bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024‒06‒16
thirty-one papers selected by
Peio Azcoaga, Biodonostia HRI

  1. Redox Biol. 2024 May 25. pii: S2213-2317(24)00187-3. [Epub ahead of print]74 103209
      Alterations in the tumor microenvironment are closely associated with the metabolic phenotype of tumor cells. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor growth and metastasis. Existing studies have suggested that lactate produced by tumor cells can activate CAFs, yet the precise underlying mechanisms remain largely unexplored. In this study, we initially identified that lactate derived from lung cancer cells can promote nuclear translocation of NUSAP1, subsequently leading to the recruitment of the transcriptional complex JUNB-FRA1-FRA2 near the DESMIN promoter and facilitating DESMIN transcriptional activation, thereby promoting CAFs' activation. Moreover, DESMIN-positive CAFs, in turn, secrete IL-8, which recruits TAMs or promotes M2 polarization of macrophages, further contributing to the alterations in the tumor microenvironment and facilitating lung cancer progression. Furthermore, we observed that the use of IL-8 receptor antagonists, SB225002, or Navarixin, significantly reduced TAM infiltration and enhanced the therapeutic efficacy of anti-PD-1 or anti-PD-L1 treatment. This finding indicates that inhibiting IL-8R activity can attenuate the impact of CAFs on the tumor microenvironment, thus restraining the progression of lung cancer.
    Keywords:  Cancer-associated fibroblasts; Lung cancer; Tumor microenvironment; Tumor progression; Tumor-associated macrophages
  2. APL Bioeng. 2024 Jun;8(2): 021507
      The understanding of cancer has evolved significantly, with the tumor microenvironment (TME) now recognized as a critical factor influencing the onset and progression of the disease. This broader perspective challenges the traditional view that cancer is primarily caused by mutations, instead emphasizing the dynamic interaction between different cell types and physicochemical factors within the TME. Among these factors, cancer-associated fibroblasts (CAFs) command attention for their profound influence on tumor behavior and patient prognoses. Despite their recognized importance, the biophysical and mechanical interactions of CAFs within the TME remain elusive. This review examines the distinctive physical characteristics of CAFs, their morphological attributes, and mechanical interactions within the TME. We discuss the impact of mechanotransduction on CAF function and highlight how these cells communicate mechanically with neighboring cancer cells, thereby shaping the path of tumor development and progression. By concentrating on the biomechanical regulation of CAFs, this review aims to deepen our understanding of their role in the TME and to illuminate new biomechanical-based therapeutic strategies.
  3. Clin Exp Med. 2024 Jun 12. 24(1): 126
      In recent decades, many reports have been published on the composition and function of the tumor microenvironment (TME), among which cancer-associated fibroblasts (CAFs) have received much attention. CAFs have different degrees of heterogeneity in terms of their origin, phenotype, and function and can be divided into different subpopulations. These subgroups may play different roles in the occurrence and development of tumors. In addition, CAFs are closely associated with tumor immunity and have been found to regulate immune cell activity and to suppress the tumor immune response. In this review, we systematize the heterogeneity and characteristics of CAFs, discuss how specific CAF subgroups contribute to cancer progression by inducing an immunosuppressive microenvironment, and finally, we examine the future clinical applications of CAF subgroups.
    Keywords:  Cancer cells; Cancer-associated fibroblasts; Heterogeneity; Immunosuppression
  4. Front Mol Biosci. 2024 ;11 1379971
      The interaction between the tumor microenvironment (TME) and the cancer cells is a complex and mutually beneficial system that leads to rapid cancer cells proliferation, metastasis, and resistance to therapy. It is now recognized that cancer cells are not isolated, and tumor progression is governed among others, by many components of the TME. The reciprocal cross-talk between cancer cells and their microenvironment can be indirect through the secretion of extracellular matrix (ECM) proteins and paracrine signaling through exosomes, cytokines, and growth factors, or direct by cell-to-cell contact mediated by cell surface receptors and adhesion molecules. Among TME components, cancer-associated fibroblasts (CAFs) are of unique interest. As one of the most abundant components of the TME, CAFs play key roles in the reorganization of the extracellular matrix, facilitating metastasis and chemotherapy evasion. Both direct and indirect roles have been described for CAFs in modulating tumor progression. In this review, we focus on recent advances in understanding the role of direct contact between cancer cells and cancer-associated fibroblasts (CAFs) in driving tumor development and metastasis. We also summarize recent findings on the role of direct contact between cancer cells and CAFs in chemotherapy resistance.
