bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024‒02‒04
27 papers selected by
Peio Azcoaga, Biodonostia HRI

  1. Adv Healthc Mater. 2024 Jan 30. e2303294
      Cancer immunotherapy, a field within immunology that aims to enhance the host's anti-cancer immune response, frequently encounters challenges associated with suboptimal response rates. The presence of myeloid-derived suppressor cells (MDSCs), crucial constituents of the tumor microenvironment (TME), exacerbates this issue by fostering immunosuppression and impeding T cell differentiation and maturation. Consequently, targeting MDSCs has emerged as crucial for immunotherapy aimed at enhancing anti-tumor responses. The development of nanomedicines specifically designed to target MDSCs aims to improve the effectiveness of immunotherapy by transforming immunosuppressive tumors into ones more responsive to immune intervention. This review provides a detailed overview of MDSCs in the TME and current strategies targeting these cells. We also highlight the benefits of nanoparticle-assisted drug delivery systems, including design flexibility, efficient drug loading, and protection against enzymatic degradation. It summarizes advances in nanomedicine targeting MDSCs, covering enhanced treatment efficacy, safety, and modulation of the TME, laying the groundwork for more potent cancer immunotherapy. This article is protected by copyright. All rights reserved.
    Keywords:  cancer immunotherapy; myeloid-derived suppressor cells; nanomedicines; targeted therapy; tumor microenvironment
  2. Lipids Health Dis. 2024 Feb 01. 23(1): 35
      Lipid metabolism in cancer cells has garnered increasing attention in recent decades. Cancer cells thrive in hypoxic conditions, nutrient deficiency, and oxidative stress and cannot be separated from alterations in lipid metabolism. Therefore, cancer cells exhibit increased lipid metabolism, lipid uptake, lipogenesis and storage to adapt to a progressively challenging environment, which contribute to their rapid growth. Lipids aid cancer cell activation. Cancer cells absorb lipids with the help of transporter and translocase proteins to obtain energy. Abnormal levels of a series of lipid synthases contribute to the over-accumulation of lipids in the tumor microenvironment (TME). Lipid reprogramming plays an essential role in the TME. Lipids are closely linked to several immune cells and their phenotypic transformation. The reprogramming of tumor lipid metabolism further promotes immunosuppression, which leads to immune escape. This event significantly affects the progression, treatment, recurrence, and metastasis of cancer. Therefore, the present review describes alterations in the lipid metabolism of immune cells in the TME and examines the connection between lipid metabolism and immunotherapy.
    Keywords:  Immunotherapy; Lipid metabolism; Programmed cell death protein 1; Targeted therapy; Tumor microenvironment
  3. J Hematol Oncol. 2024 Jan 31. 17(1): 6
      The liver is essential for metabolic homeostasis. The onset of liver cancer is often accompanied by dysregulated liver function, leading to metabolic rearrangements. Overwhelming evidence has illustrated that dysregulated cellular metabolism can, in turn, promote anabolic growth and tumor propagation in a hostile microenvironment. In addition to supporting continuous tumor growth and survival, disrupted metabolic process also creates obstacles for the anticancer immune response and restrains durable clinical remission following immunotherapy. In this review, we elucidate the metabolic communication between liver cancer cells and their surrounding immune cells and discuss how metabolic reprogramming of liver cancer impacts the immune microenvironment and the efficacy of anticancer immunotherapy. We also describe the crucial role of the gut-liver axis in remodeling the metabolic crosstalk of immune surveillance and escape, highlighting novel therapeutic opportunities.
    Keywords:  Gut–liver axis; Immune microenvironment; Liver cancer; Metabolic reprogramming
  4. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2024 Feb;40(2): 168-173
      Cancer associated fibroblasts (CAFs) are one of the main components of tumor microenvironment (TME). In TME, the interaction between tumor cells and non-tumor cells or among non tumor cells can promote the occurrence and development of tumors. CAFs can interact with a variety of immune cells and promote the occurrence and development of tumors by inhibiting the function of adaptive immune cells and reshaping the immune microenvironment in TME. The interaction between CAFs and macrophages and the induction of macrophage polarization towards M2 type play an important role in promoting tumor occurrence and development. This article reviews the research progress of CAF in promoting the polarization of M2 macrophages.
