence and mortality. To explore BC-adipocytes interaction and define the impact of glucose in such dialogue, Mammary Adipose-derived Mesenchymal Stem Cells (MAd-MSCs) were differentiated into adipocytes and co-cultured with ER+ BC cells while exposed to glucose concentration resembling hyperglycemia or normoglycemia in humans (25mM or 5.5mM). The transcriptome of both cell types in co-culture as in mono-culture was profiled by RNA-Seq to define the impact of adipocytes on BC cells and viceversa (i), the action of glucose on BC cells, adipocytes (ii) and their crosstalk (iii). Noteworthy, we provided evidence that co-culture with adipocytes in a glucose-rich environment determined a re-program of BC cell transcriptome driving lipid accumulation, a hallmark of BC aggressiveness, promoting stem-like properties and reducing Tamoxifen responsiveness. Moreover, our data point out to a transcriptional effect through which BC cells induce adipocytes de-lipidation, paralleled by pluripotency gain, as source of lipids when glucose lowering occurs. Thus, modulating plasticity of peri-tumoral adipocytes may represent a key point for halting BC progression in metabolically unbalanced patients.

Keywords:  Adipogenesis; Breast Cancer; Glucose; Mammary Adipocytes; Transcriptional signatures; Tumor Microenvironment

DOI:  https://doi.org/10.1038/s41598-024-76522-7
Front Oncol. 2024 ;14 1431418

Targeted therapy approaches for epithelial-mesenchymal transition in triple negative breast cancer.

Mazharul Haque, Ritis K Shyanti, Manoj K Mishra.

  Triple-negative breast cancer (TNBC) is distinguished by negative expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), making it an aggressive subtype of breast cancer and contributes to 15-20% of the total incidence. TNBC is a diverse disease with various genetic variations and molecular subtypes. The tumor microenvironment involves multiple cells, including immune cells, fibroblast cells, extracellular matrix (ECM), and blood vessels that constantly interact with tumor cells and influence each other. The ECM undergoes significant structural changes, leading to induced cell proliferation, migration, adhesion, invasion, and epithelial-to-mesenchymal transition (EMT). The involvement of EMT in the occurrence and development of tumors through invasion and metastasis in TNBC has been a matter of concern. Therefore, EMT markers could be prognostic predictors and potential therapeutic targets in TNBC. Chemotherapy has been one of the primary options for treating patients with TNBC, but its efficacy against TNBC is still limited. Targeted therapy is a critical emerging option with enhanced efficacy and less adverse effects on patients. Various targeted therapy approaches have been developed based on the specific molecules and the signaling pathways involved in TNBC. These include inhibitors of signaling pathways such as TGF-β, Wnt/β-catenin, Notch, TNF-α/NF-κB and EGFR, as well as immune checkpoint inhibitors, such as pembrolizumab, 2laparib, and talazoparib have been widely explored. This article reviews recent developments in EMT in TNBC invasion and metastasis and potential targeted therapy strategies.

Keywords:  breast cancer; epithelial-mesenchymal transition; regulatory pathway; targeted therapy; triple-negative breast cancer; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2024.1431418
Front Immunol. 2024 ;15 1472430

Tumor-associated macrophages and CD8+ T cells: dual players in the pathogenesis of HBV-related HCC.

Muhammad Naveed Khan, Binli Mao, Juan Hu, Mengjia Shi, Shunyao Wang, Adeel Ur Rehman, Xiaosong Li.