    Keywords:  EMT-epithelial to mesenchymal transformation; TME; cancer-associated fibroblasts; chemotherapy resistance; direct cell-cell communication
  5. Cancer Immunol Res. 2024 Jun 14.
      Semaphorin-Plexin signaling plays a major role in the tumor microenvironment (TME). In particular, Semaphorin 4D (SEMA4D) has been shown to promote tumor growth and metastasis; however, the role of its high-affinity receptor Plexin-B1 (PLXNB1), which is expressed in the TME, is poorly understood. In this study, we directly targeted PLXNB1 in the TME of triple-negative murine breast carcinoma to elucidate its relevance in cancer progression. We found that primary tumor growth, and metastatic dissemination were strongly reduced in PLXNB1-deficient mice, which showed longer survival. PLXNB1-loss in the TME induced a switch in the polarization of tumor-associated macrophages (TAMs) towards a pro-inflammatory M1 phenotype and enhanced the infiltration of CD8+ T lymphocytes both in primary tumors and in distant metastases. Moreover, PLXNB1-deficiency promoted a shift in the Th1/Th2 balance of the T-cell population and an antitumor gene signature, with the up-regulation of Icos, Perforin-1, Stat3 and Ccl5 in tumor infiltrating lymphocytes (TILs). We thus tested the translational relevance of TME re-programming driven by PLXNB1 inactivation for responsiveness to immunotherapy. Indeed, in the absence of PLXNB1, the efficacy of anti-PD-1 blockade was strongly enhanced, efficiently reducing tumor growth and distant metastasis. Consistent with this, pharmacological PLXNB1 blockade by systemic treatment with a specific inhibitor significantly hampered breast cancer growth and enhanced the antitumor activity of the anti-PD1 treatment in a preclinical model. Altogether, these data indicate that PLXNB1 signaling controls the antitumor immune response in the TME and highlight this receptor as a promising immune therapeutic target for metastatic breast cancers.
  6. Curr Gene Ther. 2024 Jun 10.
      Tumor cells achieve their adaptability through various metabolic reprogramming processes. Among them, ammonia, as a traditional metabolic waste, plays an increasingly important role in the tumor microenvironment along with its associated metabolites. Other cells in the microenvironment can also reshape the immune status of the microenvironment by regulating ammonia-related metabolism, and targeting this metabolic aspect has emerged as a potential strategy for tumor treatment. In this study, we have systematically reviewed the source and destination of ammonia in tumor cells, as well as the links between ammonia and other biological processes. We have also analyzed the ammonia-related metabolic regulation of other cells (including T cells, macrophages, dendritic cells, natural killer cells, myeloid-derived suppressor cells, and stromal cells) in the tumor microenvironment, and summarized the tumor treatment methods that target this metabolism. Through ammonia-related metabolic reprogramming, tumor cells obtain the energy they need for rapid growth and proliferation. Multiple immune cells and stromal cells in the microenvironment also interact with each other through this metabolic regulation, ultimately leading to immune suppression. Despite the heterogeneity of tumors and the complexity of cellular functions, further research into therapeutic interventions targeting ammonia-related metabolism is warranted. This review has focused on the role and regulation of ammonia-related metabolism in tumor cells and other cells in the microenvironment, and highlighted the efficacy and prospects of targeted ammonia-related metabolism therapy.
    Keywords:  Ammonia; Anti-tumor therapy; Immune cell; Metabolism; Reprogramming; Tumor microenvironment
  7. Biochem Soc Trans. 2024 Jun 10. pii: BST20231427. [Epub ahead of print]
      The tumor microenvironment (TME) is a complex and dynamic ecosystem that adjoins the cancer cells within solid tumors and comprises distinct components such as extracellular matrix, stromal and immune cells, blood vessels, and an abundance of signaling molecules. In recent years, the mechanical properties of the TME have emerged as critical determinants of tumor progression and therapeutic response. Aberrant mechanical cues, including altered tissue architecture and stiffness, contribute to tumor progression, metastasis, and resistance to treatment. Moreover, burgeoning immunotherapies hold great promise for harnessing the immune system to target and eliminate solid malignancies; however, their success is hindered by the hostile mechanical landscape of the TME, which can impede immune cell infiltration, function, and persistence. Consequently, understanding TME mechanoimmunology - the interplay between mechanical forces and immune cell behavior - is essential for developing effective solid cancer therapies. Here, we review the role of TME mechanics in tumor immunology, focusing on recent therapeutic interventions aimed at modulating the mechanical properties of the TME to potentiate T cell immunotherapies, and innovative assays tailored to evaluate their clinical efficacy.
    Keywords:  T-cells; biophysics; cancer; extracellular matrix; immune response; tumor microenvironments
  8. APMIS. 2024 Jun 14.
      Cancer-associated fibroblasts (CAFs) are crucial component of tumor microenvironment (TME) which undergo significant phenotypic changes and metabolic reprogramming, profoundly impacting tumor growth. This review delves into CAF plasticity, diverse origins, and the molecular mechanisms driving their continuous activation. Emphasis is placed on the intricate bidirectional crosstalk between CAFs and tumor cells, promoting cancer cell survival, proliferation, invasion, and immune evasion. Metabolic reprogramming, a cancer hallmark, extends beyond cancer cells to CAFs, contributing to the complex metabolic interplay within the TME. The 'reverse Warburg effect' in CAFs mirrors the Warburg effect, involving the export of high-energy substrates to fuel cancer cells, supporting their rapid proliferation. Molecular regulations by key players like p53, Myc, and K-RAS orchestrate this metabolic adaptation. Understanding the metabolic symbiosis between CAFs and tumor cells opens avenues for targeted therapeutic strategies to disrupt this dynamic crosstalk. Unraveling CAF-mediated metabolic reprogramming provides valuable insights for developing novel anticancer therapies. This comprehensive review consolidates current knowledge, shedding light on CAFs' multifaceted roles in the TME and offering potential targets for future therapies.