  5. Phys Act Nutr. 2023 Dec;27(4): 41-47
      PURPOSE: This review aimed to comprehensively explore and elucidate multifaceted neutrophils in breast cancer, particularly in the context of physical activity. Neutrophils play a critical role in the tumor microenvironment and systemic immune response, despite their short half-life and terminal differentiation. Through a thorough review of research related to changes in immunity in breast cancer during exercise, this review aims to provide comprehensive insights into immunological changes, especially focusing on neutrophils. Recognizing that much of the existing research has predominantly focused on T cells and nature killer (NK) cells, our review seeks to shift the spotlight toward understanding how exercise affects neutrophils, a less-explored but critical immune response component in breast cancer.METHODS: This study involved an extensive review of the literature (from 2000 to 2023) using the PubMed, Science Direct, and Google Scholar databases. The keywords chosen for the searches were "immune cells and exercise," "exercise and breast cancer," "tumor microenvironment and neutrophils," and "neutrophils and exercise and breast cancers."
    RESULTS: Neutrophils in the tumor microenvironment can exhibit distinct phenotypes and functions. These differences have yielded conflicting results regarding tumor progression. Exercise plays a positive role in breast cancer and alters the immune system. Physical activity can quantitatively and functionally regulate neutrophils under various conditions such as metabolic disruption or senescence.
    CONCLUSION: This short communication outlines exercise-induced neutrophil diversification and its role in breast cancer progression, both within and systemically within the tumor microenvironment. Exercise may provide benefits through the potential neutrophil involvement in breast cancer.
    Keywords:  TGF- β; breast cancer; exercise; neutrophils; tumor microenvironment; type I IFN
  6. Clin Exp Med. 2024 Jan 27. 24(1): 15
      Dysregulation of WNT/β-catenin is a hallmark of many cancer types and a key mediator of metastasis in solid tumors. Overactive β-catenin signaling hampers dendritic cell (DC) recruitment, promotes CD8+ T cell exclusion and increases the population of regulatory T cells (Tregs). The activity of WNT/β-catenin also induces the expression of programmed death-ligand 1 (PD-L1) on tumor cells and promotes programmed death-1 (PD-1) upregulation. Increased activity of WNT/β-catenin signaling after anti-PD-1 therapy is indicative of a possible implication of this signaling in bypassing immune checkpoint inhibitor (ICI) therapy. This review is aimed at giving a comprehensive overview of the WNT/β-catenin regulatory roles on PD-1/PD-L1 axis in tumor immune ecosystem, discussing about key mechanistic events contributed to the WNT/β-catenin-mediated bypass of ICI therapy, and representing inhibitors of this signaling as promising combinatory regimen to go with anti-PD-(L)1 in cancer immunotherapy. Ideas presented in this review imply the synergistic efficacy of such combination therapy in rendering durable anti-tumor immunity.
    Keywords:  Immune checkpoint inhibitor (ICI); Programmed death-1 (PD-1); Programmed death-ligand 1 (PD-L1); Resistance; Tumor microenvironment (TME); β-catenin
  7. Nat Commun. 2024 Feb 01. 15(1): 966
      The tumor microenvironment is reprogrammed by cancer cells and participates in all stages of tumor progression. Neutral ceramidase is a key regulator of ceramide, the central intermediate in sphingolipid metabolism. The contribution of neutral ceramidase to the reprogramming of the tumor microenvironment is not well understood. Here, we find that deletion of neutral ceramidase in multiple breast cancer models in female mice accelerates tumor growth. Our result show that Ly6C+CD39+ tumor-infiltrating CD8 T cells are enriched in the tumor microenvironment and display an exhausted phenotype. Deletion of myeloid neutral ceramidase in vivo and in vitro induces exhaustion in tumor-infiltrating Ly6C+CD39+CD8+ T cells. Mechanistically, myeloid neutral ceramidase is required for the generation of lipid droplets and for the induction of lipolysis, which generate fatty acids for fatty-acid oxidation and orchestrate macrophage metabolism. Metabolite ceramide leads to reprogramming of macrophages toward immune suppressive TREM2+ tumor associated macrophages, which promote CD8 T cells exhaustion.
