bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–12–22
24 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Functional heterogeneity of fibroblasts in primary tumors and metastases.
  2. MDSC: a new potential breakthrough in CAR-T therapy for solid tumors.
  3. Targeting extracellular matrix stiffness for cancer therapy.
  4. Immune checkpoints in B-cell Lymphoma: Still an Unmet challenge from Basic research to clinical practice.
  5. Plasticity and Tumor Microenvironment in Pancreatic Cancer: Genetic, Metabolic, and Immune Perspectives.
  6. The Two Faces of Angiopoietin-Like Protein 2 in Cancer.
  7. Cancer-associated fibroblasts: heterogeneity, tumorigenicity and therapeutic targets.
  8. Research progress on ferroptosis regulation in tumor immunity of hepatocellular carcinoma.
  9. How to Use Macrophages Against Cancer.
  10. Recent Advances of Small Extracellular Vesicles for the Regulation and Function of Cancer-Associated Fibroblasts.
  11. Metabolic immunoengineering approaches to enhance CD8+ T cell-based cancer immunotherapy.
  12. Tumor Microenvironment Drives the Cross-Talk Between Co-Stimulatory and Inhibitory Molecules in Tumor-Infiltrating Lymphocytes: Implications for Optimizing Immunotherapy Outcomes.
  13. Regulation of Stromal Cells by Sex Steroid Hormones in the Breast Cancer Microenvironment.
  14. Current status of research on the mechanisms of tumor-associated macrophages in esophageal cancer progression.
  15. Emerging nanomedicines for macrophage-mediated cancer therapy.
  16. Disrupting Notch signaling related HES1 in myeloid cells reinvigorates antitumor T cell responses.
  17. The possible anti-tumor effects of regulatory T cells plasticity / IL-35 in the tumor microenvironment of the major three cancer types.
  18. Cancer-associated fibroblasts, tumor and radiotherapy: interactions in the tumor micro-environment.
  19. The Hippo Pathway in Breast Cancer: The Extracellular Matrix and Hypoxia.
  20. CB2R activation enhances tumor-associated macrophages-mediated phagocytosis of glioma cell.
  21. Spatial organization and stochastic fluctuations of immune cells impact clinical responsiveness to immunotherapy in melanoma patients.
  22. Pathobiological Features and Therapeutic Opportunities Linked to TNF Family Member Expression in Classic Hodgkin Lymphoma.
  23. Berberine shaping the tumor immune landscape via pyroptosis.
  24. IL-17A in gastric carcinogenesis: good or bad?
  1. Trends Cancer. 2024 Dec 13. pii: S2405-8033(24)00260-7. [Epub ahead of print]
    Functional heterogeneity of fibroblasts in primary tumors and metastases.
    Priscilla S W Cheng, Marta Zaccaria, Giulia Biffi.
      Cancer-associated fibroblasts (CAFs) are abundant components of the tumor microenvironment (TME) of most solid malignancies and have emerged as key regulators of cancer progression and therapy response. Although recent technological advances have uncovered substantial CAF molecular heterogeneity at the single-cell level, defining functional roles for most described CAF populations remains challenging. With the aim of bridging CAF molecular and functional heterogeneity, this review focuses on recently identified functional interactions of CAF subtypes with malignant cells, immune cells, and other stromal cells in primary tumors and metastases. Dissecting the heterogeneous functional crosstalk of specific CAF populations with other components is starting to uncover candidate combinatorial strategies for therapeutically targeting the TME and cancer progression.
    Keywords:  cancer-associated fibroblasts; fibroblast heterogeneity; metastases; primary tumors; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2024.11.005
  2. Cell Commun Signal. 2024 Dec 19. 22(1): 612
    MDSC: a new potential breakthrough in CAR-T therapy for solid tumors.
    Nada Mohamady Farouk Abdalsalam, Abdulrahman Ibrahim, Muhammad Auwal Saliu, Tzu-Ming Liu, Xiaochun Wan, Dehong Yan.
      Chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable success in hematologic malignancies but has encountered challenges in effectively treating solid tumors. One major obstacle is the presence of the immunosuppressive tumor microenvironment (TME), which is mainly built by myeloid-derived suppressor cells (MDSCs). Recent studies have shown that MDSCs have a detrimental effect on CAR-T cells due to their potent immunosuppressive capabilities. Targeting MDSCs has shown promising results to enhance CAR-T immunotherapy in preclinical solid tumor models. In this review, we first highlight that MDSCs increase tumor proliferation, transition, angiogenesis and encourage circulating tumor cells (CTCs) extravasation leading to tumor progression and metastasis. Moreover, we describe the main characteristics of the immunosuppressive activities of MDSCs on T cells in TME. Most importantly, we summarize targeting therapeutic strategies of MDSCs in CAR-T therapies against solid tumors. These strategies include (1) therapeutic targeting of MDSCs through small molecule inhibitors and large molecule antibodies; (2) CAR-T targeting cancer cell antigen combination with MDSC modulatory agents; (3) cytokine receptor antigen-targeted CAR-T indirectly or directly targeting MDSCs reshapes TME; (4) modified natural killer (NK) cells expressing activating receptor directly targeting MDSCs; and (5) CAR-T directly targeting MDSC selective antigens. In the near future, we are expected to witness the improvement of CAR-T cell therapies for solid tumors by targeting MDSCs in clinical practice.
