bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–02–02
twenty-two papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Antitumor Research Based on Drug Delivery Carriers: Reversing the Polarization of Tumor-Associated Macrophages.
  2. Understanding the Dual Role of Macrophages in Tumor Growth and Therapy: A Mechanistic Review.
  3. Melanoma-derived versican reactivates tumor-associated macrophages by upregulating pyruvate carboxylase through TLR2-MyD88-RelB axis under normoxia.
  4. Metabolic reprogramming of neutrophils in the tumor microenvironment: Emerging therapeutic targets.
  5. Role of the AKT signaling pathway in regulating tumor-associated macrophage polarization and in the tumor microenvironment: A review.
  6. Sensory neurotransmission and pain in solid tumor progression.
  7. Characterizing tumor-infiltrating group 1 innate lymphoid cells in PyMT breast tumors.
  8. Emerging insights into the impact of systemic metabolic changes on tumor-immune interactions.
  9. Engineering Resilient CAR T Cells for Immunosuppressive Environment.
  10. CXCR4 antagonist-loaded nanoparticles reprogram the tumor microenvironment and enhance immunotherapy in hepatocellular carcinoma.
  11. Epigenetic Regulation of Stromal and Immune Cells and Therapeutic Targets in the Tumor Microenvironment.
  12. Inflammation and Immune Escape in Ovarian Cancer: Pathways and Therapeutic Opportunities.
  13. Inhibition of Glutamine Metabolism Suppresses Tumor Progression through Remodeling of the Macrophage Immune Microenvironment.
  14. Despicable role of epithelial-mesenchymal transition in breast cancer metastasis: Exhibiting de novo restorative regimens.
  15. Leveraging Single-Cell Multi-Omics to Decode Tumor Microenvironment Diversity and Therapeutic Resistance.
  16. Gut Microbiota-Tumor Microenvironment Interactions: Mechanisms and Clinical Implications for Immune Checkpoint Inhibitor Efficacy in Cancer.
  17. Effects of macrophages in OSCC progression.
  18. The Role of the Tumor Microenvironment in T-Cell Redirecting Therapies of Large B-Cell Lymphoma: Lessons Learned from CAR-T to Bispecific Antibodies.
  19. Cell Membrane-Integrated Neuroligin-1 Regulates the Anti-Inflammatory Effects of CRC Cell-Derived Exosomes.
  20. Targeting intracellular proteins with cell type-specific functions for cancer immunotherapy.
  21. The Impact of Metabolic Rewiring in Glioblastoma: The Immune Landscape and Therapeutic Strategies.
  22. Natural and Bioengineered Extracellular Vesicles in Diagnosis, Monitoring and Treatment of Cancer.
  1. Mol Pharm. 2025 Jan 27.
    Antitumor Research Based on Drug Delivery Carriers: Reversing the Polarization of Tumor-Associated Macrophages.
    Xinyu Cao, Shen Wan, Bingyu Wu, Zhikuan Liu, Lixing Xu, Yu Ding, Haiqin Huang.
      The development of malignant tumors is a complex process that involves the tumor microenvironment (TME). An immunosuppressive TME presents significant challenges to current cancer therapies, serving as a key mechanism through which tumor cells evade immune detection and play a crucial role in tumor progression and metastasis. This impedes the optimal effectiveness of immunotherapeutic approaches, including cytokines, immune checkpoint inhibitors, and cancer vaccines. Tumor-associated macrophages (TAMs), a major component of tumor-infiltrating immune cells, exhibit dual functionalities: M1-like TAMs suppress tumorigenesis, while M2-like TAMs promote tumor growth and metastasis. Consequently, the development of various nanocarriers aimed at polarizing M2-like TAMs to M1-like phenotypes through distinct mechanisms has emerged as a promising therapeutic strategy to inhibit tumor immune escape and enhance antitumor responses. This Review covers the origin and types of TAMs, common pathways regulating macrophage polarization, the role of TAMs in tumor progression, and therapeutic strategies targeting TAMs, aiming to provide a comprehensive understanding and guidance for future research and clinical applications.
    Keywords:  M1 phenotype; M2 phenotype; TAM; nanocarriers; tumor treatment
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.4c01277
  2. Chem Biodivers. 2025 Jan 27. e202402976
    Understanding the Dual Role of Macrophages in Tumor Growth and Therapy: A Mechanistic Review.
    Muhammad Summer, Saima Riaz, Shaukat Ali, Qudsia Noor, Rimsha Ashraf, Rana Rashad Mahmood Khan.