  8. Front Immunol. 2023 ;14 1301506
      Significant advancements have been made in comprehending the interactions between the microbiome and cancer. However, prevailing research predominantly directs its focus toward the gut microbiome, affording limited consideration to the interactions of intratumoral microbiota and tumors. Within the tumor microenvironment (TME), the intratumoral microbiome and its associated products wield regulatory influence, directing the modulation of cancer cell properties and impacting immune system functionality. However, to grasp a more profound insight into the intratumoral microbiota in cancer, further research into its underlying mechanisms is necessary. In this review, we delve into the intricate associations between intratumoral microbiota and cancer, with a specific focus on elucidating the significant contribution of intratumoral microbiota to the onset and advancement of cancer. Notably, we provide a detailed exploration of therapeutic advances facilitated by intratumoral microbiota, offering insights into recent developments in this burgeoning field.
    Keywords:  cancer; immunotherapy; intratumoral microbiota; treatment; tumor microenvironment
  9. Recent Pat Anticancer Drug Discov. 2024 Jan 04.
      Digestive system neoplasms are highly heterogeneous and exhibit complex resistance mechanisms that render anti-programmed cell death protein (PD) therapies poorly effective. The tumor microenvironment (TME) plays a pivotal role in tumor development, apart from supplying energy for tumor proliferation and impeding the body's anti-tumor immune response, the TME actively facilitates tumor progression and immune escape via diverse pathways, which include the modulation of heritable gene expression alterations and the intricate interplay with the gut microbiota. In this review, we aim to elucidate the mechanisms underlying drug resistance in digestive tumors, focusing on immune-mediated resistance, microbial crosstalk, metabolism, and epigenetics. We will highlight the unique characteristics of each digestive tumor and emphasize the significance of the tumor immune microenvironment (TIME). Furthermore, we will discuss the current therapeutic strategies that hold promise for combination with cancer immune normalization therapies. This review aims to provide a thorough understanding of the resistance mechanisms in digestive tumors and offer insights into potential therapeutic interventions.
    Keywords:  Immunotherapy resistance; PD-1/B7-H1; anti-PD-1/PD-L1 therapy; digestive system neoplasms.; normalization cancer immunotherapy
  10. Pathol Res Pract. 2024 Jan 11. pii: S0344-0338(24)00031-1. [Epub ahead of print]254 155120
      In the immunological surveillance against cancer, natural killer (NK) cells are essential effectors that help eradicate altered cells. The complex interactions that occur between NK cells and the tumor microenvironment (TME) are thoroughly examined in this review. The review examines how cytokine stimulation affects NK cell activation, focusing on the dynamic modulation of NK cell function within the TME. It looks at NK cell-related biomarkers such as PD-1/PD-L1, methylation HOXA9 (Homeobox A9), Stroma AReactive Invasion Front Areas (SARIFA), and NKG2A/HLA-E, providing critical information about prognosis and treatment outcomes. The changing landscape of immunotherapies-including checkpoint inhibitors, CAR-NK cells, and cytokine-based interventions-is examined in the context of enhancing NK cell activity. The review highlights the potential pathways for precision medicine going forward, focusing on customized immunotherapies based on unique biomarker profiles and investigating combination medicines to produce more robust anti-tumor responses.
    Keywords:  Cancer; Cytokine stimulation; Immune surveillance; Natural killer cells; Tumor microenvironment
  11. Gan To Kagaku Ryoho. 2023 Dec;50(13): 1361-1363
      Near-infrared photoimmunotherapy(NIR-PIT)is a novel cancer treatment modality that employs antibody-IRDye700DX (IR700)conjugates. Recently, the clinical application of NIR-PIT has received approval in Japan for patients with inoperable head and neck cancer, specifically targeting the human epidermal growth factor receptor(hEGFR). Furthermore, NIR-PIT extends beyond the scope of tumor antigens and can be employed to eliminate specific host cells that contribute to the creation of immune-permissive environments supporting tumor growth. One of the distinguishing features of NIR-PIT is its ability to selectively eliminate various cell types within the tumor microenvironment(TME)by specifically targeting distinct antigens. By employing podoplanin(PDPN)-targeted NIR-PIT, PDPN-expressing fibroblasts were selectively eradicated, resulting in the suppression of tumor progression and a notable extension of overall survival. Additionally, we investigated the efficacy of depleting myeloid-derived suppressor cells(MDSCs)using NIR-PIT. This approach led to the selective elimination of MDSCs within tumors, and remarkable abscopal effects were observed in bilateral tumor models. Hence, NIR-PIT holds immense promise for the treatment of diverse cancer types by precisely targeting tumor cells, fibroblasts, and immune cells.