    Keywords:  Chimeric antigen receptor T (CAR-T); Myeloid-derived suppressor cells (MDSCs); Solid tumor; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1186/s12964-024-01995-y
  3. Front Immunol. 2024 ;15 1467602
    Targeting extracellular matrix stiffness for cancer therapy.
    Xiuqin Feng, Fujun Cao, Xiangji Wu, Wenyan Xie, Ping Wang, Hong Jiang.
      The physical characteristics of the tumor microenvironment (TME) include solid stress, interstitial fluid pressure, tissue stiffness and microarchitecture. Among them, abnormal changes in tissue stiffness hinder drug delivery, inhibit infiltration of immune killer cells to the tumor site, and contribute to tumor resistance to immunotherapy. Therefore, targeting tissue stiffness to increase the infiltration of drugs and immune cells can offer a powerful support and opportunities to improve the immunotherapy efficacy in solid tumors. In this review, we discuss the mechanical properties of tumors, the impact of a stiff TME on tumor cells and immune cells, and the strategies to modulate tumor mechanics.
    Keywords:  immunotherapy; matrix stiffness; mechanical properties; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1467602
  4. Int Immunopharmacol. 2024 Dec 13. pii: S1567-5769(24)02239-2. [Epub ahead of print]146 113717
    Immune checkpoints in B-cell Lymphoma: Still an Unmet challenge from Basic research to clinical practice.
    Sijia Li, Yuanyuan Pan, Ruyu Ye, Yu Wang, Li Li.
      In the last decade, advancements in immunotherapy knowledge have highlighted CTLA-4, PD-1, LAG-3, TIM-3, and TIGIT, decisive immune checkpoints exhibiting within the tumor microenvironment (TME), as fundamental objects for cancer immunotherapy. The widespread clinical use of immune checkpoint inhibitors (ICls), employing PD-1/PD-L1 or CTLA-4 antibodies to obstruct crucial checkpoint regulators, is noted in treating B-cell lymphoma patients. Nevertheless, the prolonged advantages of the currently employed treatments against CTLA-4, PD-1, and PD-L1 are uncommon among patients. Thus, recent focus has been progressively moved to additional immune checkpoints on T cells, like LAG-3, TIM-3, and TIGIT, which are now seen as reassuring targets for treatment and broadly acknowledged. There are several types of immunecheckpoint molecules expressed by T cells, and inhibitors targeting immune checkpoints can revive and amplify the immune response of T lymphocytes against tumors, a crucial aspect in lymphoma therapy. However, there is little knowledge about their regulation. Herein, we discuss the anti-tumor effects and functions of ICIs in controlling T-cell activity, as well as the progress in combined application with other immunotherapies.
    Keywords:  B-cell lymphoma; CTLA-4; LAG-3; PD-1; TIGIT; TIM-3
    DOI:  https://doi.org/10.1016/j.intimp.2024.113717
  5. Cancers (Basel). 2024 Dec 06. pii: 4094. [Epub ahead of print]16(23):
    Plasticity and Tumor Microenvironment in Pancreatic Cancer: Genetic, Metabolic, and Immune Perspectives.
    Ari Hashimoto, Shigeru Hashimoto.
      Cancer has long been believed to be a genetic disease caused by the accumulation of mutations in key genes involved in cellular processes. However, recent advances in sequencing technology have demonstrated that cells with cancer driver mutations are also present in normal tissues in response to aging, environmental damage, and chronic inflammation, suggesting that not only intrinsic factors within cancer cells, but also environmental alterations are important key factors in cancer development and progression. Pancreatic cancer tissue is mostly comprised of stromal cells and immune cells. The desmoplasmic microenvironment characteristic of pancreatic cancer is hypoxic and hypotrophic. Pancreatic cancer cells may adapt to this environment by rewiring their metabolism through epigenomic changes, enhancing intrinsic plasticity, creating an acidic and immunosuppressive tumor microenvironment, and inducing noncancerous cells to become tumor-promoting. In addition, pancreatic cancer has often metastasized to local and distant sites by the time of diagnosis, suggesting that a similar mechanism is operating from the precancerous stage. Here, we review key recent findings on how pancreatic cancers acquire plasticity, undergo metabolic reprogramming, and promote immunosuppressive microenvironment formation during their evolution. Furthermore, we present the following two signaling pathways that we have identified: one based on the small G-protein ARF6 driven by KRAS/TP53 mutations, and the other based on the RNA-binding protein Arid5a mediated by inflammatory cytokines, which promote both metabolic reprogramming and immune evasion in pancreatic cancer. Finally, the striking diversity among pancreatic cancers in the relative importance of mutational burden and the tumor microenvironment, their clinical relevance, and the potential for novel therapeutic strategies will be discussed.
    Keywords:  ARF6; Arid5a; PDAC; metabolic reprogramming; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/cancers16234094
  6. Cancer Sci. 2024 Dec 17.
    The Two Faces of Angiopoietin-Like Protein 2 in Cancer.
    Haruki Horiguchi, Tsuyoshi Kadomatsu, Yuichi Oike.