  HBV infection is a key risk factor for the development and progression of hepatocellular carcinoma (HCC), a highly invasive tumor, and is characterized by its persistent immunosuppressive microenvironment. This review provides an in-depth analysis of HBV-related HCC and explores the interactions between neutrophils, natural killer cells, and dendritic cells, examining their roles in regulating tumor-associated macrophages and CD8+ T cells and shaping the tumor microenvironment. Two critical players in the immunosuppressive milieu of HBV-related HCC are CD8+ T cells and tumor-associated macrophages (TAMs). The study explores how TAMs, initially recruited to combat infection, transform, adopting a tumor-promoting phenotype, turning against the body, promoting tumor cell proliferation, suppressing anti-tumor immunity, and assisting in the spread of cancer. Meanwhile, CD8+ T cells, crucial for controlling HBV infection, become dysfunctional and exhausted in response to persistent chronic viral inflammation. The review then dissects how TAMs manipulate this immune response, further depleting CD8+ T cell functions through mechanisms like arginine deprivation and creating hypoxic environments that lead to exhaustion. Finally, it explores the challenges and promising therapeutic avenues that target TAMs and CD8+ T cells, either separately or in combination with antiviral therapy and personalized medicine approaches, offering hope for improved outcomes in HBV-related HCC.

Keywords:  CD8+ T cell; HBV-related HCC; TAMs-like macrophage; hepatitis B virus; immunology; pathogenesis

DOI:  https://doi.org/10.3389/fimmu.2024.1472430
J Immunother Cancer. 2024 Oct 23. pii: e009877. [Epub ahead of print]12(10):

AKAP12 positive fibroblast determines immunosuppressive contexture and immunotherapy response in patients with TNBC by promoting macrophage M2 polarization.

Zhenkun Liu, Siyuan Hu, Xinlei Zhao, Wenxin Xu, Feng Ju, Meiying Gu, Jialei Weng, Yabing Du.

  BACKGROUND: Triple-negative breast cancer (TNBC) is a molecular subtype of breast cancer with high aggressiveness and poor prognosis. Cancer-associated fibroblasts (CAFs) are major components of the TNBC microenvironment and play an important role in tumor progression and treatment responses. Our goal is to identify specific CAFs subpopulations contributing to TNBC development.METHODS: Multiomics analyses were applied to identify the CAFs-specific genes related to immunotherapy response. The clinical significance of a CAFs subset with A-kinase anchoring protein 12 (AKAP12) positive was explored in 80 patients with TNBC through double-labeling immunofluorescence assay. Cytometry by time-of-flight and RNA sequencing were performed to elucidate the immune landscape of TNBC microenvironment and functional mechanism of AKAP12+ CAFs.
RESULTS: Multiomics analyses identified an AKAP12+ CAFs subset associated with the immunotherapy response of TNBC, and a high population of these cells is correlated with poor prognosis in patients with TNBC. Intratumoral AKAP12+ CAFs promote formation of an immunosuppressive tumor microenvironment by spatially mediating macrophage M2 polarization via interleukin-34 (IL-34)/macrophage-colony stimulating factor receptor (CSF1R) signaling in TNBC. Single-cell RNA sequencing analyses revealed that AKAP12+ fibroblasts interact with macrophages through the PI3K/AKT/IL-34 axis. In addition, pharmacological blockade of the IL-34/CSF1R signaling enhances the efficacy of anti-programmed cell death protein-1 antibody in TNBC rodent models.
CONCLUSIONS: AKAP12 is mainly expressed in fibroblasts in TNBC. AKAP12+ CAFs population is negatively associated with the prognosis of patients with TNBC. AKAP12+ CAFs shape the immunosuppressive TNBC microenvironment by releasing IL-34 to promote macrophage M2 polarization. Targeting IL-34 may boost the immunotherapeutic efficacy for TNBC.

Keywords:  Biomarker; Breast Cancer; Immunotherapy

DOI:  https://doi.org/10.1136/jitc-2024-009877
Biofactors. 2024 Oct 21.

CXC chemokine receptor 4 - mediated immune modulation and tumor microenvironment heterogeneity in gastric cancer: Utilizing multi-omics approaches to identify potential therapeutic targets.

Jing Tang, Wei Wei, Yaoqing Xu, Kexin Chen, Yaping Miao, Weining Fan, Zhi Huang, Jie Liu, Ping Chen, Honghao Luo, Lexin Wang.