    Keywords:  Tumor microenvironment; Warburg effect; cancer‐associated fibroblasts; metabolic reprogramming
  9. Trends Cancer. 2024 Jun 08. pii: S2405-8033(24)00097-9. [Epub ahead of print]
      Chimeric antigen receptor (CAR) T cell therapy has emerged as a revolutionary treatment for hematological malignancies, but its adaptation to solid tumors is impeded by multiple challenges, particularly T cell dysfunction and exhaustion. The heterogeneity and inhospitableness of the solid tumor microenvironment (TME) contribute to diminished CAR T cell efficacy exhibited by reduced cytotoxicity, proliferation, cytokine secretion, and the upregulation of inhibitory receptors, similar to the phenotype of tumor-infiltrating lymphocytes (TILs). In this review, we highlight recent advances in T cell therapy for solid tumors, particularly brain cancer. Innovative strategies, including locoregional delivery and 'armoring' CAR T cells with cytokines such as interleukin (IL)-18, are under investigation to improve efficacy and safety. We also highlight emerging issues with toxicity management of CAR T cell adverse events. This review discusses the obstacles associated with CAR T cell therapy in the context of solid tumors and outlines current and future strategies to overcome these challenges.
    Keywords:  adoptive immunotherapy; chimeric antigen receptor; cytokine release syndrome
  10. World J Gastroenterol. 2024 May 28. 30(20): 2618-2620
      In this editorial we comment on the review by Wang et al published in the recent issue of the World Journal of Gastroenterology in 2023. Small extracellular vesicles (exosomes) play important roles in the tumor microenvironment. In this review, the authors introduce the following points: (1) The composition and function of exosomal microRNAs (miRNAs) of different cell origins in hepatocellular carcinoma (HCC); (2) the crosstalk between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC; and (3) the potential applicability of exosomal miRNAs derived from mesen-chymal stem cells in the treatment of HCC. In addition, the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC was introduced. In this review, the authors give us an overview of the exosomal RNA and summarize the function of exosomal RNA in HCC, which provides a deeper understanding of exosomal miRNAs to the readers.
    Keywords:  Exosomes; Hepatocellular carcinoma; Liver cancer; MicroRNA; Tumor microenvironment
  11. Cell Biochem Funct. 2024 Jun;42(4): e4055
      The heterogeneity of the solid tumor microenvironment (TME) impairs the therapeutic efficacy of standard therapies and also reduces the infiltration of antitumor immune cells, all of which lead to tumor progression and invasion. In addition, self-renewing cancer stem cells (CSCs) support tumor dormancy, drug resistance, and recurrence, all of which might pose challenges to the eradication of malignant tumor masses with current therapies. Natural forms of oncolytic viruses (OVs) or engineered OVs are known for their potential to directly target and kill tumor cells or indirectly eradicate tumor cells by involving antitumor immune responses, including enhancement of infiltrating antitumor immune cells, induction of immunogenic cell death, and reprogramming of cold TME to an immune-sensitive hot state. More importantly, OVs can target stemness factors that promote tumor progression, which subsequently enhances the efficacy of immunotherapies targeting solid tumors, particularly the CSC subpopulation. Herein, we describe the role of CSCs in tumor heterogeneity and resistance and then highlight the potential and remaining challenges of immunotherapies targeting CSCs. We then review the potential of OVs to improve tumor immunogenicity and target CSCs and finally summarize the challenges within the therapeutic application of OVs in preclinical and clinical trials.
    Keywords:  cancer stemness; drug resistance; immunotherapy; oncolytic viruses; tumor microenvironment
  12. J Cancer Res Clin Oncol. 2024 Jun 08. 150(6): 296
      Spatial transcriptomics (ST) provides novel insights into the tumor microenvironment (TME). ST allows the quantification and illustration of gene expression profiles in the spatial context of tissues, including both the cancer cells and the microenvironment in which they are found. In cancer research, ST has already provided novel insights into cancer metastasis, prognosis, and immunotherapy responsiveness. The clinical precision oncology application of next-generation sequencing (NGS) and RNA profiling of tumors relies on bulk methods that lack spatial context. The ability to preserve spatial information is now possible, as it allows us to capture tumor heterogeneity and multifocality. In this narrative review, we summarize precision oncology, discuss tumor sequencing in the clinic, and review the available ST research methods, including seqFISH, MERFISH (Vizgen), CosMx SMI (NanoString), Xenium (10x), Visium (10x), Stereo-seq (STOmics), and GeoMx DSP (NanoString). We then review the current ST literature with a focus on solid tumors organized by tumor type. Finally, we conclude by addressing an important question: how will spatial transcriptomics ultimately help patients with cancer?