      The tumor microenvironment is composed of tumor cells and various stromal cell types, such as immune cells, fibroblasts, and vascular cells. Signaling interactions between tumor and stromal cells orchestrate the tumor microenvironment's contribution to tumor progression. Angiopoietin-like protein 2 (ANGPTL2) is a secreted glycoprotein homologous to angiopoietins. Previous studies indicate that tumor cell-derived ANGPTL2 serves as a tumor promoter. However, recent studies suggest that tumor stroma-derived ANGPTL2 shows tumor-suppressive activity by enhancing anti-tumor immune responses, supporting a dual function for ANGPTL2 in cancer pathology. Such complexity can complicate development of effective therapeutic strategies targeting ANGPTL2. In this Review, we focus on ANGPTL2 activity in the tumor microenvironment and its function in anti-cancer immunity.
    Keywords:  angiopoietin‐like protein 2; cancer immunity; cancer immunotherapy; cancer‐associated fibroblast; tumor microenvironment
    DOI:  https://doi.org/10.1111/cas.16434
  7. Mol Biomed. 2024 Dec 16. 5(1): 70
    Cancer-associated fibroblasts: heterogeneity, tumorigenicity and therapeutic targets.
    Keke Lv, Tianlin He.
      Cancer, characterized by its immune evasion, active metabolism, and heightened proliferation, comprises both stroma and cells. Although the research has always focused on parenchymal cells, the non-parenchymal components must not be overlooked. Targeting cancer parenchymal cells has proven to be a formidable challenge, yielding limited success on a broad scale. The tumor microenvironment(TME), a critical niche for cancer cell survival, presents a novel way for cancer treatment. Cancer-associated fibroblast (CAF), as a main component of TME, is a dynamically evolving, dual-functioning stromal cell. Furthermore, their biological activities span the entire spectrum of tumor development, metastasis, drug resistance, and prognosis. A thorough understanding of CAFs functions and therapeutic advances holds significant clinical implications. In this review, we underscore the heterogeneity of CAFs by elaborating on their origins, types and function. Most importantly, by elucidating the direct or indirect crosstalk between CAFs and immune cells, the extracellular matrix, and cancer cells, we emphasize the tumorigenicity of CAFs in cancer. Finally, we highlight the challenges encountered in the exploration of CAFs and list targeted therapies for CAF, which have implications for clinical treatment.
    Keywords:  Cancer associated fibroblasts; Cancer cell; Cancer targeting therapy; Extracellular matrix; Immune cells; Mechanisms; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s43556-024-00233-8
  8. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2024 Dec 18. 1-11
    Research progress on ferroptosis regulation in tumor immunity of hepatocellular carcinoma.
    Yuqian Mo, Zhilin Zou, Erbao Chen.
      Ferroptosis is a form of regulated cell death, which is dependent on iron metabolism imbalance and characterized by lipid peroxidation; it plays a crucial role in various pathological processes. Studies have shown that the occurrence of ferroptosis is closely associated with the progression of hepatocellular carcinoma (HCC). Ferroptosis is involved in regulating the lipid metabolism, iron homeostasis, mitochondrial metabolism, and redox processes in HCC. Additionally, ferroptosis plays a key role in HCC tumor immunity by modulating the phenotype and function of various immune cells in the tumor microenvironment, affecting tumor immune escape and progression. Ferroptosis-induced lipid peroxidation and oxidative stress can promote the polarization of M1 macrophages and enhance the pro-inflammatory response in tumors, inhibiting immune suppressive cells such as myeloid-derived suppressor cells and Treg cells to disrupt their immune suppression function. The expression regulation of ferroptosis-related molecules such as GPX4 and SLC7A11 not only affects the sensitivity of tumor cells to immunotherapy but also directly influences the activity and survival of effector cells such as T cells and dendritic cells, further enhancing or weakening host anti-tumor immune response. Targeting ferroptosis has demonstrated significant clinical potential in HCC treatment. Induction of ferroptosis by nanomedicine and molecular targeting strategies can directly kills tumor cells or enhances antitumor immune responses. The integration of multimodal therapies with immunotherapy further expands the application of targeting ferroptosis as a cancer therapy. This article reviews the relationship between ferroptosis and anti-tumor immune responses and the role of ferroptosis in HCC progression from the perspective of tumor immune microenvironment, to provide insights for the development of anti-tumor immune therapies based on targeting ferroptosis.
    Keywords:  Ferroptosis; Hepatocellular carcinoma; Immune microenvironment; Immunotherapy; Review; Tumor immunity
    DOI:  https://doi.org/10.3724/zdxbyxb-2024-0117
  9. Cells. 2024 Nov 23. pii: 1948. [Epub ahead of print]13(23):
    How to Use Macrophages Against Cancer.
    Jacek Kuźnicki, Natalia Janicka, Barbara Białynicka-Birula, Wojciech Kuźnicki, Hanna Chorążyczewska, Iwona Deszcz, Julita Kulbacka.
      Numerous studies have demonstrated the significant influence of immune cells on cancer development and treatment. This study specifically examines tumor-associated macrophages (TAMs), detailing their characteristics and roles in tumorigenesis and analyzing the impact of the ratio of TAM subtypes on patient survival and prognosis. It is established that TAMs interact with immunotherapy, radiotherapy, and chemotherapy, thereby influencing the efficacy of these treatments. Emerging therapies are explored, such as the use of nanoparticles (NPs) for drug delivery to target TAMs and modify the tumor microenvironment (TME). Additionally, novel anticancer strategies like the use of chimeric antigen receptor macrophages (CAR-Ms) show promising results. Investigations into the training of macrophages using magnetic fields, plasma stimulation, and electroporation are also discussed. Finally, this study presents prospects for the combination of TAM-based therapies for enhanced cancer treatment outcomes.