  G-protein-coupled receptors (GPRs) are critical regulators of various biological behaviors, and their role in gastric cancer (GC) progression is gaining increasing attention. Among them, the immune regulatory mechanisms mediated by chemokine receptor 4 (CXCR4) remain insufficiently understood. This study aims to explore the immune regulatory functions of CXCR4 and the heterogeneity of the tumor microenvironment (TME) by examining GPR-related gene expression in GC. Through multi-omics approaches, including spatial transcriptomics and single-cell RNA sequencing, we investigated the oncogenic mechanisms of CXCR4, particularly its role in T cell immune exhaustion. In vitro experiments, including ELISA, PCR, CCK8 assays, cell scratch assays, and colony formation assays, were used to validate the role of CXCR4 in the migration and invasion of AGS and SNU-1 cell lines. CXCR4 silencing using siRNA further demonstrated its regulatory effects on these cellular processes. Our results revealed a strong correlation between elevated CXCR4 expression and increased exhaustion of regulatory T cells (Tregs) in the TME. Furthermore, heightened CXCR4 expression was linked to increased TME heterogeneity, driven by oxidative stress and activation of the NF-κB pathway, promoting immune evasion and tumor progression. Silencing CXCR4 significantly inhibited the invasive and proliferative abilities of AGS and SNU-1 cells, while also reducing the expression of pro-inflammatory cytokines IL-1β and interleukin-6, thus alleviating chronic inflammation and improving TME conditions. In conclusion, our comprehensive investigation highlights CXCR4 as a key mediator of TME dynamics and immune modulation in GC. Targeting CXCR4 presents a promising therapeutic strategy to slow tumor progression by reducing Tregs-mediated immune exhaustion and TME heterogeneity, positioning it as a novel therapeutic target in GC treatment.

Keywords:  CXCR4; biomarkers; cancer immunology; immune evasion; single‐cell multi‐omics integration; therapeutic targets in immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1002/biof.2130
J Transl Med. 2024 Oct 22. 22(1): 959

Microplastics: an often-overlooked issue in the transition from chronic inflammation to cancer.

Yicong Cheng, Yang Yang, Ling Bai, Jiuwei Cui.

  The presence of microplastics within the human body has raised significant concerns about their potential health implications. Numerous studies have supported the hypothesis that the accumulation of microplastics can trigger inflammatory responses, disrupt the microbiome, and provoke immune reactions due to their physicochemical properties. Chronic inflammation, characterized by tissue damage, angiogenesis, and fibrosis, plays a crucial role in cancer development. It influences cancer progression by altering the tumor microenvironment and impairing immune surveillance, thus promoting tumorigenesis and metastasis. This review explores the fundamental properties and bioaccumulation of microplastics, as well as their potential role in the transition from chronic inflammation to carcinogenesis. Additionally, it provides a comprehensive overview of the associated alterations in signaling pathways, microbiota disturbances, and immune responses. Despite this, the current understanding of the toxicity and biological impacts of microplastics remains limited. To mitigate their harmful effects on human health, there is an urgent need to improve the detection and removal methods for microplastics, necessitating further research and elucidation.

Keywords:  Chronic inflammation; Immune regulation; Microplastics; Oncogenesis; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12967-024-05731-5
Int Immunopharmacol. 2024 Oct 22. pii: S1567-5769(24)01839-3. [Epub ahead of print]143(Pt 2): 113317

Single-cell transcriptomics reveals tumor microenvironment changes and prognostic gene signatures in hepatocellular carcinoma.

Yilin Wu, Yangyang Zhai, Zhilong Ding, Tong Xie, WeiJie Zhu, Cui Zhang, Ying Lu, Yunli Chen, Shiying Ren, Yihuai Hu, Xiangqian Li, Fei Zhong, Yong Liang, Shiyan Wang.