      Macrophages are heterogeneous cells that are the mediators of tissue homeostasis. These immune cells originated from monocytes and are classified into two basic categories, M1 and M2 macrophages. M1 macrophages exhibit anti-tumorous inflammatory reactions due to the behavior of phagocytosis. M2 macrophages or tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and have a basic role in tumor progression by interacting with other immune cells in TME. By the expression of various cytokines, chemokines, and growth factors, TAMs lead to strengthening tumor cell proliferation, angiogenesis, and suppression of the immune system which further support invasion and metastasis. This review discusses recent and updated mechanisms regarding tumor progression by M2 macrophages. Moreover, the current therapeutic approaches targeting TAMs, their advantages, and limitations are also summarized, and further treatment approaches are outlined along with an elaboration of the tumor regression role of macrophages. This comprehensive review article possibly helps to understand the mechanisms underlying the tumor progression and regression role of macrophages in a comparative way from a basic level to the advanced one.
    Keywords:  antitumor strategies; macrophages; tumor microenvironment; tumor‐associated macrophages
    DOI:  https://doi.org/10.1002/cbdv.202402976
  3. Acta Biochim Biophys Sin (Shanghai). 2025 Jan 24.
    Melanoma-derived versican reactivates tumor-associated macrophages by upregulating pyruvate carboxylase through TLR2-MyD88-RelB axis under normoxia.
    Yuxin Shu, Linmin Zhou, Jinqin Qian, Wei-Guo Zhu.
      Relieving hypoxia in the tumor microenvironment (TME) promotes innate and adaptive immunity. Our previous research demonstrated that reoxygenation of the TME promotes the phagocytosis and tumor-killing functions of tumor-associated macrophages (TAMs) by upregulating pyruvate carboxylase (PCB). However, the mechanism remains obscure. In the present study, we find that versican derived from melanoma cells binds to TLR2 and activates the downstream transcription factor RelB, which transcribes PCB under normoxia. Blocking the versican-TLR2-MyD88-RelB axis not only reverses the upregulation of PCB in TAMs but also hinders the clearance of tumor cells by TAMs. Our work suggests a pathway that modulates the functions of TAMs under normoxia, which could be harnessed for strengthening anti-tumor immunity.
    Keywords:  RelB; phagocytosis; pyruvate carboxylase; tumor-associated macrophages; versican.
    DOI:  https://doi.org/10.3724/abbs.2025011
  4. Cancer Lett. 2025 Jan 23. pii: S0304-3835(25)00030-8. [Epub ahead of print]612 217466
    Metabolic reprogramming of neutrophils in the tumor microenvironment: Emerging therapeutic targets.
    Shiyun Huang, Jiahao Shi, Jianfeng Shen, Xianqun Fan.
      Neutrophils are pivotal in the immune system and have been recognized as significant contributors to cancer development and progression. These cells undergo metabolic reprogramming in response to various stimulus, including infections, diseases, and the tumor microenvironment (TME). Under normal conditions, neutrophils primarily rely on aerobic glucose metabolism for energy production. However, within the TME featured by hypoxic and nutrient-deprived conditions, they shift to altered anaerobic glycolysis, lipid metabolism, mitochondrial metabolism and amino acid metabolism to perform their immunosuppressive functions and facilitate tumor progression. Targeting neutrophils within the TME is a promising therapeutic approach. Yet, focusing on their metabolic pathways presents a novel strategy to enhance cancer immunotherapy. This review synthesizes the current understanding of neutrophil metabolic reprogramming in the TME, with an emphasis on the underlying molecular mechanisms and signaling pathways. Studying neutrophil metabolism in the TME poses challenges, such as their short lifespan and the metabolic complexity of the environment, necessitating the development of advanced research methodologies. This review also discusses emerging solutions to these challenges. In conclusion, given their integral role in the TME, targeting the metabolic pathways of neutrophils could offer a promising avenue for cancer therapy.
    Keywords:  Metabolism; Neutrophil; Therapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2025.217466
  5. Medicine (Baltimore). 2025 Jan 31. 104(5): e41379
    Role of the AKT signaling pathway in regulating tumor-associated macrophage polarization and in the tumor microenvironment: A review.
    Changming Liang, Song Wang, Chengwei Wu, Jiawei Wang, Lishuai Xu, Senlin Wan, Xu Zhang, Yinfen Hou, Yabin Xia, Li Xu, Xiaoxu Huang, Hao Xie.
      Tumor-associated macrophages (TAMs) are present in and are important components of the tumor microenvironment (TME). TAMs differentiate into 2 functionally distinct morphologies, classically activated (M1)-type TAMs and alternatively activated (M2)-type TAMs, when stimulated by different cytokines. The 2 types of TAMs exhibit distinct properties and functions. M1 TAMs secrete high levels of pro-inflammatory and chemotactic factors, exerting proinflammatory, antitumor effects. Conversely, M2 TAMs alter the extracellular matrix, facilitate cellular immune escape, and stimulate tumor angiogenesis, thereby promoting anti-inflammatory responses and tumor growth. The ratio of M1 TAMs to M2 TAMs in the TME is closely related to the prognosis of the tumor. Tumor cells and other cells in the TME can regulate the polarization of TAMs and thus promote tumor progression through the secretion of various substances; however, polarized TAMs can also act on various cells in the TME through the secretion of exosomes, thus forming a positive feedback loop. Therefore, modulating the phenotype of TAMs in the TME or blocking the polarization of M2 TAMs might be a new approach for cancer treatment. However, the intracellular signaling pathways involved in the polarization of TAMs are poorly understood. The AKT signaling pathway is an important signaling pathway involved in the polarization, growth, proliferation, recruitment, and apoptosis of TAMs, as well as the action of TAMs on other cells within the TME. This paper reviews the AKT signaling pathway in the polarization of TAMs and the regulation of the TME and provides new ideas for tumor immunotherapy.