    Keywords:  TAM subtype impact; cancer immunotherapy; combined cancer therapies; tumor microenvironment (TME); tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.3390/cells13231948
  10. Int J Mol Sci. 2024 Nov 22. pii: 12548. [Epub ahead of print]25(23):
    Recent Advances of Small Extracellular Vesicles for the Regulation and Function of Cancer-Associated Fibroblasts.
    Chengdong Liang, Maoye Wang, Yongli Huang, Judy Wai Ping Yam, Xu Zhang, Xiaoxin Zhang.
      Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population in the tumor microenvironment (TME) that critically affect cancer progression. Small extracellular vesicles (sEVs) act as information messengers by transmitting a wide spectrum of biological molecules, including proteins, nucleic acids, and metabolites, from donor cells to recipient cells. Previous studies have demonstrated that CAFs play important roles in tumor progression by regulating tumor cell proliferation, metastasis, therapeutic resistance, and metabolism via sEVs. In turn, tumor-derived sEVs can also regulate the activation and phenotype switch of CAFs. The dynamic crosstalk between CAFs and cancer cells via sEVs could ultimately determine cancer progression. In this review, we summarized the recent advance of the biological roles and underlying mechanisms of sEVs in mediating CAF-tumor cell interaction and its impact on cancer progression. We also reviewed the clinical applications of tumor- and CAF-derived sEVs, which could identify novel potential targets and biomarkers for cancer diagnosis, therapy, and prognosis.
    Keywords:  cancer-associated fibroblasts; crosstalk; small extracellular vesicles
    DOI:  https://doi.org/10.3390/ijms252312548
  11. Cell Syst. 2024 Dec 18. pii: S2405-4712(24)00346-6. [Epub ahead of print]15(12): 1225-1244
    Metabolic immunoengineering approaches to enhance CD8+ T cell-based cancer immunotherapy.
    Bing Feng, Rongrong Li, Weilin Li, Li Tang.
      Many cancer immunotherapies rely on robust CD8+ T cells capable of eliminating cancer cells and establishing long-term tumor control. Recent insights into immunometabolism highlight the importance of nutrients and metabolites in T cell activation and differentiation. Within the tumor microenvironment (TME), CD8+ tumor-infiltrating lymphocytes (TILs) undergo metabolic adaptations to survive but compromise their effector function and differentiation. Targeting metabolism holds promise for enhancing CD8+ T cell-mediated antitumor immunity. Here, we overview the metabolic features of CD8+ TILs and their impact on T cell effector function and differentiation. We also highlight immunoengineering strategies by leveraging the Yin-Yang of metabolic modulation for improving cancer immunotherapy.
    Keywords:  CD8(+) T cell; cancer immunotherapy; metabolic immunoengineering
    DOI:  https://doi.org/10.1016/j.cels.2024.11.010
  12. Int J Mol Sci. 2024 Nov 29. pii: 12848. [Epub ahead of print]25(23):
    Tumor Microenvironment Drives the Cross-Talk Between Co-Stimulatory and Inhibitory Molecules in Tumor-Infiltrating Lymphocytes: Implications for Optimizing Immunotherapy Outcomes.
    Ornella Franzese.
      This review explores some of the complex mechanisms underlying antitumor T-cell response, with a specific focus on the balance and cross-talk between selected co-stimulatory and inhibitory pathways. The tumor microenvironment (TME) fosters both T-cell activation and exhaustion, a dual role influenced by the local presence of inhibitory immune checkpoints (ICs), which are exploited by cancer cells to evade immune surveillance. Recent advancements in IC blockade (ICB) therapies have transformed cancer treatment. However, only a fraction of patients respond favorably, highlighting the need for predictive biomarkers and combination therapies to overcome ICB resistance. A crucial aspect is represented by the complexity of the TME, which encompasses diverse cell types that either enhance or suppress immune responses. This review underscores the importance of identifying the most critical cross-talk between inhibitory and co-stimulatory molecules for developing approaches tailored to patient-specific molecular and immune profiles to maximize the therapeutic efficacy of IC inhibitors and enhance clinical outcomes.
    Keywords:  T cells; T-cell activation; axis; co-stimulatory molecules; cross-talk; immune checkpoint; immune checkpoint blockade; inhibitory molecules; tumor micro-environment
    DOI:  https://doi.org/10.3390/ijms252312848
  13. Cancers (Basel). 2024 Dec 02. pii: 4043. [Epub ahead of print]16(23):
    Regulation of Stromal Cells by Sex Steroid Hormones in the Breast Cancer Microenvironment.
    Mio Yamaguchi-Tanaka, Kiyoshi Takagi, Ai Sato, Yuto Yamazaki, Minoru Miyashita, Atsushi Masamune, Takashi Suzuki.