    Keywords:  Genetics; Precision oncology; Solid tumors; Spatial transcriptomics; Tumor microenvironment
  13. Cancer Treat Res Commun. 2024 Jun 02. pii: S2468-2942(24)00035-2. [Epub ahead of print]40 100823
      Tumors can produce bioactive substances called tumor-derived supernatants (TDS) that modify the immune response in the host body. This can result in immunosuppressive effects that promote the growth and spread of cancer. During tumorigenesis, the exudation of these substances can disrupt the function of immune sentinels in the host and reinforce the support for cancer cell growth. Tumor cells produce cytokines, growth factors, and proteins, which contribute to the progression of the tumor and the formation of premetastatic niches. By understanding how cancer cells influence the host immune system through the secretion of these factors, we can gain new insights into cancer diagnosis and therapy.
    Keywords:  Cancer immunotherapy; Host immune system; Premetastasis niche; Tumor microenvironment; Tumor-derived supernatants; Tumorigenesis
  14. Biomed Pharmacother. 2024 Jun 13. pii: S0753-3322(24)00767-4. [Epub ahead of print]176 116883
      The unresectable or postoperative recurrence of advanced metastatic colorectal cancer (CRC) is the difficulty of its clinical management, and pharmacological therapy is the main source of benefit. Immune checkpoint inhibitors are therapeutic options but are effective in approximately 5 % of patients with deficient mismatch repair (MMR)/microsatellite instability CRC and are ineffective in patients with MMR-proficient (pMMR)/microsatellite stable (MSS) CRCs, which may be associated with the tumor microenvironment (TME). Here, we propose a new combination strategy and evaluate the efficacy of rapamycin (Rapa) combined with anti-PD-1 (αPD-1) in CT26 tumor-bearing mice, azoxymethane (AOM)/dextran sodium sulfate (DSS) inflammation-associated CRC mice, CT26-Luc tumor-bearing mice with postoperative recurrence, and CT26 liver metastasis mice. The results revealed that Rapa improved the therapeutic effect of αPD-1 and effectively inhibited colorectal carcinogenesis, postoperative recurrence, and liver metastasis. Mechanistically, Rapa improved the anticancer effect of αPD-1, associated with Rapa reprograming of the immunosuppressive TME. Rapa effectively depleted α-SMA+ cancer-associated fibroblasts and degraded collagen in the tumor tissue, increasing T lymphocyte infiltration into the tumor tissue. Rapa induced the downregulation of programed cell death 1 ligand 1 (PD-L1) protein and transcript levels in CT26 cells, which may be associated with the inhibition of the mTOR/P70S6K signaling axis. Furthermore, co-culture of tumor cells and CD8+ T lymphocytes demonstrated that Rapa-induced PD-L1 downregulation in tumor cells increased spleen-derived CD8+ T lymphocyte activation. Therefore, Rapa improves the anti-tumor effect of αPD-1 in CRCs, providing new ideas for its use to improve combinatorial strategies for anti-PD-1 immunotherapy.
    Keywords:  Colorectal cancer; Combination treatment; PD-1/PD-L1; Rapamycin; Tumor microenvironment
  15. Cold Spring Harb Perspect Med. 2024 Jun 10. pii: a041544. [Epub ahead of print]
      Metabolic reprogramming in cancer allows cells to survive in harsh environments and sustain macromolecular biosynthesis to support proliferation. In addition, metabolites play crucial roles as signaling molecules. Metabolite fluctuations are detected by various sensors in the cell to regulate gene expression, metabolism, and signal transduction. Metabolic signaling mechanisms contribute to tumorigenesis by altering the physiology of cancer cells themselves, as well as that of neighboring cells in the tumor microenvironment. In this review, we discuss principles of metabolic signaling and provide examples of how cancer cells take advantage of metabolic signals to promote cell proliferation and evade the immune system, thereby contributing to tumor growth and progression.
  16. Front Immunol. 2024 ;15 1400112
      Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and has a poor prognosis. Although immune checkpoint inhibitors have entered a new era of HCC treatment, their response rates are modest, which can be attributed to the immunosuppressive tumor microenvironment within HCC tumors. Accumulating evidence has shown that tumor growth is fueled by cancer stem cells (CSCs), which contribute to therapeutic resistance to the above treatments. Given that CSCs can regulate cellular and physical factors within the tumor niche by secreting various soluble factors in a paracrine manner, there have been increasing efforts toward understanding the roles of CSC-derived secretory factors in creating an immunosuppressive tumor microenvironment. In this review, we provide an update on how these secretory factors, including growth factors, cytokines, chemokines, and exosomes, contribute to the immunosuppressive TME, which leads to immune resistance. In addition, we present current therapeutic strategies targeting CSC-derived secretory factors and describe future perspectives. In summary, a better understanding of CSC biology in the TME provides a rational therapeutic basis for combination therapy with ICIs for effective HCC treatment.