    DOI:  https://doi.org/10.1097/MD.0000000000041379
  6. Trends Cancer. 2025 Jan 29. pii: S2405-8033(25)00003-2. [Epub ahead of print]
    Sensory neurotransmission and pain in solid tumor progression.
    Andre A Martel Matos, Nicole N Scheff.
      Sensory nerves form a crucial component of the tumor microenvironment (TME) that relays vital information to the central nervous system and modulates tumor progression via immunosurveillance. Afferent activity processed by the brain can sensitize brain circuitry and influence host behaviors. Peripheral sensory signaling (e.g., release of neuropeptides in the TME) can drive phenotypic changes in the tumor immune response, such as increased exhaustion markers and inhibited effector cell activity, which promote cancer progression. In this review we highlight the most recent evidence demonstrating the pivotal role of the sensory nervous system in cancer, with a focus on primary tumor pain, and we discuss the extent to which pain can influence cancer progression and treatment response, including immunotherapeutic strategies.
    Keywords:  cancer; immunology; immunotherapy; neuroscience; nociception; pain
    DOI:  https://doi.org/10.1016/j.trecan.2025.01.003
  7. Methods Cell Biol. 2025 ;pii: S0091-679X(24)00098-0. [Epub ahead of print]192 1-15
    Characterizing tumor-infiltrating group 1 innate lymphoid cells in PyMT breast tumors.
    Douglas C Chung, Alisha R Elford, Nicolas Jacquelot.
      Breast cancer is the most common cancer in women and continues to have a significant impact in cancer-associated deaths worldwide. Investigating the complex roles of infiltrating immune subsets within the tumor microenvironment (TME) will enable a better understanding of disease progression and reveal novel therapeutic strategies for patients with breast cancer. The mammary-specific expression of polyomavirus middle T oncoprotein (MMTV-PyMT) was first established in 1992 by William Muller and is the most commonly used genetically engineered mouse model (GEMM) for breast cancer research. Innate lymphoid cells (ILCs) are composed of a diverse family of effector cells known to play important roles in defense against pathogens, tissue homeostasis, and tumor immunity. In mice, group 1 ILCs are composed of NK cells and ILC1s, which have been shown to have differential roles within the TME. Here, we provide a detailed methodology in characterizing tumor-infiltrating NK cells and ILC1s in MMTV-PyMT breast tumor model.
    Keywords:  Breast cancer; ILC1; Innate lymphoid cells; NK cells; PyMT; Tumor microenvironment
    DOI:  https://doi.org/10.1016/bs.mcb.2024.03.008
  8. Cell Rep. 2025 Jan 23. pii: S2211-1247(25)00005-1. [Epub ahead of print]44(2): 115234
    Emerging insights into the impact of systemic metabolic changes on tumor-immune interactions.
    Andrea L Cote, Chad J Munger, Alison E Ringel.
      Tumors are inherently embedded in systemic physiology, which contributes metabolites, signaling molecules, and immune cells to the tumor microenvironment. As a result, any systemic change to host metabolism can impact tumor progression and response to therapy. In this review, we explore how factors that affect metabolic health, such as diet, obesity, and exercise, influence the interplay between cancer and immune cells that reside within tumors. We also examine how metabolic diseases influence cancer progression, metastasis, and treatment. Finally, we consider how metabolic interventions can be deployed to improve immunotherapy. The overall goal is to highlight how metabolic heterogeneity in the human population shapes the immune response to cancer.
    Keywords:  CP: Cancer; CP: Metabolism; anti-tumor immunity; systemic metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2025.115234
  9. Mol Ther. 2025 Jan 25. pii: S1525-0016(25)00039-5. [Epub ahead of print]
    Engineering Resilient CAR T Cells for Immunosuppressive Environment.
    Malak Khalifeh, Huda Salman.
