bims-flamet 2024-09-15 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–09–15
34 papers selected by
Peio Azcoaga, Biodonostia HRI

TP53 Mutation-Mediated Immune Evasion in Cancer: Mechanisms and Therapeutic Implications.
Tumor-infiltrating B cells: Their dual mechanistic roles in the tumor microenvironment.
CSF1R Ligands Expressed by Murine Gliomas Promote M-MDSCs to Suppress CD8+ T Cells in a NOS-Dependent Manner.
The molecular landscape of T cell exhaustion in the tumor microenvironment and reinvigoration strategies.
CD4+ T cells in antitumor immunity.
Spatial resolved transcriptomics reveals distinct cross-talk between cancer cells and tumor-associated macrophages in intrahepatic cholangiocarcinoma.
Cell Identity and Spatial Distribution of PD-1/PD-L1 Blockade Responders.
Extracellular Vesicles & Co.: scaring immune cells in the TME since ever.
Roles of M1 Macrophages and Their Extracellular Vesicles in Cancer Therapy.
Therapeutic Opportunities in Breast Cancer by Targeting Macrophage Migration Inhibitory Factor as a Pleiotropic Cytokine.
Naive primary neutrophils play a dual role in the tumor microenvironment.
Mutant p53 Exploits Enhancers to Elevate Immunosuppressive Chemokine Expression and Impair Immune Checkpoint Inhibitors in Pancreatic Cancer.
SMS2 siRNA inhibits pancreatic tumor growth by tumor microenvironment modulation.
Emerging role of tumor microenvironmental nutrients and metabolic molecules in ferroptosis: Mechanisms and clinical implications.
Focal adhesion kinase-mediated interaction between tumor and immune cells in the tumor microenvironment: implications for cancer-associated therapies and tumor progression.
A call for clinical trials in glioblastoma multiforme for interleukin 4, interleukin 6, interleukin 13 and CD40.
Improving the efficacy of immunotherapy for colorectal cancer: Targeting tumor microenvironment-associated immunosuppressive cells.
Engineered Nanoparticles for Enhanced Antitumoral Synergy Between Macrophages and T Cells in the Tumor Microenvironment.
Classifying cancer-associated fibroblasts-The good, the bad, and the target.
Spatiotemporal dynamics of tumor - CAR T-cell interaction following local administration in solid cancers.
Old concepts, new tricks: How peptide vaccines are reshaping cancer immunotherapy?
NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer.
The mitochondrial stress signaling tunes immunity from a view of systemic tumor microenvironment and ecosystem.
Melatonin enhances the efficacy of anti-PD-L1 by improving hypoxia in residual tumors after insufficient radiofrequency ablation.
The role of Hippo/YAP1 in cancer-associated fibroblasts: Literature review and future perspectives.
Deciphering the impact of aggregated autophagy-related genes TUBA1B and HSP90AA1 on colorectal cancer evolution: a single-cell sequencing study of the tumor microenvironment.
Interleukin-10 overexpression in 4T1 cells: A gateway to suppressing mammary carcinoma growth.
Exosomal SLC16A1-AS1-induced M2 macrophages polarization facilitates hepatocellular carcinoma progression.
The Dark Knight: Functional Reprogramming of Neutrophils in the Pathogenesis of Colitis-Associated Cancer.
A nanodrug provokes antitumor immune responses via synchronous multicellular regulation for enhanced cancer immunotherapy.
Microcystin-LR Regulates Interaction between Tumor Cells and Macrophages via the IRE1α/XBP1 Signaling Pathway to Promote the Progression of Colorectal Cancer.
Circadian rhythms and breast cancer: from molecular level to therapeutic advancements.
Unveiling the role of taurine and SLC6A6 in tumor immune evasion: Implications for gastric cancer therapy.
Immunomodulatory nanoparticles activate cytotoxic T cells for enhancement of the effect of cancer immunotherapy.

Cancers (Basel). 2024 Sep 03. pii: 3069. [Epub ahead of print]16(17):

TP53 Mutation-Mediated Immune Evasion in Cancer: Mechanisms and Therapeutic Implications.

Chuqi Wang, Jordan Yong Ming Tan, Nishtha Chitkara, Shruti Bhatt.

  Mutation in p53 is the most frequent event in cancer development and a leading cause of cancer therapy resistance due to evasion of the apoptosis cascade. Beyond chemotherapies and radiation therapies, growing evidence indicates that p53-mutant tumors are resistant to a broad range of immune-based therapies, such as immune checkpoint inhibitors, chimeric antigen receptor (CAR) T, and hematopoietic stem cell transplantation (HSCT). This highlights the role of p53 mutations in driving immune evasion of tumor cells. In this review, we first summarize recent studies revealing mechanisms by which p53-mutant tumors evade immune surveillance from T cells, natural killer (NK) cells, and macrophages. We then review how these mutant tumor cells reshape the tumor microenvironment (TME), modulating bystander cells such as macrophages, neutrophils, and regulatory T (Treg) cells to foster immunosuppression. Additionally, we review clinical observations indicative of immune evasion associated with p53 loss or mutations. Finally, we discuss therapeutic strategies to enhance immune response in p53 wild-type (WT) or mutant tumors.

Keywords:  immune evasion; immunotherapy; mouse double minute 2; p53; p53 mutation

DOI:  https://doi.org/10.3390/cancers16173069
Biomed Pharmacother. 2024 Sep 12. pii: S0753-3322(24)01322-2. [Epub ahead of print]179 117436

Tumor-infiltrating B cells: Their dual mechanistic roles in the tumor microenvironment.

Demin Xue, Shaozhen Hu, Runchen Zheng, Huidan Luo, Xi Ren.

  The occurrence and development of tumors are closely associated with abnormalities in the immune system's structure and function, with tumor immunotherapy being intricately linked to the tumor microenvironment (TME). Early studies on lymphocytes within the TME primarily concentrated on T cells. However, as research has advanced, the multifaceted roles of tumor-infiltrating B cells (TIL-Bs) in tumor immunity, encompassing both anti-tumor and pro-tumor effects, have garnered increasing attention. This paper explored the composition of the TME and the biological characteristics of TIL-Bs, investigating the dual roles within the TME to offer new insights and strategies for tumor immunotherapy.

Keywords:  Immune microenvironment; Immunotherapy; Tumor microenvironment; Tumor-infiltrating B cells

DOI:  https://doi.org/10.1016/j.biopha.2024.117436
Cancers (Basel). 2024 Sep 01. pii: 3055. [Epub ahead of print]16(17):

CSF1R Ligands Expressed by Murine Gliomas Promote M-MDSCs to Suppress CD8+ T Cells in a NOS-Dependent Manner.

Gregory P Takacs, Julia S Garcia, Caitlyn A Hodges, Christian J Kreiger, Alexandra Sherman, Jeffrey K Harrison.

  Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2+/CX3CR1+ M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2+/CX3CR1+ cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma-secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in the M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that is driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma.

Keywords:  CSF; MDSC; NOS; T cell; chemokine receptor; glioma; immune; myeloid; suppression

DOI:  https://doi.org/10.3390/cancers16173055
Int Rev Immunol. 2024 Sep 11. 1-22

The molecular landscape of T cell exhaustion in the tumor microenvironment and reinvigoration strategies.

Mahsa Heidari-Foroozan, Alaleh Rezalotfi, Nima Rezaei.