  12. Cell Mol Gastroenterol Hepatol. 2024 Jan 31. pii: S2352-345X(24)00013-4. [Epub ahead of print]
      Cancer-associated fibroblasts (CAFs) are an abundant component of the tumor microenvironment and have been shown to possess critical functions in tumor progression. While their roles have been predominantly described as tumor-promoting, more recent findings have identified subsets of CAFs with tumor-restraining functions. Accumulating evidence underscores large heterogeneity in fibroblasts subsets where distinct subsets differentially impact the initiation, progression and metastasis of colorectal cancer (CRC). In this review, we summarize and discuss the evolving role of CAFs in CRC, highlighting the ongoing controversies regarding their distinct origins and multifaceted functions. In addition, we explore how CAFs can confer resistance to current therapies and the challenges of developing effective CAF-directed therapies. Taken together, we believe that, in this rapidly evolving field, it is crucial to first comprehensively understand the CAF dynamics and to bridge existing knowledge gaps regarding CAF heterogeneity and plasticity, before further exploring the clinical targeting of CAFs.
    Keywords:  Colorectal cancer; adenoma-to-carcinoma transition; cancer-associated fibroblast; heterogeneity
  13. Clin Exp Med. 2024 Jan 29. 24(1): 26
      A link exists between chronic inflammation and cancer and immune cells, angiogenesis, and tumor progression. In hematologic malignancies, tumor-associated macrophages (TAMs) are a significant part of the tumor microenvironment. Macrophages are classified into M1/classically activated and M2/alternatively activated. In tumors, TAMs are mainly constituted by M2 subtype, which promotes angiogenesis, lymphangiogenesis, repair, and remodeling, suppressing adaptive immunity, increasing tumor cell proliferation, drug resistance, histological malignancy, and poor clinical prognosis. The aim of our review article is to define the role of TAMs and their relationship with the angiogenesis in patients with lymphoma reporting both an analysis of main published data and those emerging from our studies. Finally, we have discussed the anti-angiogenic approach in the treatment of lymphomas.
    Keywords:  Angiogenesis; Anti-angiogenesis; Lymphoma; Tumor-associated macrophages
  14. Mol Biol Rep. 2024 Jan 28. 51(1): 235
      Gliomas, the most common malignant brain tumor, present a grim prognosis despite available treatments such as surgical resection, temozolomide (TMZ) therapy, and radiation therapy. This is due to their aggressive growth, high level of immunosuppression, and the blood-brain barrier (BBB), which obstruct the effective exchange of therapeutic drugs. Gliomas can significantly affect differentiation and function of immune cells by releasing extracellular vesicles (EVs), resulting in a systemic immunosuppressive state and a highly immunosuppressive microenvironment. In the tumor immune microenvironment (TIME), the primary immune cells are regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). In particular, glioma-associated TAMs are chiefly composed of monocyte-derived macrophages and brain-resident microglia. These cells partially exhibit characteristics of a pro-tumorigenic, anti-inflammatory M2-type. Glioma-derived EVs can hijack TAMs to differentiate into tumor-supporting phenotypes or directly affect the maturation of peripheral blood monocytes (PBMCs) and promote the activation of MDSCs. In addition, EVs impair the ability of dendritic cells (DCs) to process antigens, subsequently hindering the activation of lymphocytes. EVs also impact the proliferation, differentiation, and activation of lymphocytes. This is primarily evident in the overall reduction of CD4 + helper T cells and CD8 + T cells, coupled with a relative increase in Tregs, which possess immunosuppressive characteristics. This study investigates thoroughly how tumor-derived EVs impair the function of immune cells and enhance immunosuppression in gliomas, shedding light on their potential implications for immunotherapy strategies in glioma treatment.