      Chimeric Antigen Receptor (CAR) T cell therapy has revolutionized cancer treatment and is now being explored for other diseases, such as autoimmune disorders. While the tumor microenvironment (TME) in cancer is often immunosuppressive, in autoimmune diseases, the environment is typically inflammatory. Both environments can negatively impact CAR T cell survival: the former through direct suppression, hypoxia, and nutrient deprivation, and the latter through chronic T cell receptor (TCR) engagement, risking exhaustion. Mechanisms of resistance include T cell exhaustion, dysfunction, and the impact of the TME. Chronic antigenic stimulation leads to CAR T cell exhaustion. CAR construct design, including co-stimulatory domains, hinge, transmembrane regions, promoters, the affinity of the binder site and on /off rate plays a crucial role in modulating CAR T cell function and resistance. This review discusses the impact of the in vitro development of CAR T cells, albeit in relation to the TME, on therapeutic outcomes. The use of alternative cell sources, multi-antigen targeting, and re-engineering the TME, are discussed. The review emphasizes the need for continued innovation in CAR T cell design and manufacturing to optimize therapeutic efficacy and durability, especially in the face of varying environmental challenges.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.01.035
  10. J Control Release. 2025 Jan 23. pii: S0168-3659(25)00076-8. [Epub ahead of print]
    CXCR4 antagonist-loaded nanoparticles reprogram the tumor microenvironment and enhance immunotherapy in hepatocellular carcinoma.
    Sheng-Liang Cheng, Chien-Huang Wu, Yun-Jen Tsai, Jen-Shin Song, Hsin-Min Chen, Teng-Kuang Yeh, Chia-Tung Shen, Jou-Chien Chiang, Hsin-Mei Lee, Kuan-Wei Huang, Yuling Chen, J Timothy Qiu, Yu-Ting Yen, Kak-Shan Shia, Yunching Chen.
      Hepatocellular carcinoma (HCC) is a leading cause of cancer death that has limited treatment options for advanced stages. Although PD-1 inhibitors such as nivolumab and pembrolizumab have been approved for advanced HCC treatment, their effectiveness is often hampered by the immunosuppressive tumor microenvironment (TME), which is due to hypoxia-driven CXCL12/CXCR4 axis activation. In this study, we developed 807-NPs, lipid-coated tannic acid (TA) nanoparticles that encapsulate BPRCX807, a potent CXCR4 antagonist to target HCC. 807-NPs enhance the pharmacokinetics and improve the tumor availability of BPRCX807 without causing systemic toxicity. Our findings show that 807-NPs block the CXCR4/CXCL12 pathway, inhibiting Akt and mTOR activation in HCC cells and M2 macrophages and promoting their repolarization toward the antitumor M1 phenotype. In orthotopic murine HCC models, systemic administration of 807-NPs significantly remodeled the immunosuppressive TME by reprogramming tumor-associated macrophages (TAMs) toward an immunostimulatory phenotype and promoting cytotoxic T-cell infiltration into tumors. This led to suppressed primary tumor growth and metastasis, while enhancing the efficacy of cancer immunotherapies, including PD-1 blockade and whole-cancer cell vaccines, by promoting T-cell activation. Our work demonstrates the potential of using nanotechnology to deliver CXCR4 antagonists for cancer immunotherapy.
    Keywords:  CXCL12/CXCR4 axis; Hepatocellular carcinoma; Immunotherapy; PD-1 inhibitor; Tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.jconrel.2025.01.066
  11. Biomolecules. 2025 Jan 06. pii: 71. [Epub ahead of print]15(1):
    Epigenetic Regulation of Stromal and Immune Cells and Therapeutic Targets in the Tumor Microenvironment.
    Kang Liu, Yue Li, Minmin Shen, Wei Xu, Shanshan Wu, Xinxin Yang, Bo Zhang, Nengming Lin.
      The tumor microenvironment (TME) plays a pivotal role in neoplastic initiation and progression. Epigenetic machinery, governing the expression of core oncogenes and tumor suppressor genes in transformed cells, significantly contributes to tumor development at both primary and distant sites. Recent studies have illuminated how epigenetic mechanisms integrate external cues and downstream signals, altering the phenotype of stromal cells and immune cells. This remolds the area surrounding tumor cells, ultimately fostering an immunosuppressive microenvironment. Therefore, correcting the TME by targeting the epigenetic modifications holds substantial promise for cancer treatment. This review synthesizes recent research that elucidates the impact of specific epigenetic regulations-ranging from DNA methylation to histone modifications and chromatin remodeling-on stromal and immune cells within the TME. Notably, we highlight their functional roles in either promoting or restricting tumor progression. We also discuss the potential applications of epigenetic agents for cancer treatment, envisaging their ability to normalize the ecosystem. This review aims to assist researchers in understanding the dynamic interplay between epigenetics and the TME, paving the way for better epigenetic therapy.
    Keywords:  epigenetic modification; epigenetic therapy; immune therapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/biom15010071
  12. J Inflamm Res. 2025 ;18 895-909
    Inflammation and Immune Escape in Ovarian Cancer: Pathways and Therapeutic Opportunities.
    Chunyan Liu, Qinan Yin, Zhaoying Wu, Wenhui Li, Jun Huang, Bo Chen, Yanjun Yang, Xuewei Zheng, Li Zeng, Jingjing Wang.