    Keywords:  cancer stem cell (CSC); hepatocellular carcinoma; immunosuppression; secretory factors; tumor microenvironment
  17. J Transl Med. 2024 Jun 10. 22(1): 553
      Gamma delta (γδ) T cells demonstrate strong cytotoxicity against diverse cancer cell types in an MHC-independent manner, rendering them promising contenders for cancer therapy. Although amplification and adoptive transfer of γδ T cells are being evaluated in the clinic, their therapeutic efficacy remains unsatisfactory, primarily due to the influence of the immunosuppressive tumor microenvironment (TME). Currently, the utilization of targeted therapeutic antibodies against inhibitory immune checkpoint (ICP) molecules is a viable approach to counteract the immunosuppressive consequences of the TME. Notably, PD-1/PD-L1 checkpoint inhibitors are considered primary treatment options for diverse malignancies, with the objective of preserving the response of αβ T cells. However, γδ T cells also infiltrate various human cancers and are important participants in cancer immunity, thereby influencing patient prognosis. Hence, it is imperative to comprehend the reciprocal impact of the PD-1/PD-L1 axis on γδ T cells. This understanding can serve as a therapeutic foundation for improving γδ T cells adoptive transfer therapy and may offer a novel avenue for future combined immunotherapeutic approaches.
    Keywords:  Antitumor immunotherapy; Immune checkpoint inhibitors (ICIs); Immune checkpoints (ICPs); Immunosuppressive molecules; PD-1/PD-L1; Tumor microenvironment (TME); γδ T cells
  18. Cancer Res Treat. 2024 Jun 05.
      Tumor microenvironment is intrinsically hypoxic with abundant hypoxia-inducible factors-1α (HIF-1α), a primary regulator of the cellular response to hypoxia and various stresses imposed on the tumor cells. HIF-1α increases radioresistance and chemoresistance by reducing DNA damage, increasing repair of DNA damage, enhancing glycolysis that increases antioxidant capacity of tumors cells, and promoting angiogenesis. In addition, HIF-1α markedly enhances drug efflux, leading to multidrug resistance. Radiotherapy and certain chemotherapy drugs evoke profound anti-tumor immunity by inducing immunologic cell death that release tumor associated antigens together with numerous pro-immunological factors, leading to priming of cytotoxic CD8+ T cells and enhancing the cytotoxicity of macrophages and NK cells. Radiotherapy and chemotherapy of tumors significantly increase HIF-1α activity in tumor cells. Unfortunately, HIF-1α effectively promotes various immune suppressive pathways including secretion of immune suppressive cytokines, activation of myeloid-derived suppressor cells (MIDSCs), activation of regulatory T cells (Tregs), inhibition of T cells priming and activity, and upregulation of immune checkpoints. Consequently, the anti-tumor immunity elevated by radiotherapy and chemotherapy is counterbalanced or masked by the potent immune suppression promoted by HIF-1α. Effective inhibition of HIF-1α may significantly increase the efficacy of radiotherapy and chemotherapy by increasing radiosensitivity and chemosensitivity of tumor cells and also by upregulating anti-tumor immunity.
    Keywords:  Anti-tumor immunity; Chemosensitivity; Chemotherapy; HIF-1ɑ; Immunologic cell death; Radiosensitivity; Radiotherapy
  19. J Biosci. 2024 ;pii: 63. [Epub ahead of print]49
      Immunotherapy is a promising and safer alternative to conventional cancer therapies. It involves adaptive T-cell therapy, cancer vaccines, monoclonal antibodies, immune checkpoint blockade (ICB), and chimeric antigen receptor (CAR) based therapies. However, most of these modalities encounter restrictions in solid tumours owing to a dense, highly hypoxic and immune-suppressive microenvironment as well as the heterogeneity of tumour antigens. The elevated intra-tumoural pressure and mutational rates within fastgrowing solid tumours present challenges in efficient drug targeting and delivery. The tumour microenvironment is a dynamic niche infiltrated by a variety of immune cells, most of which are macrophages. Since they form a part of the innate immune system, targeting macrophages has become a plausible immunotherapeutic approach. In this review, we discuss several versatile approaches (both at pre-clinical and clinical stages) such as the direct killing of tumour-associated macrophages, reprogramming pro-tumour macrophages to anti-tumour phenotypes, inhibition of macrophage recruitment into the tumour microenvironment, novel CAR macrophages, and genetically engineered macrophages that have been devised thus far. These strategies comprise a strong and adaptable macrophage-toolkit in the ongoing fight against cancer and by understanding their significance, we may unlock the full potential of these immune cells in cancer therapy.
  20. Breast Cancer Res Treat. 2024 Jun 14.
      PURPOSE: Rapid proliferation and nutrition starvation in the tumor microenvironment pose significant challenges to cellular protein homeostasis. The accumulation of misfolded proteins in the endoplasmic reticulum lumen induces stress on cells and causes irreversible damage to cells if unresolved. Emerging reports emphasize the influence of the tumor microenvironment on therapeutic molecule efficacy and treatment outcomes. Hence, we aimed to understand the influence of tamoxifen on the cellular adaptation to endoplasmic reticulum stress during metabolic stress in breast cancer cells.METHODS: Nutrition deprivation induces endoplasmic reticulum stress (ER stress), and the unfolded protein response (UPR) in breast cancer cells was confirmed by a Thioflavin B assay and western blotting. Tamoxifen-indued ER-phagy was studied using an MCD assay, confocal microscopy, and western blotting.