    Keywords:  Extracellular vesicles; Glioma; Immunosuppression; Immunotherapy; M2 polarization
  15. Int J Biol Macromol. 2024 Jan 26. pii: S0141-8130(24)00477-X. [Epub ahead of print]261(Pt 1): 129674
      The pro-tumorigenic M2-type tumor-associated macrophages (TAMs) in the immunosuppressive tumor microenvironment (TME) promote the progression, angiogenesis, and metastasis of breast cancer. The repolarization of TAMs from an M2-type toward an M1-type holds great potential for the inhibition of breast cancer. Here, we report that Lycium barbarum polysaccharides (LBPs) can significantly reconstruct the TME by modulating the function of TAMs. Specifically, we separated four distinct molecular weight segments of LBPs and compared their repolarization effects on TAMs in TME. The results showed that LBP segments within 50-100 kDa molecular weight range exhibited the prime effect on the macrophage repolarization, augmented phagocytosis effect of the repolarized macrophages on breast cancer cells, and regression of breast tumor in a tumor-bearing mouse model. In addition, RNA-sequencing confirms that this segment of LBP displays an enhanced anti-breast cancer effect through innate immune responses. This study highlights the therapeutic potential of LBP segments within the 50-100 kDa molecular weight range for macrophage repolarization, paving ways to offer new strategies for the treatment of breast cancer.
    Keywords:  Lycium barbarum polysaccharides; Macrophages repolarization; Molecular weight
  16. Front Immunol. 2023 ;14 1335326
      Therapies for bladder cancer patients are limited by side effects and failures, highlighting the need for novel targets to improve disease management. Given the emerging evidence highlighting the key role of innate lymphoid cell subsets, especially type 2 innate lymphoid cells (ILC2s), in shaping the tumor microenvironment and immune responses, we investigated the contribution of ILC2s in bladder tumor development. Using the orthotopic murine MB49 bladder tumor model, we found a strong enrichment of ILC2s in the bladder under steady-state conditions, comparable to that in the lung. However, as tumors grew, we observed an increase in ILC1s but no changes in ILC2s. Targeting ILC2s by blocking IL-4/IL-13 signaling pathways, IL-5, or IL-33 receptor, or using IL-33-deficient or ILC2-deficient mice, did not affect mice survival following bladder tumor implantation. Overall, these results suggest that ILC2s do not contribute significantly to bladder tumor development, yet further investigations are required to confirm these results in bladder cancer patients.
    Keywords:  MB49 bladder tumor model; bladder cancer; innate lymphoid cell (ILC); tumor microenvironment; type 2 innate lymphoid cell (ILC2)
  17. Biochim Biophys Acta Rev Cancer. 2024 Jan 26. pii: S0304-419X(24)00010-6. [Epub ahead of print]1879(2): 189079
      Angiogenesis is a crucial process for tissue development, repair, and tumor survival. Vascular endothelial growth factor (VEGF) is a key driver secreted by cancer cells, promoting neovascularization. While VEGF's role in angiogenesis is well-documented, its influence on the other aspects in tumor microenvironemt is less discussed. This review elaborates on VEGF's impact on intercellular interactions within the tumor microenvironment, including how VEGF affects pericyte proliferation and migration and mediates interactions between tumor-associated macrophages and cancer cells, resulting in PDL-1-mediated immunosuppression and Nrf2-mediated epithelial-mesenchymal transition. The review discusses VEGF's involvement in intra-organelle crosstalk, tumor metabolism, stemness, and epithelial-mesenchymal transition. It also provides insights into current anti-VEGF therapies and their limitations in cancer treatment. Overall, this review aims to provide a thorough overview of the current state of knowledge concerning VEGF signaling and its impact, not only on angiogenesis but also on various other oncogenic processes.