      Ovarian cancer (OC) remains one of the most lethal gynecological malignancies, largely due to its late-stage diagnosis and high recurrence rates. Chronic inflammation is a critical driver of OC progression, contributing to immune evasion, tumor growth, and metastasis. Inflammatory cytokines, including IL-6, TNF-α, and IL-8, as well as key signaling pathways such as nuclear factor kappa B (NF-kB) and signal transducer and activator of transcription 3 (STAT3), are upregulated in OC, promoting a tumor-promoting environment. The tumor microenvironment (TME) is characterized by immune cells like tumor-associated macrophages (TAMs) and regulatory T cells (Tregs), which suppress anti-tumor immune responses, facilitating immune evasion. Furthermore, OC cells utilize immune checkpoint pathways, including PD-1/PD-L1, to inhibit cytotoxic T cell activity. Targeting these inflammatory and immune evasion mechanisms offers promising therapeutic strategies. COX-2 inhibitors, Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway blockers, and NF-kB inhibitors have shown potential in preclinical studies, while immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 have been explored with mixed results in OC. Additionally, emerging research on the microbiome and inflammation-related biomarkers, such as microRNAs (miRNAs) and exosomes, points to new opportunities for early detection and precision medicine. Future approaches to OC treatment must focus on personalized strategies that target the inflammatory TME, integrating anti-inflammatory therapies with immunotherapy to enhance patient outcomes. Continued research into the interplay between inflammation and immune evasion in OC is essential for developing effective, long-lasting treatments.
    Keywords:  evasion of immune response; inflammation-driven mechanisms; ovarian cancer; therapeutic strategies
    DOI:  https://doi.org/10.2147/JIR.S503479
  13. bioRxiv. 2025 Jan 14. pii: 2025.01.10.632174. [Epub ahead of print]
    Inhibition of Glutamine Metabolism Suppresses Tumor Progression through Remodeling of the Macrophage Immune Microenvironment.
    Tianhe Li, Sepehr Akhtarkhavari, Tu-Yung Chang, Yao-An Shen, JinMing Yang, Barbara Slusher, Ie-Ming Shih, Stephanie Gaillard, Tian-Li Wang.
       Background: Targeting glutamine metabolism has emerged as a promising strategy in cancer therapy. However, several barriers, such as in vivo anti-tumor efficacy, drug toxicity, and safety, remain to be overcome to achieve clinical utility. Prior preclinical in vivo studies had generated encouraging data showing promises of cancer metabolism targeting drugs, although most were performed on immune-deficient murine models. It is being recognized that aside from tumor cells, normal cells such as immune cells in the tumor microenvironment may also utilize glutamine for maintaining physiological functions. To provide an in-depth view of glutamine antagonist (GLNi) treatment on the tumor immune microenvironment, the current study made several unique approaches.
    Method: First, to evaluate GLNi treatment modality that potentially involves immune cells, the study was performed on immunocompetent murine models of gynecological cancers. Second, to enhance safety and reduce potential off-target effects, we developed a GLNi prodrug, JHU083, which is bio-activated restrictively in cancer tissues. Third, to unbiasedly decode the response of single cells in the tumor microenvironment to GLNi treatment, single-cell RNA sequencing (scRNA-seq) was performed on cells prepared from tumors of the JHU083 or vehicle control-treated mice.
    Results: In both immunocompetent murine tumor models, we observed a significant anti-tumor efficacy, resulting in reduced tumor burden and impeded tumor progression. Similarly, in both tumor models, scRNA-seq revealed significantly impeded immunosuppressive M2-like macrophages by JHU083, while the treatment spared pro-inflammatory M1-like tumor macrophages. In many tumor microenvironment (TME) cells, JHU083 downregulated genes regulated by Myc and hypoxia. M2 macrophages' greater sensitivity to glutamine antagonism when compared to M1 macrophages or monocytes was further validated on ex vivo cultures of bone marrow-derived macrophages.
    Conclusion: Our findings support a converged mechanism of glutamine metabolism antagonists. JHU083 exerted its anti-tumor efficacy through not only direct targeting of glutamine-addicted cancer cells but also by suppressing glutamine-dependent M2 macrophages, leading to a shift in the M1/M2 macrophage landscape in favor of an immune-stimulatory microenvironment.
    DOI:  https://doi.org/10.1101/2025.01.10.632174
  14. Cancer Pathog Ther. 2025 Jan;3(1): 30-47
    Despicable role of epithelial-mesenchymal transition in breast cancer metastasis: Exhibiting de novo restorative regimens.
    Paras Famta, Saurabh Shah, Biswajit Dey, Kondasingh Charan Kumar, Deepkumar Bagasariya, Ganesh Vambhurkar, Giriraj Pandey, Anamika Sharma, Dadi A Srinivasarao, Rahul Kumar, Santosh Kumar Guru, Rajeev Singh Raghuvanshi, Saurabh Srivastava.