      Breast cancer is a prevalent hormone-dependent malignancy, and estrogens/estrogen receptor (ER) signaling are pivotal therapeutic targets in ER-positive breast cancers, where endocrine therapy has significantly improved treatment efficacy. However, the emergence of both de novo and acquired resistance to these therapies continues to pose challenges. Additionally, androgens are produced locally in breast carcinoma tissues by androgen-producing enzymes, and the androgen receptor (AR) is commonly expressed in breast cancer cells. Intratumoral androgens play a significant role in breast cancer progression and are closely linked to resistance to endocrine treatments. The tumor microenvironment, consisting of tumor cells, immune cells, fibroblasts, extracellular matrix, and blood vessels, is crucial for tumor progression. Stromal cells influence tumor progression through direct interactions with cancer cells, the secretion of soluble factors, and modulation of tumor immunity. Estrogen and androgen signaling in breast cancer cells affects the tumor microenvironment, and the expression of hormone receptors correlates with the diversity of the stromal cell profile. Notably, various stromal cells also express ER or AR, which impacts breast cancer development. This review describes how sex steroid hormones, particularly estrogens and androgens, affect stromal cells in the breast cancer microenvironment. We summarize recent findings focusing on the effects of ER/AR signaling in breast cancer cells on stromal cells, as well as the direct effects of ER/AR signaling in stromal cells.
    Keywords:  androgen; breast cancer; estrogen; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers16234043
  14. Front Oncol. 2024 ;14 1450603
    Current status of research on the mechanisms of tumor-associated macrophages in esophageal cancer progression.
    Yuchao Tang, Tingting Shi, Shu Lin, Taiyong Fang.
      Esophageal carcinoma (EC) is one of the most common tumors in China and seriously affects patient survival and quality of life. In recent years, increasing studies have shown that the tumor microenvironment is crucial in promoting tumor progression and metastasis. Tumor-associated macrophages (TAM) are key components of the tumor immune microenvironment and promote both tumor growth and antitumor immunity. Much evidence suggests that TAMs are closely associated with esophageal tumors. However, understanding of the clinical value and mechanism of action of TAM in esophageal cancer remains limited. Therefore, we reviewed the status of research on the role and mechanism of action of TAM in EC progression and summarized its potential clinical application value to provide a theoretical basis for the clinical treatment of EC.
    Keywords:  clinical treatment; esophageal carcinoma; mechanism; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fonc.2024.1450603
  15. Biomaterials. 2024 Dec 15. pii: S0142-9612(24)00564-7. [Epub ahead of print]316 123028
    Emerging nanomedicines for macrophage-mediated cancer therapy.
    Xueying Shi, Syed Faheem Askari Rizvi, Yinxian Yang, Gang Liu.
      Tumor-associated macrophages (TAMs) contribute to tumor progression by promoting angiogenesis, remodeling the tumor extracellular matrix, inducing tumor invasion and metastasis, as well as immune evasion. Due to the high plasticity of TAMs, they can polarize into different phenotypes with distinct functions, which are primarily categorized as the pro-inflammatory, anti-tumor M1 type, and the anti-inflammatory, pro-tumor M2 type. Notably, anti-tumor macrophages not only directly phagocytize tumor cells, but also present tumor-specific antigens and activate adaptive immunity. Therefore, targeted regulation of TAMs to unleash their potential anti-tumor capabilities is crucial for improving the efficacy of cancer immunotherapy. Nanomedicine serves as a promising vehicle and can inherently interact with TAMs, hence, emerging as a new paradigm in cancer immunotherapy. Due to their controllable structures and properties, nanomedicines offer a plethora of advantages over conventional drugs, thus enhancing the balance between efficacy and toxicity. In this review, we provide an overview of the hallmarks of TAMs and discuss nanomedicines for targeting TAMs with a focus on inhibiting recruitment, depleting and reprogramming TAMs, enhancing phagocytosis, engineering macrophages, as well as targeting TAMs for tumor imaging. We also discuss the challenges and clinical potentials of nanomedicines for targeting TAMs, aiming to advance the exploitation of nanomedicine for cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Macrophage polarization; Nanomedicine and nanomaterials; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.biomaterials.2024.123028
  16. Exp Hematol Oncol. 2024 Dec 19. 13(1): 122
    Disrupting Notch signaling related HES1 in myeloid cells reinvigorates antitumor T cell responses.
    Myung Sup Kim, Hyeokgu Kang, Jung-Hwan Baek, Moon-Gyu Cho, Eun Joo Chung, Seok-Jun Kim, Joon-Yong Chung, Kyung-Hee Chun.
       BACKGROUND: Tumor-associated macrophages (TAMs) are immunosuppressive cells within the tumor microenvironment (TME) that hinder anti-tumor immunity. Notch signaling is a pathway crucial for TAM differentiation and function. Here, we investigate the role of HES1, a downstream target of Notch signaling, in TAM-mediated immunosuppression and explore its potential as a target for cancer immunotherapy.
    METHODS: In this work, we constructed conditional Hes1 knockout mice to selectively delete Hes1 in TAMs. We further analyzed the TME composition, T cell infiltration and activation, and anti-tumor effects in these mice, both alone and in combination with PD-1 checkpoint blockade.