    Keywords:  Angiogenesis; Anti-VEGF therapies; Intercellular crosstalk; Intra-organelle crosstalk; Tumor microenvironment; VEGF-VEGFR
  18. Cell Death Dis. 2024 Jan 30. 15(1): 103
      Cancer cells can evade immune elimination by activating immunosuppressive signaling pathways in the tumor microenvironment (TME). Targeting immunosuppressive signaling pathways to promote antitumor immunity has become an attractive strategy for cancer therapy. Aurora-A is a well-known oncoprotein that plays a critical role in tumor progression, and its inhibition is considered a promising strategy for treating cancers. However, targeting Aurora-A has not yet got a breakthrough in clinical trials. Recent reports have indicated that inhibition of oncoproteins may reduce antitumor immunity, but the role of tumor-intrinsic Aurora-A in regulating antitumor immunity remains unclear. In this study, we demonstrated that in tumors with high lymphocyte infiltration (hot tumors), higher tumor-intrinsic Aurora-A expression is associated with a better prognosis in CRC patients. Mechanically, tumor-intrinsic Aurora-A promotes the cytotoxic activity of CD8+ T cells in immune hot CRC via negatively regulating interleukin-16 (IL-16), and the upregulation of IL-16 may impair the therapeutic effect of Aurora-A inhibition. Consequently, combination treatment with IL-16 neutralization improves the therapeutic response to Aurora-A inhibitors in immune hot CRC tumors. Our study provides evidence that tumor-intrinsic Aurora-A contributes to anti-tumor immunity depending on the status of lymphocyte infiltration, highlighting the importance of considering this aspect in cancer therapy targeting Aurora-A. Importantly, our results suggest that combining Aurora-A inhibitors with IL-16-neutralizing antibodies may represent a novel and effective approach for cancer therapy, particularly in tumors with high levels of lymphocyte infiltration.
  19. Stem Cells Int. 2024 ;2024 9893249
      [This retracts the article DOI: 10.1155/2022/5775696.].
  20. Mol Biol Rep. 2024 Jan 30. 51(1): 238
      T cells are broadly categorized into two groups, namely conventional and unconventional T cells. Conventional T cells are the most prevalent and well-studied subset of T cells. On the other hand, unconventional T cells exhibit diverse functions shared between innate and adaptive immune cells. During recent decades, γδ T cells have received attention for their roles in cancer immunity. These cells can detect various molecules, such as lipids and metabolites. Also, they are known for their distinctive ability to recognize and target cancer cells in the tumor microenvironment (TME). This feature of γδ T cells could provide a unique therapeutic tool to fight against cancer. Understanding the role of γδ T cells in TME is essential to prepare the groundwork to use γδ T cells for clinical purposes. Here, we provide recent knowledge regarding the role γδ T cell subsets in different cancer types.
    Keywords:  Cancer; T cell; Tumor microenvironment; Unconventional T cells; γδ T cells
  21. Exp Mol Med. 2024 Feb 01.
      M2-like tumor-associated macrophages (TAMs) are risk factors for cancer progression and metastasis. However, the mechanisms underlying their polarization are still not fully understood. Although cathepsin D (Cat D) has been reported as a procarcinogenic factor, little is known about the functional role of Cat D in the tumor microenvironment (TME). This study aimed to explore the effect and molecular mechanisms of Cat D in the TME. Cat D knockout (KO) altered the cytokine secretion pattern and induced TAM reprogramming from the M2 to M1 subtype, thereby preventing epithelial-mesenchymal transition and tumor metastasis. Mechanistically, we identified transforming growth factor beta-induced protein (TGFBI) as a Cat D target protein that is specifically associated with TAM polarization. Elevated TGFBI expression in Cat D KO cancer cells resulted in a decline in M2-like TAM polarization. Our RNA-sequencing results indicated that the cancer cell-secreted chemokine CCL20 is a major secretory chemokine for Cat D-TGFBI-mediated TAM polarization. In contrast, Cat D overexpression accelerated TAM polarization into M2-like cells by suppressing TGFBI expression. In addition, the double Cat D and TGFBI KO rescued the inhibitory effects of Cat D KO on tumor metastasis by controlling TAM and T-cell activation. These findings indicated that Cat D contributes to cancer metastasis through TGFBI-mediated TAM reprogramming. Cat D deletion inhibits M2-like TAM polarization through TGFBI-mediated CCL20 expression, reprogramming the immunosuppressive TME. Our results open a potential new avenue for therapy focused on eliminating tumor metastasis.