  Immunotherapy has emerged as a promising therapeutic approach for cancer treatment by harnessing the immune system to target cancer cells. However, the efficacy of immunotherapy is hindered by the tumor microenvironment (TME), comprising regulatory T cells (Tregs), macrophages, myeloid-derived suppressor cells (MDSCs), neutrophils, soluble factors (TGF-β, IL-35, IL-10), and hypoxia. These components interact with inhibitory receptors (IRs) on T cells, leading to alterations in T cell transcriptomes, epigenomes, and metabolism, ultimately resulting in T cell exhaustion and compromising the effectiveness of immunotherapy. T cell exhaustion occurs in two phases: pre-exhaustion and exhaustion. Pre-exhausted T cells exhibit reversibility and distinct molecular properties compared to terminally exhausted T cells. Understanding these differences is crucial for designing effective interventions. This comprehensive review summarizes the characteristics of pre-exhausted and exhausted T cells and elucidates the influence of TME components on T cell activity, transcriptomes, epigenomes, and metabolism, ultimately driving T cell exhaustion in cancer. Additionally, potential intervention strategies for reversing exhaustion are discussed. By gaining insights into the mechanisms underlying T cell exhaustion and the impact of the TME, this review aims to inform the development of innovative approaches for combating T cell exhaustion and enhancing the efficacy of immunotherapy in cancer treatment.

Keywords:  Immunotherapy; T cell exhaustion; neoplasms; pre-exhausted T cells; tumor microenvironment

DOI:  https://doi.org/10.1080/08830185.2024.2401352
Trends Cancer. 2024 Sep 05. pii: S2405-8033(24)00157-2. [Epub ahead of print]

CD4+ T cells in antitumor immunity.

Elena Montauti, David Y Oh, Lawrence Fong.

  Advances in cancer immunotherapy have transformed cancer care and realized unprecedented responses in many patients. The growing arsenal of novel therapeutics - including immune checkpoint inhibition (ICI), adoptive T cell therapies (ACTs), and cancer vaccines - reflects the success of cancer immunotherapy. The therapeutic benefits of these treatment modalities are generally attributed to the enhanced quantity and quality of antitumor CD8+ T cell responses. Nevertheless, CD4+ T cells are now recognized to play key roles in both the priming and effector phases of the antitumor immune response. In addition to providing T cell help through co-stimulation and cytokine production, CD4+ T cells can also possess cytotoxicity either directly on MHC class II-expressing tumor cells or to other cells within the tumor microenvironment (TME). The presence of specific populations of CD4+ T cells, and their intrinsic plasticity, within the TME can represent an important determinant of clinical response to immune checkpoint inhibitors, vaccines, and chimeric antigen receptor (CAR) T cell therapies. Understanding how the antitumor functions of specific CD4+ T cell types are induced while limiting their protumorigenic attributes will enable more successful immunotherapies.

Keywords:  CD4(+) T lymphocytes; antigen-presenting cells; cancer immunotherapy

DOI:  https://doi.org/10.1016/j.trecan.2024.07.009
Biomark Res. 2024 Sep 11. 12(1): 100

Spatial resolved transcriptomics reveals distinct cross-talk between cancer cells and tumor-associated macrophages in intrahepatic cholangiocarcinoma.

Zhao-Ru Dong, Meng-Ya Zhang, Ling-Xin Qu, Jie Zou, Yong-Heng Yang, Yun-Long Ma, Chun-Cheng Yang, Xue-Lei Cao, Li-Yuan Wang, Xiao-Lu Zhang, Tao Li.

   BACKGROUND: Multiple studies have shown that tumor-associated macrophages (TAMs) promote cancer initiation and progression. However, the reprogramming of macrophages in the tumor microenvironment (TME) and the cross-talk between TAMs and malignant subclones in intrahepatic cholangiocarcinoma (iCCA) has not been fully characterized, especially in a spatially resolved manner. Deciphering the spatial architecture of variable tissue cellular components in iCCA could contribute to the positional context of gene expression containing information pathological changes and cellular variability.
METHODS: Here, we applied spatial transcriptomics (ST) and digital spatial profiler (DSP) technologies with tumor sections from patients with iCCA.
RESULTS: The results reveal that spatial inter- and intra-tumor heterogeneities feature iCCA malignancy, and tumor subclones are mainly driven by physical proximity. Tumor cells with TME components shaped the intra-sectional heterogenetic spatial architecture. Macrophages are the most infiltrated TME component in iCCA. The protein trefoil factor 3 (TFF3) secreted by the malignant subclone can induce macrophages to reprogram to a tumor-promoting state, which in turn contributes to an immune-suppressive environment and boosts tumor progression.
CONCLUSIONS: In conclusion, our description of the iCCA ecosystem in a spatially resolved manner provides novel insights into the spatial features and the immune suppressive landscapes of TME for iCCA.

Keywords:  Digital spatial profiler; Intrahepatic cholangiocarcinoma; Spatial transcriptomics; Trefoil factor 3 (TFF3); Tumor associated macrophage

DOI:  https://doi.org/10.1186/s40364-024-00648-z
Adv Sci (Weinh). 2024 Sep 09. e2400702

Cell Identity and Spatial Distribution of PD-1/PD-L1 Blockade Responders.

Xintong Li, Yuanxin Liu, Jun Gui, Lu Gan, Jianxin Xue.

  The programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis inhibits T cell activity, impairing anti-tumor immunity. Blocking this axis with therapeutic antibodies is one of the most promising anti-tumor immunotherapies. It has long been recognized that PD-1/PD-L1 blockade reinvigorates exhausted T (TEX) cells already present in the tumor microenvironment (TME). However, recent advancements in high-throughput gene sequencing and bioinformatic tools have provided researchers with a more granular and dynamic insight into PD-1/PD-L1 blockade-responding cells, extending beyond the TME and TEX populations. This review provides an update on the cell identity, spatial distribution, and treatment-induced spatiotemporal dynamics of PD-1/PD-L1 blockade responders. It also provides a synopsis of preliminary reports of potential PD-1/PD-L1 blockade responders other than T cells to depict a panoramic picture. Important questions to answer in further studies and the translational and clinical potential of the evolving understandings are also discussed.

Keywords:  PD‐1/PD‐L1 blockades; T‐cell exhaustion; cancer; cell therapy; immunotherapy; stem‐like T‐cells

DOI:  https://doi.org/10.1002/advs.202400702
Front Immunol. 2024 ;15 1451003

Extracellular Vesicles & Co.: scaring immune cells in the TME since ever.

Carlo Rodolfo, Silvia Campello.

  The health tissue surrounding a solid tumor, namely the tumor microenvironment (TME), is an extremely complex universe of cells, extracellular matrix, and signals of various nature, that support and protect the growth of cancer cells. The interactions taking place between cancer cells and the TME are crucial not only for tumor growth, invasion, and metastasis but they also play a key role in modulating immune system responses to cancer, and vice-versa. Indeed, tumor-infiltrating immune cells (e.g., T lymphocytes and natural killers) activity is greatly affected by signals (mostly ligands/receptors and paracrine) they receive in the TME, which frequently generate an immunosuppressive milieu. In the last years, it has become evident that soluble and receptor signaling is not the only way of communication between cells in the TME, with extracellular vesicles, such as exosomes, playing a central role. Among the different new kind of vesicles recently discovered, migrasomes look like to be of extreme interest as they are not only different from the others, but also have been reported as able to deliver a very heterogeneous kind of messages, able to profoundly affect recipient cells' behavior. Indeed, the role played by the different classes of extracellular vesicles, especially in the TME, relies on their not-directional diffusion from the originating cells, while migrasomes released from migrating cells do have a directional effect. Migrasomes biology and their involvement in cancer progression, dissemination, and resistance to therapy is still a largely obscure field, but with promising development foreseen in the next future.