    RESULTS: Our study showed that expression levels of Notch target Hes1 were increase in TAMs and mice with conditional knockout of Hes1 gene in TAMs exhibited decreased tumor growth, with increased infiltration and activation of cytotoxic T cells in tumors. Expression of tumor promoting factors was critically altered in Hes1-conditional KO TAMs, leading to the improved tumor microenvironment. Notably, arginase-1 expression was decreased in Hes1-conditional KO mice. Arg1 is known to deplete arginine and deactivate T cells in the TME. Administration of anti-PD-1 monoclonal antibody inhibited tumor growth to a greater extent in Hes1-conditional KO mice than in WT mice.
    CONCLUSIONS: We identified a pivotal role for the Notch signaling pathway in shaping TAM function, suggesting that T-cell dysfunction in the TME is caused when the Notch target, HES1, in TAMs is upregulated by tumor-associated factors (TAFs), which, in turn, increases the expression of arginase-1. Targeting HES1 in TAMs appears to be a promising strategy for cancer immunotherapy.
    DOI:  https://doi.org/10.1186/s40164-024-00588-2
  17. Cytokine. 2024 Dec 17. pii: S1043-4666(24)00338-7. [Epub ahead of print]186 156834
    The possible anti-tumor effects of regulatory T cells plasticity / IL-35 in the tumor microenvironment of the major three cancer types.
    Rehab G Khalil, Dina A Mohammed, Hadeer M Hamdalla, Osama M Ahmed.
      T lymphocytes are among the immunological cells that make up the tumor microenvironment (TME), and they are essential in the growth of tumors and anti-tumor reactions. Regulatory T cells (Treg cells) are a subset of CD4+ T cells in the immune system that suppress the immune system. They are distinguished by their expression of the master transcription factor forkhead box protein P3 (FOXP3). Furthermore, Treg cells are essential for maintaining immunological homeostasis, inhibiting inflammation, and maintaining self-tolerance. In a variety of malignancies within the TME, Treg cells demonstrate notable flexibility and functional diversity. Highly plastic Treg cells can change into Th-like Treg cells in specific circumstances, which allow them to secrete particular pro-inflammatory cytokines. Interleukin 35 (IL-35) is a part of the immunosuppressive cytokines that belong to the IL-12 family. Treg cells release IL-35, which was elevated in the peripheral blood and TME of numerous cancer patients, implying that IL-35 in the TME may be an intriguing target for cancer therapy. In cancer, IL-35 is a two-edged sword; it promotes tumorigenicity in cancer cells while shielding them from apoptosis. Nonetheless, other investigations have mentioned its conflicting effects on cancer prevention. Herein, we provide an updated understanding of the critical mechanisms behind the anticancer immunity mediated by Treg cells plasticity, the role of IL-35, and tactics to strengthen the immune response against malignancies, outlining major clinical trials that used Treg cells/IL-35 therapies in the three main cancer types (lung, breast, and colorectal cancers).
    Keywords:  And colorectal cancer; Breast; Interleukin-35; Lung; Regulatory T cells; Therapeutic role; Treg cells plasticity
    DOI:  https://doi.org/10.1016/j.cyto.2024.156834
  18. J Exp Clin Cancer Res. 2024 Dec 19. 43(1): 323
    Cancer-associated fibroblasts, tumor and radiotherapy: interactions in the tumor micro-environment.
    Kris T P M Raaijmakers, Gosse J Adema, Johan Bussink, Marleen Ansems.
      Cancer-associated fibroblasts (CAFs) represent a group of genotypically non-malignant stromal cells in the tumor micro-environment (TME) of solid tumors that encompasses up to 80% of the tumor volume. Even though the phenotypic diversity and plasticity of CAFs complicates research, it is well-established that CAFs can affect many aspects of tumor progression, including growth, invasion and therapy resistance. Although anti-tumorigenic properties of CAFs have been reported, the majority of research demonstrates a pro-tumorigenic role for CAFs via (in)direct signaling to cancer cells, immunomodulation and extracellular matrix (ECM) remodeling. Following harsh therapeutic approaches such as radio- and/or chemotherapy, CAFs do not die but rather become senescent. Upon conversion towards senescence, many pro-tumorigenic characteristics of CAFs are preserved or even amplified. Senescent CAFs continue to promote tumor cell therapy resistance, modulate the ECM, stimulate epithelial-to-mesenchymal transition (EMT) and induce immunosuppression. Consequently, CAFs play a significant role in tumor cell survival, relapse and potentially malignant transformation of surviving cancer cells following therapy. Modulating CAF functioning in the TME therefore is a critical area of research. Proposed strategies to enhance therapeutic efficacy include reverting senescent CAFs towards a quiescent phenotype or selectively targeting (non-)senescent CAFs. In this review, we discuss CAF functioning in the TME before and during therapy, with a strong focus on radiotherapy. In the future, CAF functioning in the therapeutic TME should be taken into account when designing treatment plans and new therapeutic approaches.
    Keywords:  Cancer-associated fibroblasts; Radioresistance; Therapy resistance; Tumor micro-environment
    DOI:  https://doi.org/10.1186/s13046-024-03251-0
  19. Int J Mol Sci. 2024 Nov 29. pii: 12868. [Epub ahead of print]25(23):
    The Hippo Pathway in Breast Cancer: The Extracellular Matrix and Hypoxia.
    Hanyu Yang, Jiaxin Yang, Xiang Zheng, Tianshun Chen, Ranqi Zhang, Rui Chen, Tingting Cao, Fancai Zeng, Qiuyu Liu.