  22. Front Immunol. 2023 ;14 1255443
      Ferroptosis is an iron-dependent, novel form of programmed cell death characterized by lipid peroxidation and glutathione depletion and is widespread in a variety of diseases. CD8+ T cells are the most important effector cells of cytotoxic T cells, capable of specifically recognizing and killing cancer cells. Traditionally, CD8+ T cells are thought to induce cancer cell death mainly through perforin and granzyme, and Fas-L/Fas binding. In recent years, CD8+ T cell-derived IFN-γ was found to promote cancer cell ferroptosis by multiple mechanisms, including upregulation of IRF1 and IRF8, and downregulation of the system XC-, while cancer cells ferroptosis was shown to enhance the anti-tumor effects of CD8+ T cell by heating the tumor immune microenvironment through the exposure and release of tumor-associated specific antigens, which results in a positive feedback pathway. Unfortunately, the intra-tumoral CD8+ T cells are more sensitive to ferroptosis than cancer cells, which limits the application of ferroptosis inducers in cancer. In addition, CD8+ T cells are susceptible to being regulated by other immune cell ferroptosis in the TME, such as tumor-associated macrophages, dendritic cells, Treg, and bone marrow-derived immunosuppressive cells. Together, these factors build a complex network of CD8+ T cells and ferroptosis in cancer. Therefore, we aim to integrate relevant studies to reveal the potential mechanisms of crosstalk between CD8+ T cells and ferroptosis, and to summarize preclinical models in cancer therapy to find new therapeutic strategies in this review.
    Keywords:  CD8+ T cells; DAMPs; IFN-γ; ferroptosis; immunotherapy
  23. J Immunother Cancer. 2024 Jan 31. pii: e007983. [Epub ahead of print]12(1):
      BACKGROUND: Extensive attention has been given to the role of myeloid-derived suppressor cells (MDSCs) in driving tumor progression and treatment failure. Preclinical studies have identified multiple agents that eliminate MDSCs. However, none have been authorized in the cliniccal ues due to the safety reasons. In the present study, we investigated the efficacy and mechanism of sulforaphane (SFN) to eliminate MDSCs in the tumor microenvironment (TME).METHODS: We monitored SFN effect on tumor growth and the percents or apoptosis of immune cell subsets in mice models bearing LLC or B16 cells. Flow cytometry, quantitative reverse transcription-PCR, immunohistochemistry, ELISA, immunofluorescence, imaging flow cytometry and western blot were performed to validate the role of SFN on MDSCs function in vivo and in vitro. RNA sequencing was then used to interrogate the mechanisms of how SFN regulated MDSCs function. Tumor xenograft models were established to evaluate the involvement of IL-12RB2/MMP3/FasL induced MDSCs apoptosis in vivo. We verified the effect of SFN on MDSCs and CD8+ T cells in the blood samples from a phase I clinical trial (KY-2021-0350).
    RESULTS: In this study, we elucidated that SFN liberated CD8+ T-cell antitumor ability by reducing MDSCs abundance, leading to repressed tumor growth. SFN treatment suppressed MDSCs accumulation in the peripheral blood and tumor sites of mice, but had no effect on the bone marrow. Mechanistically, SFN activates IL-12RB2, which stimulates the MMP3/FasL signaling cascade to trigger caspase 3 cleavage and induce apoptosis in MDSCs. Clinically, SFN treatment eliminates peripheral MDSCs and increases the percentage and activation of CD8+ T cells.
    CONCLUSIONS: Collectively, we uncovered the role of SFN in eliminating MDSCs to emancipate CD8+ T cells through IL-12RB2/MMP3/FasL induced apoptosis, thus providing a strategy for targeting MDSCs to control tumors and improve clinical efficacy.
    Keywords:  Adaptive Immunity; Myeloid-Derived Suppressor Cells
  24. Biomed Pharmacother. 2024 Jan 26. pii: S0753-3322(24)00084-2. [Epub ahead of print]171 116203
      Tumor immunotherapy, an innovative anti-cancer therapy, has showcased encouraging outcomes across diverse tumor types. Among these, the PD-1/PD-L1 signaling pathway is a well-known immunological checkpoint, which is significant in the regulation of immune evasion by tumors. Nevertheless, a considerable number of patients develop resistance to anti-PD-1/PD-L1 immunotherapy, rendering it ineffective in the long run. This research focuses on exploring the factors of PD-1/PD-L1-mediated resistance in tumor immunotherapy. Initially, the PD-1/PD-L1 pathway is characterized by its role in facilitating tumor immune evasion, emphasizing its role in autoimmune homeostasis. Next, the primary mechanisms of resistance to PD-1/PD-L1-based immunotherapy are analyzed, including tumor antigen deletion, T cell dysfunction, increased immunosuppressive cells, and alterations in the expression of PD-L1 within tumor cells. The possible ramifications of altered metabolism, microbiota, and DNA methylation on resistance is also described. Finally, possible resolution strategies for dealing with anti-PD-1/PD-L1 immunotherapy resistance are discussed, placing particular emphasis on personalized therapeutic approaches and the exploration of more potent immunotherapy regimens.