  BACKGROUND: Hepatocellular Carcinoma (HCC) is the most common type of primary liver cancer, accounting for the majority of liver cancer cases. Hepatocellular Carcinoma not only exhibits high heterogeneity but also possesses an immune-suppressive tumor microenvironment that promotes tumor evasion, posing substantial difficulties for efficient therapy. Our aim is to utilize single-cell RNA transcriptome data to investigate the dynamic changes in the tumor microenvironment during the malignant progression of HCC, the communication among immune cells, and the marker genes associated with patient prognosis.METHODS: We constructed expression matrices from open single-cell RNA transcriptome data (GSE149614) of HCC patients (representing stages I-IV), establishing single-cell RNA transcriptional atlases for different stages of HCC progression. For each stage, we conducted cell subgroup analysis to identify cell types at each stage. Horizontally, we explored the dynamic changes of the same cell type across different stages, performing trajectory analysis and prognosis analysis. Vertically, we investigated pairwise comparisons of different stages of HCC progression, probing the dynamic alterations in tumor microenvironment immune cell signaling pathways. Finally, potential drugs for the treatment of HCC were predicted based on relevant genes.
FINDINGS: As the HCC advances towards increased malignancy, there is a shift in the predominant composition of the tumor microenvironment, with a decline in the dominance of hepatic cells. Tumor-infiltrating immune cells migrate and accumulate within the tumor microenvironment, where T cells and myeloid cells display distinct patterns of change. Genes associated with cancer-associated fibroblasts (CAFs) and T cells are correlated with adverse patient outcomes. In the late stages of HCC, the tumor microenvironment is infiltrated by more myeloid-derived suppressor cells (MDSCs), and a prognostic model constructed based on genes related to myeloid cells can predict patient outcomes. Additionally, in the analysis of transcription factors, YY1 and MYC are found to be highly expressed. Cell communication analysis among tumor-infiltrating immune cells reveals significant differences in the main signaling pathways at different stages of HCC progression. Finally, drug sensitivity analysis based on key genes identifies Acetalax, Allopurinol, and Amonafide as potential candidates for HCC treatment.

Keywords:  Cell-cell communication; Diagnostic and prognostic markers; Hepatocellular carcinoma; Intra-tumor heterogeneity; Single-cell RNA sequencing; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2024.113317
Cancer Lett. 2024 Oct 17. pii: S0304-3835(24)00701-8. [Epub ahead of print] 217306

Functional diversity and regulation of IL-9-producing T cells in cancer immunotherapy.

Muhammad Kalim, Rui Jing, Wei Guo, Hui Xing, Yong Lu.

  IL-9-producing T cells (T9) regulate immunological responses that affect various cellular biological processes, though their precise function remains fully understood. Previous studies have linked T9 cells to conditions such as allergic disorders, parasitic infection clearance, and various types of cancers. While the functional heterogeneity of IL-9 and T9 cells in cancer development has been documented, these cells present promising therapeutic opportunities for treating solid tumors. This review highlights the roles of IL-9 and T9 cells in cancer progression and treatment responses, focusing on potential discrepancies in IL-9/IL-9R signaling between murine tumors and cancer patients. Additionally, we discuss the regulation of tumor-specific Th9/Tc9 cell differentiation, the therapeutic potential of these cells, and current strategies to enhance their anti-tumor activities.

Keywords:  CAR-T; IL-9; Immunotherapy; Tc9; Th9

DOI:  https://doi.org/10.1016/j.canlet.2024.217306
Biochim Biophys Acta Rev Cancer. 2024 Oct 18. pii: S0304-419X(24)00132-X. [Epub ahead of print]1879(6): 189201

Dual roles of human endogenous retroviruses in cancer progression and antitumor immune response.

Yang Yang, Surong Dong, Benshuai You, Chenglin Zhou.