Keywords:  TME (tumor microenvironment); autophagy; exosomes; extracellular vesicles (EVs); migrasomes

DOI:  https://doi.org/10.3389/fimmu.2024.1451003
Cells. 2024 Aug 26. pii: 1428. [Epub ahead of print]13(17):

Roles of M1 Macrophages and Their Extracellular Vesicles in Cancer Therapy.

Wenli Zhou, Fengtang Yang, Xiuzhen Zhang.

  Tumor-associated macrophages (TAMs) are inflammatory cells that are important components of the tumor microenvironment. TAMs are functionally heterogeneous and divided into two main subpopulations with distinct and opposite functions: M1 and M2 macrophages. The secretory function of TAMs is essential for combating infections, regulating immune responses, and promoting tissue repair. Extracellular vesicles (EVs) are nanovesicles that are secreted by cells. They play a crucial role in mediating intercellular information transfer between cells. EVs can be secreted by almost all types of cells, and they contain proteins, microRNAs, mRNAs, and even long non-coding RNAs (lncRNAs) that have been retained from the parental cell through the process of biogenesis. EVs can influence the function and behavior of target cells by delivering their contents, thus reflecting, to some extent, the characteristics of their parental cells. Here, we provide an overview of the role of M1 macrophages and their EVs in cancer therapy by exploring the impact of M1 macrophage-derived EVs (M1-EVs) on tumors by transferring small microRNAs. Additionally, we discuss the potential of M1-EVs as drug carriers and the possibility of reprogramming M2 macrophages into M1 macrophages for disease treatment. We propose that M1-EVs play a crucial role in cancer therapy by transferring microRNAs and loading them with drugs. Reprogramming M2 macrophages into M1 macrophages holds great promise in the treatment of cancers.

Keywords:  M1 macrophage; M2 macrophage; cancer; exosome; extracellular vesicles

DOI:  https://doi.org/10.3390/cells13171428
Breast Cancer (Auckl). 2024 ;18 11782234241276310

Therapeutic Opportunities in Breast Cancer by Targeting Macrophage Migration Inhibitory Factor as a Pleiotropic Cytokine.

Ali Khezrian, Ali Shojaeian, Armin Khaghani Boroujeni, Razieh Amini.

  As a heterogeneous disease, breast cancer (BC) has been characterized by the uncontrolled proliferation of mammary epithelial cells. The tumor microenvironment (TME) also contains inflammatory cells, fibroblasts, the extracellular matrix (ECM), and soluble factors that all promote BC progression. In this sense, the macrophage migration inhibitory factor (MIF), a pleiotropic pro-inflammatory cytokine and an upstream regulator of the immune response, enhances breast tumorigenesis through escalating cancer cell proliferation, survival, angiogenesis, invasion, metastasis, and stemness, which then brings tumorigenic effects by activating key oncogenic signaling pathways and inducing immunosuppression. Against this background, this review was to summarize the current understanding of the MIF pathogenic mechanisms in cancer, particularly BC, and address the central role of this immunoregulatory cytokine in signaling pathways and breast tumorigenesis. Furthermore, different inhibitors, such as small molecules as well as antibodies (Abs) or small interfering RNA (siRNA) and their anti-tumor effects in BC studies were examined. Small molecules and other therapy target MIF. Considering MIF as a promising therapeutic target, further clinical evaluation of MIF-targeted agents in patients with BC was warranted.

Keywords:  MIF; Macrophage migration inhibitory factor; breast cancer; extracellular matrix; small molecules

DOI:  https://doi.org/10.1177/11782234241276310
iScience. 2024 Sep 20. 27(9): 110632

Naive primary neutrophils play a dual role in the tumor microenvironment.

Kehinde Adebayo Babatunde, Rupsa Datta, Nathan W Hendrikse, Jose M Ayuso, Anna Huttenlocher, Melissa C Skala, David J Beebe, Sheena C Kerr.

  The tumor microenvironment (TME) is characterized by a network of cancer cells, recruited immune cells, and extracellular matrix (ECM). However, the specific role of neutrophils during tumor development, and their interactions with other immune cells is still not well understood. Here, we use both standard well plate culture and an under oil microfluidic (UOM) assay with an integrated ECM bridge to elucidate how naive primary neutrophils respond to tumor cells. Our data demonstrated that tumor cells trigger cluster formation in neutrophils accompanied with the generation of reactive oxygen species (ROS) and neutrophil extracellular trap (NET) release. Using label-free optical metabolic imaging (OMI), we observed changes in the metabolic activities of primary neutrophils during the different clustering phases when challenged with tumor cells. Finally, our data demonstrates that neutrophils in direct contact, or in close proximity, with tumor cells exhibit greater metabolic activities compared to non-contact neutrophils.

Keywords:  Cancer; Cell biology; Immunology; Microenvironment

DOI:  https://doi.org/10.1016/j.isci.2024.110632
bioRxiv. 2024 Aug 30. pii: 2024.08.28.609802. [Epub ahead of print]

Mutant p53 Exploits Enhancers to Elevate Immunosuppressive Chemokine Expression and Impair Immune Checkpoint Inhibitors in Pancreatic Cancer.

Dig B Mahat, Heena Kumra, Sarah A Castro, Emily Metcalf, Kim Nguyen, Ryo Morisue, William W Ho, Ivy Chen, Brandon Sullivan, Leon K Yim, Arundeep Singh, Jiayu Fu, Sean K Waterton, Yu-Chi Cheng, Sylvie Roberge, Enrico Moiso, Vikash P Chauhan, Hernandez Moura Silva, Stefani Spranger, Rakesh K Jain, Phillip A Sharp.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations dysregulate cancer-cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we show that p53 R172H establishes an immunosuppressive TME, diminishes the efficacy of immune checkpoint inhibitors (ICIs), and enhances tumor growth. Our findings reveal that the upregulation of the immunosuppressive chemokine Cxcl1 mediates these pro-tumorigenic functions of p53 R172H . Mechanistically, we show that p53 R172H associates with the distal enhancers of the Cxcl1 gene, increasing enhancer activity and Cxcl1 expression. p53 R172H occupies these enhancers in an NF-κB-pathway-dependent manner, suggesting NF-κB's role in recruiting p53 R172H to the Cxcl1 enhancers. Our work uncovers how a common mutation in a tumor-suppressor transcription factor appropriates enhancers, stimulating chemokine expression and establishing an immunosuppressive TME that diminishes ICI efficacy in PDAC.

DOI: https://doi.org/10.1101/2024.08.28.609802
Int Immunopharmacol. 2024 Sep 09. pii: S1567-5769(24)01632-1. [Epub ahead of print]142(Pt A): 113111

SMS2 siRNA inhibits pancreatic tumor growth by tumor microenvironment modulation.

Xin Jiang, Ziqing Yuan, Tingbo Ding, Ker Yu, Jibin Dong.