    Keywords:  Anti-PD-1/PD-L1 therapy; Immune escape; Immunotherapy resistance; PD-1/PD-L1; Tumor immunotherapy
  25. Biofabrication. 2024 Feb 02.
      The tumor microenvironment (TME) is critical for tumor growth and metastasis. The TME contains cancer-associated cells, tumor matrix, and tumor secretory factors. The fabrication of artificial tumors, so-called tumoroids, is of great significance for understanding tumorigenesis and clinical cancer therapy. The assembly of multiple tumor cells and matrix components through interdisciplinary techniques is necessary to prepare various tumoroids. This article discusses current methods for constructing tumoroids (tumor tissue slices and tumor cell co-culture) for pre-clinical use. This article focuses on the artificial matrix materials (natural and synthetic materials) and biofabrication techniques (cell assembly, bioengineered tools, bioprinting, and microfluidic devices) used in tumoroids. This article also points out the shortcomings of current tumoroids and potential solutions. This article aims to promote the next-generation tumoroids and their potential in basic research and clinical application.
    Keywords:  artificial tumor matrix (ATM); drug screening; personalized medicine; tumor assembloid; tumor microenvironment (TME)
  26. Onco Targets Ther. 2024 ;17 7-26
      Hepatocellular carcinoma (HCC) is one of the most common aggressive tumors in the world. Despite the availability of various treatments, its prognosis remains poor due to the lack of specific diagnostic indicators and the high heterogeneity of HCC cases. CircRNAs are noncoding RNAs with stable and highly specific expression. Extensive research evidence suggests that circRNAs mediate the pathogenesis and progression of HCC through acting as miRNA sponges, protein modulators, and translation templates. Tumor microenvironment (TME) has become a hotspot of immune-related research in recent years due to its effects on metabolism, secretion and immunity of HCC. Accordingly, understanding the role played by circRNAs in TME is important for the study of HCC. This review will discuss the crosstalk between circRNAs and TME in HCC. In addition, we will discuss the current deficiencies and controversies in research on circRNAs and predict future research directions.
    Keywords:  CircRNAs; biomarker; characteristics; hepatocellular carcinoma; tumor microenvironment
  27. Adv Sci (Weinh). 2024 Feb 02. e2303177
      Nicotinamide phosphoribosyltransferase (NAMPT) is a metabolic enzyme with key roles in inflammation. Previous studies have examined the consequences of its upregulated expression in cancer cells themselves, but studies are limited with respect to its role in the other cells within the tumor microenvironment (TME) during colorectal cancer (CRC) progression. Using single-cell RNA sequencing (scRNA-seq) data, it is founded that NAMPT is highly expressed in SPP1+ tumor-associated macrophages (TAMs), a unique subset of TAMs associated with immunosuppressive activity. A NAMPThigh gene signature in SPP1+ TAMs correlated with worse prognostic outcomes in CRC patients. The effect of Nampt deletion in the myeloid compartment of mice during CRC development is explored. NAMPT deficiency in macrophages resulted in HIF-1α destabilization, leading to reduction in M2-like TAM polarization. NAMPT deficiency caused significant decreases in the efferocytosis activity of macrophages, which enhanced STING signaling and the induction of type I IFN-response genes. Expression of these genes contributed to anti-tumoral immunity via potentiation of cytotoxic T cell activity in the TME. Overall, these findings suggest that NAMPT-initiated TAM-specific genes can be useful in predicting poor CRC patient outcomes; strategies aimed at targeting NAMPT may provide a promising therapeutic approach for building an immunostimulatory TME in CRC progression.
    Keywords:  CRC; HIF-1α; M2-like TAMs; NAMPT; STING