      Breast cancer (BC) is the most prevalent cancer in women globally. Anti-cancer advancements have enabled the killing of BC cells through various therapies; however, cancer relapse is still a major limitation and decreases patient survival and quality of life. Epithelial-to-mesenchymal transition (EMT) is responsible for tumor relapse in several cancers. This highly regulated event causes phenotypic, genetic, and epigenetic changes in the tumor microenvironment (TME). This review summarizes the recent advancements regarding EMT using de-differentiation and partial EMT theories. We extensively review the mechanistic pathways, TME components, and various anti-cancer adjuvant and neo-adjuvant therapies responsible for triggering EMT in BC tumors. Information regarding essential clinical studies and trials is also discussed. Furthermore, we also highlight the recent strategies targeting various EMT pathways. This review provides a holistic picture of BC biology, molecular pathways, and recent advances in therapeutic strategies.
    Keywords:  Breast cancer; Cancer stem cells; Epigenetics; Epithelial-to-mesenchymal transition; Metastases
    DOI:  https://doi.org/10.1016/j.cpt.2024.01.001
  15. Pharmaceuticals (Basel). 2025 Jan 10. pii: 75. [Epub ahead of print]18(1):
    Leveraging Single-Cell Multi-Omics to Decode Tumor Microenvironment Diversity and Therapeutic Resistance.
    Hussein Sabit, Borros Arneth, Timothy M Pawlik, Shaimaa Abdel-Ghany, Aysha Ghazy, Rawan M Abdelazeem, Amany Alqosaibi, Ibtesam S Al-Dhuayan, Jawaher Almulhim, Noof A Alrabiah, Ahmed Hashash.
      Recent developments in single-cell multi-omics technologies have provided the ability to identify diverse cell types and decipher key components of the tumor microenvironment (TME), leading to important advancements toward a much deeper understanding of how tumor microenvironment heterogeneity contributes to cancer progression and therapeutic resistance. These technologies are able to integrate data from molecular genomic, transcriptomic, proteomics, and metabolomics studies of cells at a single-cell resolution scale that give rise to the full cellular and molecular complexity in the TME. Understanding the complex and sometimes reciprocal relationships among cancer cells, CAFs, immune cells, and ECs has led to novel insights into their immense heterogeneity in functions, which can have important consequences on tumor behavior. In-depth studies have uncovered immune evasion mechanisms, including the exhaustion of T cells and metabolic reprogramming in response to hypoxia from cancer cells. Single-cell multi-omics also revealed resistance mechanisms, such as stromal cell-secreted factors and physical barriers in the extracellular matrix. Future studies examining specific metabolic pathways and targeting approaches to reduce the heterogeneity in the TME will likely lead to better outcomes with immunotherapies, drug delivery, etc., for cancer treatments. Future studies will incorporate multi-omics data, spatial relationships in tumor micro-environments, and their translation into personalized cancer therapies. This review emphasizes how single-cell multi-omics can provide insights into the cellular and molecular heterogeneity of the TME, revealing immune evasion mechanisms, metabolic reprogramming, and stromal cell influences. These insights aim to guide the development of personalized and targeted cancer therapies, highlighting the role of TME diversity in shaping tumor behavior and treatment outcomes.
    Keywords:  cancer therapeutic resistance; immune evasion; metabolic reprogramming; personalized cancer therapy; single-cell multi-omics; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/ph18010075
  16. Cancer Manag Res. 2025 ;17 171-192
    Gut Microbiota-Tumor Microenvironment Interactions: Mechanisms and Clinical Implications for Immune Checkpoint Inhibitor Efficacy in Cancer.
    Sawsan Sudqi Said, Wisam Nabeel Ibrahim.
      Cancer immunotherapy has transformed cancer treatment in recent years, with immune checkpoint inhibitors (ICIs) emerging as a key therapeutic approach. ICIs work by inhibiting the mechanisms that allow tumors to evade immune detection. Although ICIs have shown promising results, especially in solid tumors, patient responses vary widely due to multiple intrinsic and extrinsic factors within the tumor microenvironment. Emerging evidence suggests that the gut microbiota plays a pivotal role in modulating immune responses at the tumor site and may even influence treatment outcomes in cancer patients receiving ICIs. This review explores the complex interactions between the gut microbiota and the tumor microenvironment, examining how these interactions could impact the effectiveness of ICI therapy. Furthermore, we discuss how dysbiosis, an imbalance in gut microbiota composition, may contribute to resistance to ICIs, and highlight microbiota-targeted strategies to potentially overcome this challenge. Additionally, we review recent studies investigating the diagnostic potential of microbiota profiles in cancer patients, considering how microbial markers might aid in early detection and stratification of patient responses to ICIs. By integrating insights from recent preclinical and clinical studies, we aim to shed light on the potential of microbiome modulation as an adjunct to cancer immunotherapy and as a diagnostic tool, paving the way for personalized therapeutic approaches that optimize patient outcomes.
    Keywords:  ICIs; gut microbiota; immunotherapy; microbiome; tumor microenvironment
    DOI:  https://doi.org/10.2147/CMAR.S405590
  17. Front Immunol. 2024 ;15 1517886
    Effects of macrophages in OSCC progression.