  The massive infiltration of suppressor immune cells within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is a major cause of treatment resistance. Reducing this infiltration may represent a potentially effective therapeutic strategy. Sphingomyelin synthase 2 (SMS2) is a crucial enzyme for sphingomyelin synthesis, contributing significantly to the integrity and function of the plasma membrane. In this study, we developed a self-assembling SMS2 siRNA gene expression plasmid for in vivo delivery. The SMS2 siRNA specifically inhibits SMS2 expression while preserving the expression and activity of SMS1. Administration of the self-assembling SMS2 siRNA suppresses tumor growth in a murine model of Panc02 pancreatic carcinoma, modulates the polarization of tumor-associated macrophages (TAMs), and reduces the infiltration of tumor-associated neutrophils (TANs) by regulating the NF-κB/CXCL5 pathway. Consequently, utilizing SMS2 siRNA to improve the local immunosuppressive microenvironment holds promise for pancreatic cancer therapy.

Keywords:  CXCL5; Pancreatic cancer; SMS2; SiRNA; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2024.113111
Biomed Pharmacother. 2024 Sep 09. pii: S0753-3322(24)01291-5. [Epub ahead of print]179 117406

Emerging role of tumor microenvironmental nutrients and metabolic molecules in ferroptosis: Mechanisms and clinical implications.

Dongyu Li, Zhe Zhang, Lei Wang.

  In recent years, ferroptosis has gradually attracted increasing attention because of its important role in tumors. Ferroptosis resistance is an important cause of tumor metastasis, recurrence and drug resistance. Exploring the initiating factors and specific mechanisms of ferroptosis has become a key strategy to block tumor progression and improve drug sensitivity. As the external space in direct contact with tumor cells, the tumor microenvironment has a great impact on the biological function of tumor cells. The relationships between abnormal environmental characteristics (hypoxia, lactic acid accumulation, etc.) in the microenvironment and ferroptosis of tumor cells has not been fully characterized. This review focuses on the characteristics of the tumor microenvironment and summarizes the mechanisms of ferroptosis under different environmental factors, aiming to provide new insights for subsequent targeted therapy. Moreover, considering the presence of anticancer drugs in the microenvironment, we further summarize the mechanisms of ferroptosis to provide new strategies for the sensitization of tumor cells to drugs.

Keywords:  Drug resistance; Ferroptosis; Hypoxia; Lactate; TME

DOI:  https://doi.org/10.1016/j.biopha.2024.117406
Clin Transl Oncol. 2024 Sep 13.

Focal adhesion kinase-mediated interaction between tumor and immune cells in the tumor microenvironment: implications for cancer-associated therapies and tumor progression.

Louis Boafo Kwantwi, Theophilus Tandoh.

  Focal adhesion kinase (FAK) expression has been linked to tumor growth, immunosuppression, metastasis, angiogenesis, and therapeutic resistance through kinase-dependent and kinase scaffolding functions in the nucleus and cytoplasm. Hence, targeting FAK alone or with other agents has gained attention as a potential therapeutic strategy. Moreover, mounting evidence shows that FAK activity can influence the tumor immune microenvironment crosstalk to support tumor progression. Recently, tumor immune microenvironment interaction orchestrators have shown to be promising therapeutic agents for cancer immunotherapies. Therefore, this review highlights how FAK regulates the tumor immune microenvironment interplay to promote tumor immune evasive mechanisms and their potential for combination therapies with standard cancer treatments.

Keywords:  Cancer treatments; FAK; Focal adhesion kinase; Immune cells; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12094-024-03723-x
Neurosurg Rev. 2024 Sep 07. 47(1): 571

A call for clinical trials in glioblastoma multiforme for interleukin 4, interleukin 6, interleukin 13 and CD40.

Serhat Aydin, Kwadwo Darko, Donald Detchou, Umaru Barrie.

  Glioblastoma multiforme (GBM) is one of the most aggressive and deadly forms of brain cancer, which has a very complex tumor microenvironment (TME) promoting tumor growth, immune evasion, and resistance to therapy. The main players within this environment are represented by cytokines such as Interleukin-4, Interleukin-6, and Interleukin-13, along with the costimulatory molecule CD40. The paper draws back the curtain on the complex interactions played out by these molecules in contributing to the formation of a TME within GBM. IL-4 and IL-13 induce an immunosuppressive environment through the polarization of tumor-associated macrophages (TAMs) into a pro-tumoral M2 phenotype. In contrast, IL-6 takes part in the activation of the JAK-STAT3 pathway, enhancing survival and proliferation of tumor cells. In this context, CD40 either induces anti-tumor immunity through APC activation or facilitates tumors by angiogenesis and survival pathways. The synergistic actions of these molecules create feedback loops that keep up the malignancy of GBM and present a big problem for therapy. Knowledge of these interactions opens new ways for the development of multi-targeted therapeutic strategies at the other end. This may result in the interruption of the tumor-supportive environment in GBM, reducing tumor growth and improving patient outcomes by targeting IL-4, IL-6, IL-13, and CD40 simultaneously.

Keywords:  CD40; Glioblastoma; Interleukin 13; Interleukin 4; Interleukin 6

DOI:  https://doi.org/10.1007/s10143-024-02823-0
Heliyon. 2024 Aug 30. 10(16): e36446

Improving the efficacy of immunotherapy for colorectal cancer: Targeting tumor microenvironment-associated immunosuppressive cells.

Daoyang Zou, Xi Xin, Yunxian Xu, Huangzhen Xu, Linyan Huang, Tianwen Xu.

Currently, immune checkpoint inhibitors (ICIs) have changed the treatment paradigm for many malignant tumors. As the most common digestive tract malignancy, colorectal cancer (CRC) shows a good response to ICIs only in a small subset of patients with MSI-H/dMMR CRC. In contrast, patients with MSS/pMMR CRC show minimal response to ICIs. The results of the REGONIVO study suggest that targeting the tumor microenvironment (TME) to improve immunotherapy outcomes in MSS/pMMR CRC patients is a feasible strategy. Therefore, this article focuses on exploring the feasibility of targeting the TME to enhance immunotherapy outcomes in CRC, collecting recent basic research on targeting the TME to enhance immunotherapy outcomes in CRC and analyzing ongoing clinical trials to provide a theoretical basis and future research directions for improving immunotherapy outcomes in MSS/pMMR CRC.

DOI: https://doi.org/10.1016/j.heliyon.2024.e36446
Adv Mater. 2024 Sep 10. e2410340

Engineered Nanoparticles for Enhanced Antitumoral Synergy Between Macrophages and T Cells in the Tumor Microenvironment.

Sangjun Moon, Mungyo Jung, Seokhyeong Go, Jihye Hong, Hee Su Sohn, Cheesue Kim, Mikyung Kang, Byung Joon Lee, Jungwoo Kim, Jinwoong Lim, Byung-Soo Kim.

  T cells and macrophages have the potential to collaborate to eliminate tumor cells efficiently. Macrophages can eliminate tumor cells through phagocytosis and subsequently activate T cells by presenting tumor antigens. The activated T cells, in turn, can kill tumor cells and redirect tumor-associated macrophages toward an antitumoral M1 phenotype. However, checkpoint molecules expressed on tumor cells impede the collaborative action of these immune cells. Meanwhile, monotherapy with a single immune checkpoint inhibitor (ICI) for either macrophages or T cells yields suboptimal efficacy in cancer patients. To address this challenge, here a nanoparticle capable of efficiently delivering dual ICIs to tumors for both macrophages and T cells is developed. These programmed cell death protein 1 (PD-1)-transfected macrophage membrane-derived nanoparticles (PMMNPs) can target tumors and provide signal-regulatory protein alpha and PD-1 to block CD47 and programmed cell death-ligand 1 (PD-L1), respectively, on tumor cells. PMMNPs enhance macrophage-mediated cancer cell phagocytosis and antigen presentation, promote T cell activation, and induce the reprogramming of macrophages toward an antitumoral phenotype. In syngeneic tumor-bearing mice, PMMNPs demonstrate superior therapeutic efficacy compared to nanoparticles delivering single ICIs and non-targeted delivery of anti-CD47 and anti-PD-L1 antibodies. PMMNPs capable of augmenting the antitumoral interplay between macrophages and T cells may offer a promising avenue for cancer immunotherapy.