  Human endogenous retroviruses (HERVs) are a class of transposable elements formed by the integration of ancient retroviruses into the germline genome. They are inherited in a Mendelian manner and approximately constitute 8 % of the human genome. HERVs were considered as "junk DNA" for decades, but increasing evidence suggests that they play significant roles in pathological inflammation, neural differentiation, and oncogenesis. Specifically, HERVs expression has been implicated in several oncogenic processes and the formation of the tumor microenvironment. Indeed, the dual roles of HERVs in cancer, serving as both promoters of oncogenesis and forerunners of the innate antitumor immune response, remain a subject of debate. In this review, we will discuss how HERVs participate in cancer progression and how they are regulated. Our aim is to provide a comprehensive understanding of the fundamental properties and potential function of HERVs in propagating oncogenesis and activating the antitumor immune response. We hope that updated knowledge will reshape our understanding of the critical roles played by HERVs in human evolution and cancer progression.

Keywords:  Human endogenous retroviruses; Immune response; Interferon signaling; Oncogenesis; Transposable elements

DOI:  https://doi.org/10.1016/j.bbcan.2024.189201
Expert Opin Drug Deliv. 2024 Oct 22.

The potential of nanosystems in disrupting adenosine signaling pathways for tumor immunotherapy.

Yutong Zhao, Jingqi Sun, Xiao-Ling Xu, Jin Su, Yong-Zhong Du.

  INTRODUCTION: Adenosine (ADO) is a naturally occurring nucleoside primarily synthesized through the hydrolysis of extracellular adenosine triphosphate. Within the tumor microenvironment, ADO levels substantially increase, resulting in suppressed immune responses.AREAS COVERED: Nanosystems offer a promising approach for precise drug delivery to tumor lesions. In this review, we provide an overview of the current research progress in the development of nanosystems that modulate adenosine signaling for tumor immunotherapy. These nanosystems are designed to target adenosine-hydrolyzing proteins, increase adenosine decomposition, and antagonize adenosine receptors.
EXPERT OPINION: Based on the literature review, adenosine has great potential in tumor immunotherapy, and nano-drug delivery system has great application prospects in targeted cancer therapy in the near future due to its superior characteristics.

Keywords:  Adenosine signaling; CD73; adenosine deaminase; nanotuner; tumor immunotherapy

DOI:  https://doi.org/10.1080/17425247.2024.2417687
Curr Med Chem. 2024 Oct 24.

Intermittent Fasting and Fasting-mimicking Diet: Promising Strategies in Cancer Management.

Chuanqiang Zhang, Fengqing Fu, Xingchao Zhu, Xiangyu Ni, Sijia Yue, Hongya Wu, Tongguo Shi.

  In the current review, we aim to elucidate the advancements concerning the roles and fundamental mechanisms of intermittent fasting (IF) and fasting-mimicking diet (FMD) in cancers. As a dietary intervention,IF and FMD potentially impede tumor growth by modulating multiple signaling pathways, such as AKT, Nrf2, and AMPK pathways.Moreover, IF and FMD have been reported to be associated with the tumor immune response by regulating various immune cells including tumor-associated macrophages (TAMs), monocytic myeloid-derived suppressor cells (MDSCs), T cells, and B cells.Additionally, IF and FMD can enhance the efficacy and tolerability of therapy, concurrently reducing therapy-induced side effects. Furthermore, several clinical trials have underscored the safety, feasibility, and positive impact on the quality of life associated with IF and FMD, thereby augmenting the effectiveness of conventional anti-- tumor therapies while ameliorating treatment-related side effects. This review provides a comprehensive synthesis of findings and elucidates the underlying mechanisms of IF and FMD in cancer progression and therapy.

Keywords:  Cancer; cancer therapy; clinical trials.; fasting-mimicking diet; intermittent fasting

DOI:  https://doi.org/10.2174/0109298673332052241008060857
QJM. 2024 Oct 22. pii: hcae195. [Epub ahead of print]

Multifunctional role of the tumor associated monocytes/macrophages in the metastatic potential of inflammatory breast cancer.