    Xiaodan Dong, Chunling Dong, Bo Li.
      Macrophages are crucial immune cells within the tumor microenvironment (TME), involved in regulating tumor proliferation, invasion, metastasis, ECM remodeling, angiogenesis, and immunosuppression. Although more and more experimental evidence and clinical data indicate that macrophages are involved in the onset and progression of oral squamous cell carcinoma (OSCC), the exact pathogenesis of OSCC associated with macrophages has not been fully elucidated. Enhanced knowledge of the molecular mechanisms involving macrophages in OSCC will aid in the creation of treatments targeted specifically at macrophages. This review outlines the pro-tumoral and anti-tumoral effects of macrophages in OSCC, emphasizing the interaction between OSCC cells and macrophages. It can provide theoretical basis for the establishment of complex regulatory network centered on macrophages and explore novel therapeutic strategies for OSCC.
    Keywords:  interaction; loop; macrophages; oral squamous cell carcinoma; polarization
    DOI:  https://doi.org/10.3389/fimmu.2024.1517886
  18. Cancers (Basel). 2025 Jan 20. pii: 317. [Epub ahead of print]17(2):
    The Role of the Tumor Microenvironment in T-Cell Redirecting Therapies of Large B-Cell Lymphoma: Lessons Learned from CAR-T to Bispecific Antibodies.
    Kirill V Lepik, Vladislav V Markelov.
      T-cell redirecting therapies, which include chimeric antigen receptor T-cells (CAR-Ts) and bispecific antibodies (BSAs), have revolutionized the treatment of relapsed\refractory large B-cell lymphoma (LBCL). Expanding clinical experience with these advanced therapies shows the potential for the optimization of their use with combination or consolidation strategies, which necessitates the prognostic stratification of patients. While traditional clinical prognostic factors identified in the era of chemotherapy are characterized by limited value, the tumor microenvironment (TME) is becoming a new prognostic cluster. We examine how the heterogeneity of LBCL, characterized by variations in tumor parameters and differences in TME immune cell composition, immune checkpoint expression, and cytokine milieu, correlates with both positive responses and resistance to treatment. While classical parameters such as histological subtype, cell of origin, and target antigen expression lack proven prognostic value for T-cell redirecting therapies, the density and functional state of tumor-infiltrating lymphocytes, tumor-associated macrophages, and immune checkpoint molecules are shown to be critical determinants of therapeutic success, particularly in CAR-T therapy. We identify several gaps in the current knowledge and suggest that the insights gained from CAR-T experience could be instrumental in refining BSA applications. This report also highlights limitations in the current knowledge, as TME data derive from a limited number of registrational trials with varying methodologies, complicating cross-study comparisons and often focusing on immediate response metrics rather than long-term outcomes. By dissecting the complex interactions within the TME, this review aims to identify new prognostic factors and targets, ultimately fostering more effective and tailored treatment strategies for LBCL patients.
    Keywords:  BSAs; CAR-T; LBCL; T-cell redirecting therapies; TME; bispecific antibodies; chimeric antigen receptor T-cells; immune checkpoints; large B-cell lymphoma; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers17020317
  19. Int J Mol Sci. 2025 Jan 09. pii: 503. [Epub ahead of print]26(2):
    Cell Membrane-Integrated Neuroligin-1 Regulates the Anti-Inflammatory Effects of CRC Cell-Derived Exosomes.
    Mohammad Mahmoudian, Francesco Trotta, Stefania Raimondo, Federico Bussolino, Marco Arese.
      Tumor-associated macrophages (TAMs) are one of the most abundant cell types in the colorectal cancer (CRC) tumor microenvironment (TME). CRC cell-derived exosomes support macrophage polarization toward an M2-like phenotype, which leads to tumor growth and metastasis. Neuroligin 1 (NLG1) is a transmembrane protein critical in synaptic function. We reported that NLG1 via an autocrine manner promotes CRC progression by modulating the APC/β-catenin pathway. This study aimed to answer whether NLG1 is involved in the exosome-mediated intercellular cross-talk between CRC and TAMs. Our results showed that exosomes of NLG1-expressing CRC cells induce M2-like (CD206high CD80low) polarization in macrophages. On the other hand, we found that the exosomes of the NLG1 knocked-down CRC cells reinforce the expression of CD80 and pro-inflammatory genes, including IL8, IL1β, and TNFα, in the macrophages, indicating an M1-like phenotype polarization. In conclusion, NLG1, as a cell-membrane-integrated protein, could be a therapeutic target on the surface of the CRC cells for developing clinical treatments to inhibit exosome-induced anti-inflammatory immune responses in TME.
    Keywords:  Neuroligin-1; colorectal cancer cells; exosome; macrophages
    DOI:  https://doi.org/10.3390/ijms26020503
  20. Life Med. 2023 Jun;2(3): lnad019
    Targeting intracellular proteins with cell type-specific functions for cancer immunotherapy.