Keywords:  T cells; immune checkpoint inhibitors; immunotherapy; macrophages; nanoparticles; signal‐regulatory protein alpha; tumor

DOI:  https://doi.org/10.1002/adma.202410340
Cancer Cell. 2024 Sep 09. pii: S1535-6108(24)00310-6. [Epub ahead of print]42(9): 1480-1485

Classifying cancer-associated fibroblasts-The good, the bad, and the target.

Lena Cords, Natalie de Souza, Bernd Bodenmiller.

Cancer-associated fibroblasts (CAFs) are heterogeneous and ubiquitous stromal cells within the tumor microenvironment (TME). Numerous CAF types have been described, typically using single-cell technologies such as single-cell RNA sequencing. There is no general classification system for CAFs, hampering their study and therapeutic targeting. We propose a simple CAF classification system based on single-cell phenotypes and spatial locations of CAFs in multiple cancer types, assess how our scheme fits within current knowledge, and invite the CAF research community to further refine it.

DOI: https://doi.org/10.1016/j.ccell.2024.08.011
bioRxiv. 2024 Aug 30. pii: 2024.08.29.610392. [Epub ahead of print]

Spatiotemporal dynamics of tumor - CAR T-cell interaction following local administration in solid cancers.

Katherine Owens, Aminur Rahman, Ivana Bozic.

The success of chimeric antigen receptor (CAR) T-cell therapy in treating hematologic malignancies has generated widespread interest in translating this technology to solid cancers. However, issues like tumor infiltration, the immunosuppressive tumor microenvironment, and tumor heterogeneity limit its efficacy in the solid tumor setting. Recent experimental and clinical studies propose local administration directly into the tumor or at the tumor site to increase CAR T-cell infiltration and improve treatment outcomes. Characteristics of the types of solid tumors that may be the most receptive to this treatment approach remain unclear. In this work, we develop a spatiotemporal model for CAR T-cell treatment of solid tumors, and use numerical simulations to compare the effect of introducing CAR T cells via intratumoral injection versus intracavitary administration in diverse cancer types. We demonstrate that the model can recapitulate tumor and CAR T-cell data from imaging studies of local administration of CAR T cells in mouse models. Our results suggest that locally administered CAR T cells will be most successful against slowly proliferating, highly diffusive tumors, which have the lowest average tumor cell density. These findings affirm the clinical observation that CAR T cells will not perform equally across different types of solid tumors, and suggest that measuring tumor density may be helpful when considering the feasibility of CAR T-cell therapy and planning dosages for a particular patient. We additionally find that local delivery of CAR T cells can result in deep tumor responses, provided that the initial CAR T-cell dose does not contain a significant fraction of exhausted cells.

DOI: https://doi.org/10.1101/2024.08.29.610392
Int J Biol Macromol. 2024 Sep 11. pii: S0141-8130(24)06349-9. [Epub ahead of print] 135541

Old concepts, new tricks: How peptide vaccines are reshaping cancer immunotherapy?

Qingyang Liu, Peihua Wu, Jun Lei, Peng Bai, Peiluan Zhong, Min Yang, Pengcheng Wei.

  Over the past few decades, research on cancer immunotherapy has firmly established immune cells as key players in effective cancer treatment. Peptide vaccines directly targeting immune cells have demonstrated immense potential due to their specificity and applicability. However, developing peptide vaccines to generate tumor-reactive T cells remains challenging, primarily due to suboptimal immunogenicity and overcoming the immunosuppressive tumor microenvironment (TME). In this review, we discuss various elements of effective peptide vaccines, including antigen selection, peptide epitope optimization, vaccine adjuvants, and the combination of multiple immunotherapies, in addition to recent advances in tumor neoantigens as well as epitopes bound by non-classical human leukocyte antigen (HLA) molecules, to increase the understanding of cancer peptide vaccines and provide multiple references for the design of subsequent T cell-based peptide vaccines.

Keywords:  Cancer; Immunotherapy; Peptide vaccines

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.135541
Mol Cancer. 2024 Sep 06. 23(1): 188

NAC1 promotes stemness and regulates myeloid-derived cell status in triple-negative breast cancer.

Chrispus Ngule, Ruyi Shi, Xingcong Ren, Hongyan Jia, Felix Oyelami, Dong Li, Younhee Park, Jinhwan Kim, Hami Hemati, Yi Zhang, Xiaofang Xiong, Andrew Shinkle, Nathan L Vanderford, Sara Bachert, Binhua P Zhou, Jianlong Wang, Jianxun Song, Xia Liu, Jin-Ming Yang.

  Triple negative breast cancer (TNBC) is a particularly lethal breast cancer (BC) subtype driven by cancer stem cells (CSCs) and an immunosuppressive microenvironment. Our study reveals that nucleus accumbens associated protein 1 (NAC1), a member of the BTB/POZ gene family, plays a crucial role in TNBC by maintaining tumor stemness and influencing myeloid-derived suppressor cells (MDSCs). High NAC1 expression correlates with worse TNBC prognosis. NAC1 knockdown reduced CSC markers and tumor cell proliferation, migration, and invasion. Additionally, NAC1 affects oncogenic pathways such as the CD44-JAK1-STAT3 axis and immunosuppressive signals (TGFβ, IL-6). Intriguingly, the impact of NAC1 on tumor growth varies with the host immune status, showing diminished tumorigenicity in natural killer (NK) cell-competent mice but increased tumorigenicity in NK cell-deficient ones. This highlights the important role of the host immune system in TNBC progression. In addition, high NAC1 level in MDSCs also supports TNBC stemness. Together, this study implies NAC1 as a promising therapeutic target able to simultaneously eradicate CSCs and mitigate immune evasion.

Keywords:  Cancer stem cells; MDSCs; NAC1; NK cells; TME; TNBC

DOI:  https://doi.org/10.1186/s12943-024-02102-y
iScience. 2024 Sep 20. 27(9): 110710

The mitochondrial stress signaling tunes immunity from a view of systemic tumor microenvironment and ecosystem.

Cheng-Liang Kuo, Ying-Chen Lin, Yu Kang Lo, Yu-Zhi Lu, Ananth Ponneri Babuharisankar, Hui-Wen Lien, Han-Yu Chou, Alan Yueh-Luen Lee.

  Mitochondria play important roles in cell fate, calcium signaling, mitophagy, and the signaling through reactive oxygen species (ROS). Recently, mitochondria are considered as a signaling organelle in the cell and communicate with other organelles to constitute the mitochondrial information processing system (MIPS) that transduce input-to-output biological information. The success in immunotherapy, a concept of systemic therapy, has been proved to be dependent on paracrine interactions within the tumor microenvironment (TME) and distant organs including microbiota and immune components. We will adopt a broader view from the concept of TME to tumor micro- and macroenvironment (TM 2 E) or tumor-organ ecosystem (TOE). In this review, we will discuss the role of mitochondrial signaling by mitochondrial ROS, calcium flux, metabolites, mtDNA, vesicle transportation, and mitochondria-derived peptide in the TME and TOE, in particular immune regulation and effective cancer immunotherapy.