    RESULTS: Nutrition deprivation induces ER stress in breast cancer cells. Interestingly, tamoxifen modulates the nutrition deprivation-induced endoplasmic reticulum stress through enhancing the selective ER-phagy, a specialized autophagy. The tamoxifen-induced ER-phagy is mediated by AMPK activation. The pharmacological inhibition of AMPK blocks tamoxifen-induced ER-phagy and tamoxifen modulatory effect on ER stress during nutrition deprivation.
    CONCLUSION: Tamoxifen modulates ER stress by inducing ER-phagy through AMPK, thereby, may support breast cancer cell survival during nutrition deprivation conditions.
    Keywords:  AMPK; Breast cancer; ER stress; ER-phagy; Nutrition deprivation; Tamoxifen
  21. Ups J Med Sci. 2024 ;129
      Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population recognized as a key component of the tumour microenvironment (TME). Cancer-associated fibroblasts are known to play an important role in maintaining and remodelling the extracellular matrix (ECM) in the tumour stroma, supporting cancer progression and inhibiting the immune system's response against cancer cells. This review aims to summarize the immunomodulatory roles of CAFs, particularly focussing on their T-cell suppressive effects. Cancer-associated fibroblasts have several ways by which they can affect the tumour's immune microenvironment (TIME). For example, their interactions with macrophages and dendritic cells (DCs) create an immunosuppressive milieu that can indirectly affect T-cell anticancer immunity and enable immune evasion. In addition, a number of recent studies have confirmed CAF-mediated direct suppressive effects on T-cell anticancer capacity through ECM remodelling, promoting the expression of immune checkpoints, cytokine secretion and the release of extracellular vesicles. The consequential impact of CAFs on T-cell function is then reflected in affecting T-cell proliferation and apoptosis, migration and infiltration, differentiation and exhaustion. Emerging evidence highlights the existence of specific CAF subsets with distinct capabilities to modulate the immune landscape of TME in various cancers, suggesting the possibility of their exploitation as possible prognostic biomarkers and therapeutic targets.
    Keywords:  Cancer associated fibroblasts (CAF); T-cells; tumour immunity; tumour microenvironment (TME)
  22. Cancer Cell. 2024 Jun 10. pii: S1535-6108(24)00186-7. [Epub ahead of print]42(6): 934-936
      In this issue of Cancer Cell, Zhong et al. explore the dual role of TREM2 in glioblastoma-associated myeloid cells, demonstrating its function in promoting inflammation at the tumor-neural interface and suppression within the tumor core, influenced by the local microenvironment. These findings open up promising prospects for advancements in neuro-oncological immunotherapy.
  23. Cancer Cell. 2024 Jun 06. pii: S1535-6108(24)00190-9. [Epub ahead of print]
      Bacteria exhibit key features of cancer metastasis, such as motility, invasion, and modulation of the tumor microenvironment. They migrate through lymphatic and blood systems, invade metastatic tissues, and alter local microenvironments to support metastatic growth. Bacteria also shape the tumor microenvironment, affecting immune responses and inflammation, which influence tumor progression and therapy response. While they hold therapeutic potential, challenges like contamination and complex characterization persist, necessitating advanced sequencing and research for clinical application.
  24. Adv Mater. 2024 Jun 08. e2401495
      The tumor microenvironment (TME) of typical tumor types such as triple-negative breast cancer is featured by hypoxia and immunosuppression with abundant tumor-associated macrophages (TAMs), which also emerge as potential therapeutic targets for antitumor therapy. M1-like macrophage-derived exosomes (M1-Exos) have emerged as a promising tumor therapeutic candidate for their tumor-targeting and macrophage-polarization capabilities. However, the limited drug-loading efficiency and stability of M1-Exos have hindered their effectiveness in antitumor applications. In this study, we have developed a hybrid nanovesicle by integrating M1-Exos with AS1411 aptamer-conjugated liposomes (AApt-Lips), termed M1E/AALs. The obtained M1E/AALs are loaded with PFTBA and IR780, as P-Is, to construct P-I@M1E/AALs for reprogramming TME by alleviating tumor hypoxia and engineering TAMs. P-I@M1E/AALs-mediated tumor therapy enhances the in situ generation of reactive oxygen species, repolarizes TAMs toward an antitumor phenotype, and promotes the infiltration of T lymphocytes. The synergistic antitumor therapy based on P-I@M1E/AALs significantly suppresses tumor growth and prolongs the survival of 4T1 tumor-bearing mice. By integrating multiple treatment modalities, P-I@M1E/AALs nanoplatform demonstrates a promising therapeutic approach for overcoming hypoxic and immunosuppressive TME by targeted TAM reprogramming and enhanced tumor photodynamic immunotherapy. This study highlights an innovative TAM-engineering hybrid nanovesicle platform for the treatment of tumors characterized by hypoxic and immunosuppressive TME. This article is protected by copyright. All rights reserved.