Mona Mostafa Mohamed, Robert J Schneider.

  Inflammatory breast cancer (IBC) is the most aggressive and lethal phenotype form of breast cancer, which afflicts young women at high incidence in North Africa compared to other continents of the world. IBC is characterized by highly metastatic behavior and possesses specific pathobiological properties different from non-IBC. IBC disease displays unusual common properties at typical presentation, including positive metastatic lymph-nodes, high infiltration of tumor associated monocytes/macrophages, rapid progression to distant metastasis, and possibly the production of a unique repertoire of growth factors, cytokines and chemokines, as well as a striking association with different polarized macrophages compared to non-IBC. Indeed, tumor associated monocytes/macrophages (TAM/M) play a crucial role in breast cancer development. Previously, we showed that cross talk between IBC cells and patient derived TAMs occurs via secretion of inflammatory mediators from TAMs that act on specific extracellular domain receptors activating down-stream signaling pathways that promote the epithelial-to-mesenchymal transition, cancer cell invasion, IBC stem cell properties, drug resistance, local and metastatic recurrence of residual tumor cells and other key markers of malignancy, including in vitro colony formation capacity. In this mini review, we will discuss the role of TAMs in IBC cancer metastatic potential and molecules involved. The review also discusses the recent discoveries in the field of IBC research.

Keywords:  Cytokines; Inflammatory breast cancer; Monocyte/macrophages; Tumor emboli

DOI:  https://doi.org/10.1093/qjmed/hcae195
Cancer Innov. 2024 Dec;3(6): e153

Leukocyte immunoglobulin-like receptor B4: A keystone in immune modulation and therapeutic target in cancer and beyond.

Qi Liu, Yuyang Liu, Zhanyu Yang.

  Leukocyte immunoglobulin-like receptor B4 (LILRB4) significantly impacts immune regulation and the pathogenesis and progression of various cancers. This review discusses LILRB4's structural attributes, expression patterns in immune cells, and molecular mechanisms in modulating immune responses. We describe the influence of LILRB4 on T cells, dendritic cells, NK cells, and macrophages, and its dual role in stimulating and suppressing immune activities. The review discusses the current research on LILRB4's involvement in acute myeloid leukemia, chronic lymphocytic leukemia, and solid tumors, such as colorectal cancer, pancreatic cancer, non-small cell lung cancer, hepatocellular carcinoma, and extramedullary multiple myeloma. The review also describes LILRB4's role in autoimmune disorders, infectious diseases, and other conditions. We evaluate the recent advancements in targeting LILRB4 using monoclonal antibodies and peptide inhibitors and their therapeutic potential in cancer treatment. Together, these studies underscore the need for further research on LILRB4's interactions in the tumor microenvironment and highlight its importance as a therapeutic target in oncology and for future clinical innovations.

Keywords:  cancer therapy; immune checkpoint; immunotherapy; leukocyte immunoglobulin‐like receptor B4; monoclonal antibodies

DOI:  https://doi.org/10.1002/cai2.153
Cell Oncol (Dordr). 2024 Oct 21.

SUMOylation regulates the aggressiveness of breast cancer-associated fibroblasts.

Angelica Martínez-López, Guiomar Infante, Marina Mendiburu-Eliçabe, Andrés Machuca, Olga M Antón, Mónica González-Fernández, José L Luque-García, Robert B Clarke, Sonia Castillo-Lluva.