Keywords:  Cancer; Immune response; Microenvironment

DOI:  https://doi.org/10.1016/j.isci.2024.110710
J Pharm Anal. 2024 Aug;14(8): 100942

Melatonin enhances the efficacy of anti-PD-L1 by improving hypoxia in residual tumors after insufficient radiofrequency ablation.

Yanqiao Ren, Licheng Zhu, Yusheng Guo, Jinqiang Ma, Lian Yang, Chuansheng Zheng, Xiangjun Dong.

  The hypoxic microenvironment and inflammatory state of residual tumors caused by insufficient radiofrequency ablation (iRFA) are major reasons for rapid tumor progression and pose challenges for immunotherapy. We retrospectively analyzed the clinical data of patients with hepatocellular carcinoma (HCC) treated with RFA and observed that iRFA was associated with poor survival outcomes and progression-free survival. Using an orthotopic HCC mouse model and a colorectal liver metastasis model, we observed that treatment with melatonin after iRFA reduced tumor growth and metastasis and achieved the best outcomes when combined with anti-programmed death-ligand 1 (anti-PD-L1) therapy. In mechanism, melatonin inhibited the expression of epithelial-mesenchymal transitions, hypoxia-inducible factor (HIF)-1α, and PD-L1 in tumor cells after iRFA. Flow cytometry revealed that melatonin reduced the proportion of myeloid-derived suppressor cells and increased the proportion of CD8+ T cells. Transcriptomic analysis revealed an upregulation of immune-activated function-related genes in residual tumors. These findings demonstrated that melatonin can reverse hypoxia and iRFA-induced inflammation, thereby overcoming the immunosuppressive tumor microenvironment (TME) and enhancing the efficacy of immunotherapy.

Keywords:  Hypoxia; Immunotherapy; Insufficient radiofrequency ablation; Melatonin

DOI:  https://doi.org/10.1016/j.jpha.2024.01.010
Cancer Lett. 2024 Sep 10. pii: S0304-3835(24)00639-6. [Epub ahead of print]604 217244

The role of Hippo/YAP1 in cancer-associated fibroblasts: Literature review and future perspectives.

Dipti Athavale, Curt Balch, Yanting Zhang, Xiaodan Yao, Shumei Song.

  Cancer-associated fibroblasts (CAFs) are activated fibroblasts that play a role in numerous malignant phenotypes, including hyperproliferation, invasion, and metastasis. These phenotypes correlate with activity of the Hippo pathway oncoprotein, Yes-associated protein-1 (YAP1), and its paralog, transcriptional coactivator with PDZ-binding motif (TAZ). YAP1/TAZ are normally involved in organ growth, under the regulation of various kinases and upon phosphorylation, are retained in the cytoplasm by chaperone proteins, leading to their proteasomal degradation. In CAFs and tumor cells, however, a lack of YAP1 phosphorylation results in its translocation to the nucleus, binding to TEAD transcription factors, and activation of mitogenic pathways. In this review we summarize the literature discussing the central role of YAP1 in CAF activation, the upstream cues that promote YAP1-mediated CAF activation and extracellular matrix remodeling, and how CAFs mediate tumor-stroma crosstalk to support progression, invasion and metastasis in various cancer models. We further highlight YAP1+CAFs functions in modulating an immunosuppressive tumor microenvironment and propose evaluation of several YAP1 targets regarding their role in regulating intra-tumoral immune landscapes. Finally, we propose that co-administration of YAP1- targeted therapies with immune checkpoint inhibitors can improve therapeutic outcomes in patients with advanced tumors.

Keywords:  Cancer-associated fibroblast; Hippo pathway; Immunosuppressive tumor microenvironment; TAZ; YAP1

DOI:  https://doi.org/10.1016/j.canlet.2024.217244
Discov Oncol. 2024 Sep 11. 15(1): 431

Deciphering the impact of aggregated autophagy-related genes TUBA1B and HSP90AA1 on colorectal cancer evolution: a single-cell sequencing study of the tumor microenvironment.

Qianping Xu, Chao Liu, Hailin Wang, Shujuan Li, Hanshen Yan, Ziyang Liu, Kexin Chen, Yaoqin Xu, Runqin Yang, Jingfang Zhou, Xiaolin Yang, Jie Liu, Lexin Wang.

   BACKGROUND: Colorectal cancer (CRC) is the third most prevalent cancer worldwide, with the tumor microenvironment (TME) playing a crucial role in its progression. Aggregated autophagy (AA) has been recognized as a factor that exacerbates CRC progression. This study aims to study the relationship between aggregated autophagy and CRC using single-cell sequencing techniques. Our goal is to explain the heterogeneity of the TME and to explore the potential for targeted personalized therapies.
OBJECTIVE: To study the role of AA in CRC, we employed single-cell sequencing to discern distinct subpopulations within the TME. These subpopulations were characterized by their autophagy levels and further analyzed to identify specific biological processes and marker genes.
RESULTS: Our study revealed significant correlations between immune factors and both clinical and biological characteristics of the tumor microenvironment (TME), particularly in cells expressing TUBA1B and HSP90AA1. These immune factors were associated with T cell depletion, a reduction in protective factors, diminished efficacy of immune checkpoint blockade (ICB), and enhanced migration of cancer-associated fibroblasts (CAFs), resulting in pronounced inflammation. In vitro experiments showd that silencing TUBA1B and HSP90AA1 using siRNA (Si-TUBA1B and Si-HSP90AA1) significantly reduced the expression of IL-6, IL-7, CXCL1, and CXCL2 and inhibition of tumor cell growth in Caco-2 and Colo-205 cell lines. This reduction led to a substantial alleviation of chronic inflammation and highlighted the heterogeneous nature of the TME.
CONCLUSION: This study marks an initial foray into understanding how AA-associated processes may potentiate the TME and weaken immune function. Our findings provide insights into the complex dynamics of the TME and highlight potential targets for therapeutic intervention, suggesting a key role for AA in the advancement of colorectal cancer.

Keywords:  Aggregated Autophagy (AA); Cancer-associated fibroblast (CAF); Colorectal cancer (CRC); Single-cell; TUBA1B and HSP90AA1; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1007/s12672-024-01322-4
Int Immunopharmacol. 2024 Sep 07. pii: S1567-5769(24)01610-2. [Epub ahead of print]142(Pt A): 113089

Interleukin-10 overexpression in 4T1 cells: A gateway to suppressing mammary carcinoma growth.

Xiaoqin Wang, Xiaoqian Wang, Dan Wang, Can Zhou, Kaige Lv, Yanfen Ma, Wenjing Chang, Baofeng Wang, Jian Hu, Yanhong Ji, Zhijun Dai, Yunfeng Ma.