    Keywords:  M1‐like macrophage; antitumor therapy; exosome; hypoxia alleviation; tumor microenvironment reprogramming; tumor‐associated macrophage
  25. Int Immunopharmacol. 2024 Jun 07. pii: S1567-5769(24)00926-3. [Epub ahead of print]136 112406
      Tumor-associated macrophages (TAMs) exert profound influences on cancer progression, orchestrating a dynamic interplay within the tumor microenvironment. Recent attention has focused on the role of TAM-derived exosomes, small extracellular vesicles containing bioactive molecules, in mediating this intricate communication. This review comprehensively synthesizes current knowledge, emphasizing the diverse functions of TAM-derived exosomes across various cancer types. The review delves into the impact of TAM-derived exosomes on fundamental cancer hallmarks, elucidating their involvement in promoting cancer cell proliferation, migration, invasion, and apoptosis evasion. By dissecting the molecular cargo encapsulated within these exosomes, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and proteins, the review uncovers key regulatory mechanisms governing these effects. Noteworthy miRNAs, such as miR-155, miR-196a-5p, and miR-221-3p, are highlighted for their pivotal roles in mediating TAM-derived exosomal communication and influencing downstream targets. Moreover, the review explores the impact of TAM-derived exosomes on the immune microenvironment, particularly their ability to modulate immune cell function and foster immune evasion. The discussion encompasses the regulation of programmed cell death ligand 1 (PD-L1) expression and subsequent impairment of CD8 + T cell activity, unraveling the immunosuppressive effects of TAM-derived exosomes. With an eye toward clinical implications, the review underscores the potential of TAM-derived exosomes as diagnostic markers and therapeutic targets. Their involvement in cancer progression, metastasis, and therapy resistance positions TAM-derived exosomes as key players in reshaping treatment strategies. Finally, the review outlines future directions, proposing avenues for targeted therapies aimed at disrupting TAM-derived exosomal functions and redefining the tumor microenvironment.
    Keywords:  Cancer; Exosome; Extracellular vesicle; Therapeutic approach; Tumor-associated macrophages
  26. Trends Immunol. 2024 Jun 13. pii: S1471-4906(24)00120-0. [Epub ahead of print]
      Immunotherapies have revolutionized the treatment of certain cancers, but challenges remain in overcoming immunotherapy resistance. Research shows that metabolic modulation of the tumor microenvironment can enhance antitumor immunity. Here, we discuss recent preclinical and clinical evidence for the efficacy of combining metabolic modifiers with immunotherapies. While this combination holds great promise, a few key areas must be addressed, which include identifying the effects of metabolic modifiers on immune cell metabolism, the putative biomarkers of therapeutic efficacy, the efficacy of modifiers on tumors harboring metabolic heterogeneity, and the potential development of resistance due to tumor reliance on alternative metabolic pathways. We propose solutions to these problems and posit that assessing these parameters is crucial for considering the potential of metabolic modifiers in sensitizing tumors to immunotherapies.
    Keywords:  immunotherapy; immunotherapy resistance; metabolic reprogramming
  27. Clin Exp Med. 2024 Jun 10. 24(1): 122
      Regulatory T cells (Tregs) are known to facilitate tumor progression by suppressing CD8+ T cells within the tumor microenvironment (TME), thereby also hampering the effectiveness of immune checkpoint inhibitors (ICIs). While systemic depletion of Tregs can enhance antitumor immunity, it also triggers undesirable autoimmune responses. Therefore, there is a need for therapeutic agents that selectively target Tregs within the TME without affecting systemic Tregs. In this study, as shown also by others, the chemokine (C-C motif) receptor 8 (CCR8) was found to be predominantly expressed on Tregs within the TME of both humans and mice, representing a unique target for selective depletion of tumor-residing Tregs. Based on this, we developed BAY 3375968, a novel anti-human CCR8 antibody, along with respective surrogate anti-mouse CCR8 antibodies, and demonstrated their in vitro mode-of-action through induction of potent antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) activities. In vivo, anti-mouse CCR8 antibodies effectively depleted Tregs within the TME primarily via ADCP, leading to increased CD8+ T cell infiltration and subsequent tumor growth inhibition across various cancer models. This monotherapeutic efficacy was significantly enhanced in combination with ICIs. Collectively, these findings suggest that CCR8 targeting represents a promising strategy for Treg depletion in cancer therapies. BAY 3375968 is currently under investigation in a Phase I clinical trial (NCT05537740).