  BACKGROUND: Cancer-associated fibroblasts (CAFs) are the most abundant stromal cellular component in the tumor microenvironment (TME). CAFs contribute to tumorigenesis and have been proposed as targets for anticancer therapies. Similarly, dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to tumorigenesis and drug resistance in various cancers, including breast cancer. We explored the role of SUMOylation in breast CAFs and evaluated its potential as a therapeutic strategy in breast cancer.METHODS: We used pharmacological and genetic approaches to analyse the functional crosstalk between breast tumor cells and CAFs. We treated breast CAFs with the SUMO1 inhibitor ginkgolic acid (GA) at two different concentrations and conditioned media was used to analyse the proliferation, migration, and invasion of breast cancer cells from different molecular subtypes. Additionally, we performed quantitative proteomics (SILAC) to study the differential signalling pathways expressed in CAFs treated with low or high concentrations of GA. We confirmed these results both in vitro and in vivo. Moreover, we used samples from metastatic breast cancer patients to evaluate the use of GA as a therapeutic strategy.
RESULTS: Inhibition of SUMOylation with ginkgolic acid (GA) induces death in breast cancer cells but does not affect the viability of CAFs, indicating that CAFs are resistant to this therapy. While CAF viability is unaffected, CAF-conditioned media (CM) is altered by GA, impacting tumor cell behaviour in different ways depending on the overall degree to which SUMO1-SUMOylated proteins are dysregulated. Breast cancer cell lines exhibited a concentration-dependent response to conditioned media (CM) from CAFs. At a low concentration of GA (10 µM), there was an increase in proliferation, migration and invasion of breast cancer cells. However, at a higher concentration of GA (30 µM), these processes were inhibited. Similarly, analysis of tumor development revealed that at 10 µM of GA, the tumors were heavier and there was a greater degree of metastasis compared to the tumors treated with the higher concentration of GA (30 µM). Moreover, some of these effects could be explained by an alteration in the activity of the GTPase Rac1 and the activation of the AKT signalling pathway. The results obtained using SILAC suggest that different concentrations of GA affected cellular processes differentially, possibly influencing the secretome of CAFs. Treatment of metastatic breast cancer with GA demonstrated the use of SUMOylation inhibition as an alternative therapeutic strategy.
CONCLUSION: The study highlights the importance of SUMOylation in the tumor microenvironment, specifically in cancer-associated fibroblasts (CAFs). Targeting SUMOylation in CAFs affects their signalling pathways and secretome in a concentration-dependent manner, regulating the protumorigenic properties of CAFs.

Keywords:  Breast cancer; CAFs; Ginkgolic acid; SILAC; SUMOylation

DOI:  https://doi.org/10.1007/s13402-024-01005-w
ACS Appl Mater Interfaces. 2024 Oct 21.

Mesoporous Microneedles Enabled Localized Controllable Delivery of Stimulator of Interferon Gene Agonist Nanoexosomes for FLASH Radioimmunotherapy against Breast Cancer.

Zhiran Chen, Fangjie Hu, Jingfeng Xiang, Xiaoxiang Zhou, Bo Wu, Baohang Fan, Han Tang, Bin Liu, Longyun Chen.

  The immunosuppressive nature of the tumor microenvironment (TME) contributes to radioresistance, thereby impairing the effectiveness of radiotherapy as a therapeutic intervention. Activation through the stimulator of interferon genes (STING) pathway shows potential in modulating immunogenicity. However, the therapeutic efficacy of STING agonists might be restricted by off-target effects and potential cytotoxicity. In this work, nanoexosomes (EXOs) loaded within porous microneedles were employed for precise delivery of the STING agonist MSA-2 (MEM) to the tumor site. Leveraging the enhanced tumor penetration enabled by microneedles, EXOs can be continually released and accumulate within deep residual tumors. Once internalized, these EXOs release the encapsulated MSA-2, facilitating the activation of the STING pathway upon exposure to ultrahigh dose-rate (FLASH) irradiation. This strategy elevates the type I interferon level, promotes dendric cell maturation, and modulates the immunosuppressive TME, showing efficient antitumor efficacy in both primary/metastatic tumors. Furthermore, the induction of a potent immune response effectively prevented tumor recurrence. The combination of EXO-loaded microneedles with FLASH radiotherapy resulted in minimal systemic side effects, attributed to precise drug delivery and radioprotection conferred by FLASH. Altogether, the strategic design of EXO-loaded microneedles holds promise for enhancing MSA-2 delivery, thereby mitigating the radioresistant tumor microenvironment through STING cascade activation-mediated immunotherapy, consequently optimizing the outcomes of FLASH radiotherapy.