      As one of the most prevalent malignant neoplasms among women globally, the optimization of therapeutic strategies for breast cancer has perpetually been a research hotspot. The tumor microenvironment (TME) is of paramount importance in the progression of breast cancer, among which the extracellular matrix (ECM) and hypoxia are two crucial factors. The alterations of these two factors are predominantly regulated by the Hippo signaling pathway, which promotes tumor invasiveness, metastasis, therapeutic resistance, and susceptibility. Hence, this review focuses on the Hippo pathway in breast cancer, specifically, how the ECM and hypoxia impact the biological traits and therapeutic responses of breast cancer. Moreover, the role of miRNAs in modulating ECM constituents was investigated, and hsa-miR-33b-3p was identified as a potential therapeutic target for breast cancer. The review provides theoretical foundations and potential therapeutic direction for clinical treatment strategies in breast cancer, with the aspiration of attaining more precise and effective treatment alternatives in the future.
    Keywords:  breast cancer; extracellular matrix (ECM); hippo signaling pathway; hypoxia; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/ijms252312868
  20. Heliyon. 2024 Dec 15. 10(23): e40806
    CB2R activation enhances tumor-associated macrophages-mediated phagocytosis of glioma cell.
    Siyuan Lu, Xuezhu Chen, Yang Yang, Junlong Li.
       Background: Cannabinoid administration has demonstrated promising anti-tumor effects for glioblastoma (GBM) by inhibiting glioma cell proliferation and inducing glioma cell death. However, the impact of cannabinoids and endocannabinoid receptors on immune cells within the tumor microenvironment (TME) remains largely unexplored. Tumor-associated macrophages (TAMs), the most abundant immune cells in the TME, and their mediated phagocytosis of tumor cells have shown potential in preclinical xenografts of various human malignancies. This study aimed to investigate the effect and mechanism of endocannabinoid receptor 2 (CB2R) on TAMs-mediated phagocytosis in xenografted mice with GL261-GFP cell lines.
    Methods: We measured the phagocytic activity using immunofluorescence and flow cytometry, and we used the IVIS Spectrum System for bioluminescent imaging to track the growth of the tumor.
    Results: Our findings demonstrated that administering JWH133, a selective CB2R agonist, significantly boosted TAMs-mediated phagocytosis. However, administering AM630, a selective CB2R antagonist, significantly inhibited TAMs-mediated phagocytosis. Mechanistically, CB2R activation upregulated the expression of CD36 on TAMs, a scavenger receptor known to facilitate phagocytosis. Furthermore, sulfo-N-succinimidyl oleate (SSO), an irreversible CD36 inhibitor, could reverse the CB2R activation-induced enhancement of phagocytosis by TAMs. Additionally. JHW133 also effectively augmented the chemotherapeutic efficacy of temozolomide.
    Conclusion: Overall, our findings show that CB2R activation promotes TAMs-mediated phagocytosis of tumor cells by enhancing CD36 expression, implying that JWH133 could be a useful therapeutic approach to improving chemotherapeutic efficacy against GBM.
    Keywords:  CD36; Cannabinoid receptor 2; JWH133; Phagocytosis; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e40806
  21. PNAS Nexus. 2024 Dec;3(12): pgae539
    Spatial organization and stochastic fluctuations of immune cells impact clinical responsiveness to immunotherapy in melanoma patients.
    Giuseppe Giuliani, William Stewart, Zihai Li, Ciriyam Jayaprakash, Jayajit Das.
      High-dimensional, spatial single-cell technologies, such as CyTOF imaging mass cytometry (IMC), provide detailed information regarding locations of a large variety of cancer and immune cells in microscopic scales in tumor microarray slides obtained from patients prior to immune checkpoint inhibitor (ICI) therapy. An important question is how the initial spatial organization of these cells in the tumor microenvironment (TME) changes with time and regulates tumor growth and eventually outcomes as patients undergo ICI therapy. Utilizing IMC data of melanomas of patients who later underwent ICI therapy, we develop a spatially resolved interacting cell system model that is calibrated against patient response data to address the above question. We find that the tumor fate in these patients is determined by the spatial organization of activated CD8+ T cells, macrophages, and melanoma cells and the interplay between these cells that regulate exhaustion of CD8+ T cells. We find that fencing of tumor cell boundaries by exhausted CD8+ T cells is dynamically generated from the initial conditions that can play a protumor role. Furthermore, we find that specific spatial features such as co-clustering of activated CD8+ T cells and macrophages in the pretreatment samples determine the fate of the tumor progression, despite stochastic fluctuations and changes over the treatment course. Our framework enables the determination of mechanisms of interplay between a key subset of tumor and immune cells in the TME that regulate clinical response to ICIs.
    Keywords:  imaging mass cytometry; mechanistic modeling; melanoma; stochastic fluctuations
    DOI:  https://doi.org/10.1093/pnasnexus/pgae539
  22. Cancers (Basel). 2024 Dec 05. pii: 4070. [Epub ahead of print]16(23):
    Pathobiological Features and Therapeutic Opportunities Linked to TNF Family Member Expression in Classic Hodgkin Lymphoma.
    Mohamed N Alibrahim, Annunziata Gloghini, Antonino Carbone.