  Interleukin-10 (IL-10) exerts complex effects on tumor growth, exhibiting both pro- and anti-tumor properties. Recent focus on the anti-inflammatory properties of IL-10 has highlighted its potential anti-tumor properties, particularly through the enhancement of CD8+ T cell activity. However, further research is needed to fully elucidate its other anti-tumor mechanisms. Our study investigates novel anti-tumor mechanisms of IL-10 in a murine mammary carcinoma model (4T1). We found that IL-10 overexpression in mouse 4T1 cells suppressed tumor growth in vivo. This suppression was accompanied by an increase in IFN-γ-secreting CD8+ T cells and a decrease in myeloid-derived suppressor cells (MDSCs) in tumor tissue. In vitro experiments showed that IL-10-rich tumor cell-derived supernatants inhibited myeloid cell differentiation into monocytic and granulocytic MDSCs while reducing MDSCs migration. In addition, IL-10 overexpression downregulated CXCL5 expression in 4T1 cells, resulting in decreased CXCR2+ MDSCs infiltration. Using RAG1-deficient mice and CXCL5 knockdown tumor models, we demonstrated that the anti-tumor effects of IL-10 depend on both CD8+ T cells and reduced MDSC infiltration. IL-10 attenuated the immunosuppressive tumor microenvironment by enhancing CD8+ T cell activity and inhibiting MDSCs infiltration. In human breast cancer, we observed a positive correlation between CXCL5 expression and MDSC infiltration. Our findings reveal a dual mechanism of IL-10-mediated tumor suppression: (1) direct enhancement of CD8+ T cell activity and (2) indirect reduction of immunosuppressive MDSCs through CXCL5 downregulation and inhibition of myeloid cell differentiation. This study provides new insights into the role of IL-10 in anti-tumor immunity and suggests potential strategies for breast cancer immunotherapy by modulating the IL-10-CXCL5-MDSCs axis.

Keywords:  CXCL5; IL-10; Immunotherapy; MDSCs; Mammary Carcinoma

DOI:  https://doi.org/10.1016/j.intimp.2024.113089
Int J Biol Sci. 2024 ;20(11): 4341-4363

Exosomal SLC16A1-AS1-induced M2 macrophages polarization facilitates hepatocellular carcinoma progression.

Yuhang Hu, Yang Li, Hewei Xiong, Ya Zhang, Fan Wang, Wenfeng Zhuo, Zhu Zeng, Yong Zhao, Hongda Wang, Ping Hu, Shengbo Han, Yan Huang, Guozheng Lv, Gang Zhao.

  Macrophages are the most abundant alternative immune cells in the tumor microenvironment (TME). The cross-talk between macrophages and tumor cells provides an important shelter for the occurrence and development of tumors. As an important information transfer medium, exosomes play an important role in intercellular communication. Nonetheless, how exosomal lncRNAs coordinate the communication between tumor cells and immune cells in hepatocellular carcinoma (HCC) is incompletely understood. We found that HCC exosomes-derived antisense RNA of SLC16A1(SLC16A1-AS1) promoted the malignant progression of HCC by regulating macrophage M2-type polarization. Mechanistically, the HCC exosomal SLC16A1-AS1 enhanced mRNA stabilization of SLC16A1 in macrophage by promoting the interaction between 3' untranslated regions (3'UTR) of SLC16A1 mRNA and heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1). As a lactate transporter, SLC16A1 accelerated lactate influx and then activated c-Raf/ERK signaling to induce M2 polarization of macrophages. Reciprocally, M2 macrophages secreted IL-6 to activate STAT3 and then induce METTL3 transcription in HCC cells, which increasing m6A methylation and stabilization of SLC16A1-AS1. In turn, the reciprocal SLC16A1-AS1/IL-6 signaling between HCC cells and M2 macrophages promoted the proliferation, invasion and glycolysis of HCC cells. Our study highlights that exosomal SLC16A1-AS1 acts as a signaling message that induces lactate-mediated M2 polarization of macrophages, and implies that SLC16A1-AS1 might be an applicable target for therapeutic treatment of HCC.

Keywords:  M2 polarization; SLC16A1-AS1; exosomes; m6A; macrophages

DOI:  https://doi.org/10.7150/ijbs.94440
Cancer Immunol Res. 2024 Sep 13. OF1-OF9

The Dark Knight: Functional Reprogramming of Neutrophils in the Pathogenesis of Colitis-Associated Cancer.

Sreya Ghosh, Ivan Zanoni.

Neutrophils are the primary myeloid cells that are recruited to inflamed tissues, and they are key players during colitis, being also present within the tumor microenvironment during the initiation and growth of colon cancer. Neutrophils fundamentally serve to protect the host against microorganism invasion, but during cancer development, they can become protumoral and lead to tumor initiation, growth, and eventually, metastasis-hence, playing a dichotomic role for the host. Protumoral neutrophils in cancer patients can be immunosuppressive and serve as markers for disease progression but their characteristics are not fully defined. In this review, we explore the current knowledge on how neutrophils in the gut fluctuate between an inflammatory or immunosuppressive state and how they contribute to tumor development. We describe neutrophils' antitumoral and protumoral effects during inflammatory bowel diseases and highlight their capacity to provoke the advent of inflammation-driven colorectal cancer. We present the functional ambivalence of the neutrophil populations within the colon tumor microenvironment, which can be potentially exploited to establish therapies that will prevent, or even reverse, inflammation-dependent colon cancer incidence in high-risk patients.

DOI: https://doi.org/10.1158/2326-6066.CIR-23-0642
J Colloid Interface Sci. 2024 Sep 04. pii: S0021-9797(24)02074-5. [Epub ahead of print]678(Pt B): 750-762

A nanodrug provokes antitumor immune responses via synchronous multicellular regulation for enhanced cancer immunotherapy.

Keze Hong, Jianrong Cao, Weiting Jiang, Wei Deng, Guohong Huang, Tao Huang, Jin Fang, Yong Wang.

  Hepatocellular carcinoma (HCC) exhibits a low response to immunotherapy due to the dense extracellular matrix (ECM) filled with immunosuppressive cells including dendritic cells (DCs) of blocked maturation. Herein, we develop a nanoprodrug self-assembled from polyethylene glycol-poly-4-borono-l-phenylalanine (mPEG-PBPA) conjugating with quercetin (QUE) via boronic ester bonds. In addition, an immune adjuvant of imiquimod (R837) is incorporated. The nanodrug (denoted as Q&R@NPs) is prepared from a simple mixing means with a high loading content of QUE reaching more than 30%. Owing to the acid and reactive oxygen species (ROS) sensitivities of boronic ester bonds, Q&R@NPs can respond to the tumor microenvironment (TME) and release QUE and R837 to synchronously exert multicellular regulation functions. Specifically, QUE inhibits the activation state of hepatic stellate cells and reduces highly expressed programmed death receptor ligand 1 (PD-L1) on tumor cells, meanwhile R837 exposes calreticulin on tumor cell surface as an "eat me" signal and leads to a large number of DCs maturing for enhanced antigen presentation. Consequently, the cooperative immune regulation results in a remodeled TME with high infiltration of cytotoxic T lymphocytes for enhanced HCC immunotherapy, which demonstrates an effective immunotherapy paradigm for dense ECM characterized solid tumors with high PD-L1 expression.

Keywords:  Dendritic cell maturation; Hepatic stellate cell inactivation; Hepatocellular carcinoma; Nanodrug; Tumor immunotherapy

DOI:  https://doi.org/10.1016/j.jcis.2024.09.016
Cells. 2024 Aug 27. pii: 1439. [Epub ahead of print]13(17):

Microcystin-LR Regulates Interaction between Tumor Cells and Macrophages via the IRE1α/XBP1 Signaling Pathway to Promote the Progression of Colorectal Cancer.

Xiaochang Wang, Yuechi Song, Xiaohui Lu, Hengshuo Zhang, Ting Wang.