Keywords:  FLASH RT; STING agonist; extracellular vesicles; immunotherapy; microneedles

DOI:  https://doi.org/10.1021/acsami.4c09833
Imeta. 2024 Oct;3(5): e233

LTBR acts as a novel immune checkpoint of tumor-associated macrophages for cancer immunotherapy.

Liang Wang, Jieyi Fan, Sifan Wu, Shilin Cheng, Junlong Zhao, Fan Fan, Chunchen Gao, Rong Qiao, Qiqi Sheng, Yiyang Hu, Yong Zhang, Pengjun Liu, Zhe Jiao, Tiaoxia Wei, Jie Lei, Yan Chen, Hongyan Qin.

  Tumor-associated macrophages (TAMs) greatly contribute to immune checkpoint inhibitor (ICI) resistance of cancer. However, its underlying mechanisms and whether TAMs can be promising targets to overcome ICI resistance remain to be unveiled. Through integrative analysis of immune multiomics data and single-cell RNA-seq data (iMOS) in lung adenocarcinoma (LUAD), lymphotoxin β receptor (LTBR) is identified as a potential immune checkpoint of TAMs, whose high expression, duplication, and low methylation are correlated with unfavorable prognosis. Immunofluorescence staining shows that the infiltration of LTBR+ TAMs is associated with LUAD stages, immunotherapy failure, and poor prognosis. Mechanistically, LTΒR maintains immunosuppressive activity and M2 phenotype of TAMs by noncanonical nuclear factor kappa B and Wnt/β-catenin signaling pathways. Macrophage-specific knockout of LTBR hinders tumor growth and prolongs survival time via blocking TAM immunosuppressive activity and M2 phenotype. Moreover, TAM-targeted delivery of LTΒR small interfering RNA improves the therapeutic effect of ICI via reversing TAM-mediated immunosuppression, such as boosting cytotoxic CD8+ T cells and inhibiting granulocytic myeloid-derived suppressor cells infiltration. Taken together, we bring forth an immune checkpoint discovery pipeline iMOS, identify LTBR as a novel immune checkpoint of TAMs, and propose a new immunotherapy strategy by targeting LTBR+ TAMs.

Keywords:  CD8+ T cells; LTBR; immune checkpoint; myeloid derived suppressor cells; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/imt2.233
Med Oncol. 2024 Oct 25. 41(12): 300

Intratumoral microbiota: an emerging force in diagnosing and treating hepatocellular carcinoma.

Huanxiang Liu, Jiahao Zhang, Yuye Rao, Shengjie Jin, Chi Zhang, Dousheng Bai.

  Hepatocellular carcinoma (HCC) ranks among the most prevalent types of cancer in the world and its incidence and mortality are increasing year by year, frequently diagnosed at an advanced stage. Traditional treatments such as surgery, chemotherapy, and radiotherapy have limited efficacy, so new diagnostic and treatment strategies are urgently needed. Recent research has discovered that intratumoral microbiota significantly influences the development, progression, and metastasis of HCC by modulating inflammation, immune responses, and cellular signaling pathways. Intratumoral microbiota contributes to the pathologic process of HCC by influencing the tumor microenvironment and altering the function of immune system. This article reviews the mechanism of intratumoral microbiota in HCC and anticipates the future possibilities of intratumoral microbiota-based therapeutic strategies for HCC management. This emerging field provides fresh insights into early diagnosis and personalized approaches for HCC while holding substantial clinical application potential to improve patient outcomes and tailor interventions to individual tumor profiles.

Keywords:  Hepatocellular carcinoma; Intratumoral microbiota; Microbial biomarker; Tumor immune microenvironment

DOI:  https://doi.org/10.1007/s12032-024-02545-9