    Madison E Carelock, Rohan P Master, Myung-Chul Kim, Zeng Jin, Lei Wang, Chandra K Maharjan, Nan Hua, Umasankar De, Ryan Kolb, Yufeng Xiao, Daiqing Liao, Guangrong Zheng, Weizhou Zhang.
      Immune checkpoint inhibitors (ICIs) use antibodies that block cell surface immune checkpoint proteins with great efficacy in treating immunogenic or "immune hot" tumors such as melanoma, kidney, and lung adenocarcinoma. ICIs have limited response rates to other non-immunogenic cancers. The tumor microenvironment (TME) consists of many cell types that collectively promote tumor progression. Cancer therapeutics are commonly designed to target one molecule in one defined cell type. There is growing evidence that long-term therapeutic responses require the targeting of cancer cells and tumor-promoting populations within the TME. The question remains whether we can identify targetable molecules/pathways that are critical for multiple cell types. Here, we will discuss several molecular targets that may fit a "two or multiple birds, one stone" model, including the B-cell lymphoma-2 (BCL-2) family pro-survival factors, transcriptional factors including signal transducer and activator of transcription 3, the nuclear receptor 4A family (NR4A1, NR4A2, and NR4A3), as well as epigenetic regulators such as bromodomain and extra-terminal (BET) family proteins, histone deacetylase family, SET domain bifurcated histone lysine methyltransferase 1 (SETDB1), and lysine-specific demethylase 1 (LSD1/KDM1A). We will focus on the rationale of these targets in immune modulation, as well as the strategies for targeting these important proteins for cancer therapy.
    Keywords:  immune checkpoint inhibitors; immunotherapy; multifunctional protein targets; tumor microenvironment (TME)
    DOI:  https://doi.org/10.1093/lifemedi/lnad019
  21. Int J Mol Sci. 2025 Jan 14. pii: 669. [Epub ahead of print]26(2):
    The Impact of Metabolic Rewiring in Glioblastoma: The Immune Landscape and Therapeutic Strategies.
    Yuganthini Vijayanathan, Ivy A W Ho.
      Glioblastoma (GBM) is an aggressive brain tumor characterized by extensive metabolic reprogramming that drives tumor growth and therapeutic resistance. Key metabolic pathways, including glycolysis, lactate production, and lipid metabolism, are upregulated to sustain tumor survival in the hypoxic and nutrient-deprived tumor microenvironment (TME), while glutamine and tryptophan metabolism further contribute to the aggressive phenotype of GBM. These metabolic alterations impair immune cell function, leading to exhaustion and stress in CD8+ and CD4+ T cells while favoring immunosuppressive populations such as regulatory T cells (Tregs) and M2-like macrophages. Recent studies emphasize the role of slow-cycling GBM cells (SCCs), lipid-laden macrophages, and tumor-associated astrocytes (TAAs) in reshaping GBM's metabolic landscape and reinforcing immune evasion. Genetic mutations, including Isocitrate Dehydrogenase (IDH) mutations, Epidermal Growth Factor Receptor (EGFR) amplification, and Phosphotase and Tensin Homolog (PTEN) loss, further drive metabolic reprogramming and offer potential targets for therapy. Understanding the relationship between GBM metabolism and immune suppression is critical for overcoming therapeutic resistance. This review focuses on the role of metabolic rewiring in GBM, its impact on the immune microenvironment, and the potential of combining metabolic targeting with immunotherapy to improve clinical outcomes for GBM patients.
    Keywords:  GBM; glioma; immune infiltration; metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms26020669
  22. ACS Nano. 2025 Jan 27.
    Natural and Bioengineered Extracellular Vesicles in Diagnosis, Monitoring and Treatment of Cancer.
    Xin Luo, Kathleen M McAndrews, Raghu Kalluri.
      Extracellular vesicles (EVs) are cell derived nanovesicles which are implicated in both physiological and pathological intercellular communication, including the initiation, progression, and metastasis of cancer. The exchange of biomolecules between stromal cells and cancer cells via EVs can provide a window to monitor cancer development in real time for better diagnostic and interventional strategies. In addition, the process of secretion and internalization of EVs by stromal and cancer cells in the tumor microenvironment (TME) can be exploited for delivering therapeutics. EVs have the potential to provide a targeted, biocompatible, and efficient delivery platform for the treatment of cancer and other diseases. Natural as well as engineered EVs as nanomedicine have immense potential for disease intervention. Here, we provide an overview of current knowledge of EVs' function in cancer progression, diagnostic and therapeutic applications for EVs in the cancer setting, as well as current EV engineering strategies.
    Keywords:  Extracellular vesicles (EVs); cancer; cancer immunotherapy; cargo loading methods; diagnosis; drug delivery; immune microenvironment; large scale production; monitoring; tumor microenvironment (TME)
    DOI:  https://doi.org/10.1021/acsnano.4c11630
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