  Microcystin-LR (MC-LR), a cyanobacterial toxin, is a potent carcinogen implicated in colorectal cancer (CRC) progression. However, its impact on the tumor microenvironment (TME) during CRC development remains poorly understood. This study investigates the interaction between tumor cells and macrophages mediated by MC-LR within the TME and its influence on CRC progression. CRC mice exposed to MC-LR demonstrated a significant transformation from adenoma to adenocarcinoma. The infiltration of macrophages increased, and the IRE1α/XBP1 pathway was activated in CRC cells after MC-LR exposure, influencing macrophage M2 polarization under co-culture conditions. Additionally, hexokinase 2 (HK2), a downstream target of the IRE1α/XBP1 pathway, was identified, regulating glycolysis and lactate production. The MC-LR-induced IRE1α/XBP1/HK2 axis enhanced lactate production in CRC cells, promoting M2 macrophage polarization. Furthermore, co-culturing MC-LR-exposed CRC cells with macrophages, along with the IRE1α/XBP1 pathway inhibitor 4μ8C and the hexokinase inhibitor 2-DG, suppressed M2 macrophage-induced CRC cell migration, clonogenicity, and M2 macrophage polarization. This study elucidates the mechanism by which MC-LR-mediated interactions through the IRE1α/XBP1 pathway promote CRC progression, highlighting potential therapeutic targets.

Keywords:  IRE1α/XBP1 signaling pathway; colorectal cancer; macrophage; microcystin-LR; tumor microenvironment

DOI:  https://doi.org/10.3390/cells13171439
J Cancer Res Clin Oncol. 2024 Sep 12. 150(9): 419

Circadian rhythms and breast cancer: from molecular level to therapeutic advancements.

Dou-Dou Li, Teng Zhou, Jing Gao, Guan-Lin Wu, Guang-Rui Yang.

   BACKGROUND AND OBJECTIVES: Circadian rhythms, the endogenous biological clocks that govern physiological processes, have emerged as pivotal regulators in the development and progression of breast cancer. This comprehensive review delves into the intricate interplay between circadian disruption and breast tumorigenesis from multifaceted perspectives, encompassing biological rhythms, circadian gene regulation, tumor microenvironment dynamics, and genetic polymorphisms.
METHODS AND RESULTS: Epidemiological evidence underscores the profound impact of external factors, such as night shift work, jet lag, dietary patterns, and exercise routines, on breast cancer risk and progression through the perturbation of circadian homeostasis. The review elucidates the distinct roles of key circadian genes, including CLOCK, BMAL1, PER, and CRY, in breast cancer biology, highlighting their therapeutic potential as molecular targets. Additionally, it investigates how circadian rhythm dysregulation shapes the tumor microenvironment, fostering epithelial-mesenchymal transition, chronic inflammation, and immunosuppression, thereby promoting tumor progression and metastasis. Furthermore, the review sheds light on the association between circadian gene polymorphisms and breast cancer susceptibility, paving the way for personalized risk assessment and tailored treatment strategies.
CONCLUSIONS: Importantly, it explores innovative therapeutic modalities that harness circadian rhythms, including chronotherapy, melatonin administration, and traditional Chinese medicine interventions. Overall, this comprehensive review emphasizes the critical role of circadian rhythms in the pathogenesis of breast cancer and highlights the promising prospects for the development of circadian rhythm-based interventions to enhance treatment efficacy and improve patient outcomes.

Keywords:  Breast cancer; Chronotherapy; Circadian gene regulation; Circadian rhythms; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00432-024-05917-w
Int J Biochem Cell Biol. 2024 Sep 12. pii: S1357-2725(24)00153-5. [Epub ahead of print]176 106661

Unveiling the role of taurine and SLC6A6 in tumor immune evasion: Implications for gastric cancer therapy.

Jianqiao Shentu, Xinming Su, Yueqi Yu, Shiwei Duan.

  Metabolic changes are key drivers of tumor progression. Understanding how metabolic reprogramming promotes tumor development and identifying key metabolic activities are essential for improving tumor diagnosis and treatment. Among the numerous transporters in the body, solute carriers (SLCs) are particularly significant, often overexpressed in cancer cells to meet the tumor's demand for nutrients and energy. While the role of SLCs in nutrient absorption within the gastrointestinal tract is well-established, their specific role in gastric cancer (GC) remains unclear. Recently, Xiaodi Zhao's team investigated the critical role of taurine and its transporter, SLC6A6, in anti-tumor immunity and clinical outcomes. Notably, this research marks the first instance of taurine exhibiting a dual role. It promotes tumor growth in immunodeficient mice while inhibiting it in immunocompetent mice. The study found that taurine exerts its anti-cancer effects by modulating CD8+ T cells rather than directly inhibiting tumor cells, revealing the SP1-SLC6A6 axis as a key mechanism behind chemotherapy-induced immune evasion. Our work further explored the potential, advantages, and challenges of using taurine and SLC6A6 as biomarkers and therapeutic targets in gastric cancer. We aim to underscore their importance in both basic research and clinical applications, providing valuable insights and guidance for future investigations.

Keywords:  CD8(+) T cell; Cancer therapy; Gastric cancer; SLC6A6; Taurine; Tumor immune evasion

DOI:  https://doi.org/10.1016/j.biocel.2024.106661
Nanoscale. 2024 Sep 11.

Immunomodulatory nanoparticles activate cytotoxic T cells for enhancement of the effect of cancer immunotherapy.

Kory Wells, Tongrui Liu, Lei Zhu, Lily Yang.

Cancer immunotherapy represents a promising targeted treatment by leveraging the patient's immune system or adoptive transfer of active immune cells to selectively eliminate cancer cells. Despite notable clinical successes, conventional immunotherapies face significant challenges stemming from the poor infiltration of endogenous or adoptively transferred cytotoxic T cells in tumors, immunosuppressive tumor microenvironment and the immune evasion capability of cancer cells, leading to limited efficacy in many types of solid tumors. Overcoming these hurdles is essential to broaden the applicability of immunotherapies. Recent advances in nanotherapeutics have emerged as an innovative tool to overcome these challenges and enhance the therapeutic potential of tumor immunotherapy. The unique biochemical and biophysical properties of nanomaterials offer advantages in activation of immune cells in vitro for cell therapy, targeted delivery, and controlled release of immunomodulatory agents in vivo. Nanoparticles are excellent carriers for tumor associated antigens or neoantigen peptides for tumor vaccine, empowering activation of tumor specific T cell responses. By precisely delivering immunomodulatory agents to the tumor site, immunoactivating nanoparticles can promote tumor infiltration of endogenous T cells or adoptively transferred T cells into tumors, to overcoming delivery and biological barriers in the tumor microenvironment, augmenting the immune system's ability to recognize and eliminate cancer cells. This review provides an overview of the current advances in immunotherapeutic approaches utilizing nanotechnology. With a focus on discussions concerning strategies to enhance activity and efficacy of cytotoxic T cells and explore the intersection of engineering nanoparticles and immunomodulation aimed at bolstering T cell-mediated immune responses, we introduce various nanoparticle formulations designed to deliver therapeutic payloads, tumor antigens and immunomodulatory agents for T cell activation. Diverse mechanisms through which nanoparticle-based approaches influence T cell responses by improving antigen presentation, promoting immune cell trafficking, and reprogramming immunosuppressive tumor microenvironments to potentiate anti-tumor immunity are examined. Additionally, the synergistic potential of combining nanotherapeutics with existing immunotherapies, such as immune checkpoint inhibitors and adoptive T cell therapies is explored. In conclusion, this review highlights emerging research advances on activation of cytotoxic T cells using nanoparticle agents to support the promises and potential applications of nanoparticle-based immunomodulatory agents for cancer immunotherapy.

DOI: https://doi.org/10.1039/d4nr01780c