      The tumor necrosis factor (TNF) family, which includes 19 ligands and 29 receptors, influences cellular proliferation, differentiation, and apoptosis. The TNF family plays a crucial role in the pathogenesis of Hodgkin lymphoma (HL), particularly through its influence on the tumor microenvironment (TME). Hodgkin Reed-Sternberg (HRS) cells, the hallmark of classic HL (cHL), exhibit overexpression of TNF receptor family members such as CD30 and CD40. Given the critical roles of CD30 and CD40 in the survival and proliferation of HRS cells within the TME, targeting these TNF receptors represents a promising therapeutic strategy; therapies that target CD30 have already shown efficacy in clinical settings. The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis plays a crucial role in immune evasion by HRS cells, which express PD-L1 that interacts with PD-1 on T cells, leading to T cell exhaustion and a diminished immune response against the tumor. By blocking this interaction, checkpoint inhibitors such as nivolumab and pembrolizumab have demonstrated high response rates in patients with cHL, particularly in those who have not responded to conventional therapies. The integration of immune checkpoint inhibitors (ICIs) with standard chemotherapy regimens has improved outcomes for patients with advanced-stage cHL. By understanding how TNF signaling interacts with immune checkpoints, researchers can design more effective treatment regimens that simultaneously target multiple pathways. Combining TNF inhibitors with checkpoint blockade therapies may enhance the overall anti-tumor response by addressing both direct tumor signaling and the immune evasion mechanisms employed by tumor cells.
    Keywords:  CD30; CD40; TNF family; classic Hodgkin lymphoma; new therapies; pathobiology; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers16234070
  23. Cell Immunol. 2024 Dec 09. pii: S0008-8749(24)00111-4. [Epub ahead of print]408 104908
    Berberine shaping the tumor immune landscape via pyroptosis.
    Jinjin Xie, Xin Du, Yuke Li, Chengyu Wu, Rui Li, Mengnan Zhao, Sanjun Shi.
      Pyroptosis is a programmed cell death (PCD) mainly mediated by the Gasdermin family of proteins, among which Gasdermin E (GSDME) is considered a tumor suppressor gene. GSDME can recruit immune cells to the tumor microenvironment (TME) and promote their effects. Activating and enhancing adaptive immunity through GSDME is a potential solution for anti-tumor therapy. Here we reported that berberine (BBR), a small molecule from traditional Chinese medicine, as a GSDME activator, induced caspase-3 (C-3)/GSDME pathway-mediated pyroptosis through the mitochondrial pathway, improved the immunosuppressive state of the tumor microenvironment, and thus promoted anti-tumor immunity. We determined the induction of pyroptosis of 4 T1 cells by BBR through various experiments, and investigated the immune activation effect of BBR by co-culture in vitro, which induced DCs maturation and macrophage polarization. Zebrafish embryo toxicity experiments were used to evaluate the in vivo safety of berberine. Furthermore, the in vivo antitumor and immune activation effects of BBR were investigated using 4 T1 orthotopic model mice, and the results showed that BBR could eliminate orthotopic tumor cells by activating local and systemic immunity. Moreover, we observed that BBR significantly inhibited breast cancer lung metastasis. In summary, our results showd the role of BBR as a GSDME activator stimulated both local and systemic antitumor immune responses by inducing pyroptosis, effectively preventing tumor development and metastasis.
    Keywords:  Berberine; GSDME; Immunotherapy; Pyroptosis; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cellimm.2024.104908
  24. Front Immunol. 2024 ;15 1501293
    IL-17A in gastric carcinogenesis: good or bad?
    Weidong Li, Xiaodong Huang, Xiaowen Han, Jiayi Zhang, Lei Gao, Hao Chen.
      Cytokines, which are important to the tumor microenvironment (TME), play critical roles in tumor development, metastasis, and immune responses. Interleukin-17(IL-17) has emerged as a key biomarker in many malignancies; however, its precise involvement in gastric cancer is less fully understood. Elevated levels of IL-17 have been observed in stomach diseases such as Helicobacter pylori infection and autoimmune gastritis, indicating that a sustained Th17 response may precede the development of gastric cancer. While IL-17 is related to inflammatory processes that may lead to cancer, its specific influence on gastric cancer development and therapy needs to be completely understood. Specifically, the release of IL-17A by diverse immune cells has been associated with both tumor development and inhibition in gastric cancer. It may impact tumor development through mechanisms such as boosting cell proliferation, inducing angiogenesis, and enabling immune cell recruitment or, conversely, suppressing tumor growth via the activation of anti-tumor immune responses. The dual role of IL-17 in cancer, along with its various effects depending on the TME and immune cell composition, highlights the complexity of its activity. Current research reveals that although IL-17 might serve as a target for immunotherapy, its therapeutic potential is hindered by its various activities. Some studies have shown that anti-IL-17 drugs may be helpful, especially when paired with immune checkpoint inhibitors, whereas others point to concerns about the validity of IL-17 in gastric cancer therapy. The lack of clinical trials and the heterogeneity of human tumors underscore the necessity for individualized treatment approaches. Further studies are needed to identify the specific mechanisms of IL-17 in gastric cancer and to design targeted therapeutics appropriately.
    Keywords:  Helicobacter pylori; IL-17; gastric cancer; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1501293
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