    Keywords:  Cancer immunotherapy; Chemokine receptor 8; Immunosuppression; Monoclonal antibody; Regulatory T cells
  28. bioRxiv. 2024 Jun 02. pii: 2024.05.29.596456. [Epub ahead of print]
      Introduction: The majority of ovarian cancer (OC) patients receiving standard of care chemotherapy develop chemoresistance within 5 years. The tumor microenvironment (TME) is a dynamic and influential player in disease progression and therapeutic response. However, there is a lack of models that allow us to elucidate the compartmentalized nature of TME in a controllable, yet physiologically relevant manner and its critical role in modulating drug resistance.Methods: We developed a 3D microvascularized multiniche tumor-on-a-chip formed by five chambers (central cancer chamber, flanked by two lateral stromal chambers and two external circulation chambers) to recapitulate OC-TME compartmentalization and study its influence on drug resistance. Stromal chambers included endothelial cells alone or cocultured with normal fibroblasts or cancer-associated fibroblasts (CAF).
    Results: The tumor-on-a-chip recapitulated spatial TME compartmentalization including vessel-like structure, stromal-mediated extracellular matrix (ECM) remodeling, generation of oxygen gradients, and delayed drug diffusion/penetration from the circulation chamber towards the cancer chamber. The cancer chamber mimicked metastasis-like migration and increased drug resistance to carboplatin/paclitaxel treatment in the presence of CAF when compared to normal fibroblasts. CAF-mediated drug resistance was rescued by ECM targeted therapy. Critically, these results demonstrate that cellular crosstalk recreation and spatial organization through compartmentalization are essential to determining the effect of the compartmentalized OC-TME on drug resistance.
    Conclusions: Our results present a functionally characterized microvascularized multiniche tumor-on-a-chip able to recapitulate TME compartmentalization influencing drug resistance. This technology holds the potential to guide the design of more effective and targeted therapeutic strategies to overcome chemoresistance in OC.
  29. J Hematol Oncol. 2024 Jun 11. 17(1): 44
      Macrophages infiltrating tumour tissues or residing in the microenvironment of solid tumours are known as tumour-associated macrophages (TAMs). These specialized immune cells play crucial roles in tumour growth, angiogenesis, immune regulation, metastasis, and chemoresistance. TAMs encompass various subpopulations, primarily classified into M1 and M2 subtypes based on their differentiation and activities. M1 macrophages, characterized by a pro-inflammatory phenotype, exert anti-tumoural effects, while M2 macrophages, with an anti-inflammatory phenotype, function as protumoural regulators. These highly versatile cells respond to stimuli from tumour cells and other constituents within the tumour microenvironment (TME), such as growth factors, cytokines, chemokines, and enzymes. These stimuli induce their polarization towards one phenotype or another, leading to complex interactions with TME components and influencing both pro-tumour and anti-tumour processes.This review comprehensively and deeply covers the literature on macrophages, their origin and function as well as the intricate interplay between macrophages and the TME, influencing the dual nature of TAMs in promoting both pro- and anti-tumour processes. Moreover, the review delves into the primary pathways implicated in macrophage polarization, examining the diverse stimuli that regulate this process. These stimuli play a crucial role in shaping the phenotype and functions of macrophages. In addition, the advantages and limitations of current macrophage based clinical interventions are reviewed, including enhancing TAM phagocytosis, inducing TAM exhaustion, inhibiting TAM recruitment, and polarizing TAMs towards an M1-like phenotype. In conclusion, while the treatment strategies targeting macrophages in precision medicine show promise, overcoming several obstacles is still necessary to achieve an accessible and efficient immunotherapy.
    Keywords:  Cancer cell; Immunity; Immunotherapy; Polarization; Tumour microenvironment; Tumour-associated macrophages
  30. Front Oncol. 2024 ;14 1388700
      Malignant gliomas are one of the most common and lethal brain tumors with poor prognosis. Most patients with glioblastoma (GBM) die within 2 years of diagnosis, even after receiving standard treatments including surgery combined with concomitant radiotherapy and chemotherapy. Temozolomide (TMZ) is the first-line chemotherapeutic agent for gliomas, but the frequent acquisition of chemoresistance generally leads to its treatment failure. Thus, it's urgent to investigate the strategies for overcoming glioma chemoresistance. Currently, many studies have elucidated that cancer chemoresistance is not only associated with the high expression of drug-resistance genes in glioma cells but also can be induced by the alterations of the tumor microenvironment (TME). Numerous studies have explored the use of antifibrosis drugs to sensitize chemotherapy in solid tumors, and surprisingly, these preclinical and clinical attempts have exhibited promising efficacy in treating certain types of cancer. However, it remains unclear how tumor-associated fibrotic alterations in the glioma microenvironment (GME) mediate chemoresistance. Furthermore, the possible mechanisms behind this phenomenon are yet to be determined. In this review, we have summarized the molecular mechanisms by which tumor-associated fibrotic reactions drive glioma transformation from a chemosensitive to a chemoresistant state. Additionally, we have outlined antitumor drugs with antifibrosis functions, suggesting that antifibrosis strategies may be effective in overcoming glioma chemoresistance through TME normalization.
    Keywords:  antifibrosis therapy; cancer-associate fibroblasts; chemoresistance; glioma; tumor microenvironment (TME); tumor-associated fibrotic reaction