bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–01–19
23 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Tumor-induced metabolic immunosuppression: Mechanisms and therapeutic targets.
  2. Targeting lipid metabolism in regulatory T cells for enhancing cancer immunotherapy.
  3. Insights into the mechanisms, regulation, and therapeutic implications of extracellular matrix stiffness in cancer.
  4. Drug Delivery System Targeting Cancer-Associated Fibroblast for Improving Immunotherapy.
  5. Modulation of Tumor-Associated Macrophages to Overcome Immune Suppression in the Hepatocellular Carcinoma Microenvironment.
  6. Ovarian tumor microenvironment contributes to tumor progression and chemoresistance.
  7. Slamming hepatocellular carcinoma: targeting immunosuppressive macrophages via SLAMF7 reprograms the tumor microenvironment.
  8. The role and research progress of tumor-associated macrophages in cervical cancer.
  9. AXL: shapers of tumor progression and immunosuppressive microenvironments.
  10. Recent developments in myeloid immune modulation in cancer therapy.
  11. Metabolic Signaling in the Tumor Microenvironment.
  12. Optimizing CAR-T cell function in solid tumor microenvironment: insights from culture media additives.
  13. Landscape of B lymphocytes and plasma cells in digestive tract carcinomas.
  14. Beyond the Norm: The emerging interplay of complement system and extracellular matrix in the tumor microenvironment.
  15. The crosstalk between senescence, tumor, and immunity: molecular mechanism and therapeutic opportunities.
  16. Role of exosomal miRNAs and macrophage polarization in gastric cancer: a novel therapeutic strategy.
  17. Interrogation of the Tumor Microenvironment by Nanoparticles.
  18. Calpain 2 regulates IL-1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironment.
  19. Fatty acid metabolism: A new target for nasopharyngeal carcinoma therapy.
  20. Cancer-associated fibroblast-derived exosomes in cancer progression: A focus on hepatocellular carcinoma.
  21. Metabolic Reprogramming and Adaption in Breast Cancer Progression and Metastasis.
  22. Interleukin-17A facilitates tumor progression via upregulating programmed death ligand-1 expression in hepatocellular carcinoma.
  23. Synergistic Potential of Antibiotics with Cancer Treatments.
  1. Cell Rep. 2025 Jan 10. pii: S2211-1247(24)01557-2. [Epub ahead of print]44(1): 115206
    Tumor-induced metabolic immunosuppression: Mechanisms and therapeutic targets.
    Jean-Ehrland Ricci.
      Metabolic reprogramming in both immune and cancer cells plays a crucial role in the antitumor immune response. Recent studies indicate that cancer metabolism not only sustains carcinogenesis and survival via altered signaling but also modulates immune cell function. Metabolic crosstalk within the tumor microenvironment results in nutrient competition and acidosis, thereby hindering immune cell functionality. Interestingly, immune cells also undergo metabolic reprogramming that enables their proliferation, differentiation, and effector functions. This review highlights the regulation of antitumor immune responses through metabolic reprogramming in cancer and immune cells and explores therapeutic strategies that target these metabolic pathways in cancer immunotherapy, including using chimeric antigen receptor (CAR)-T cells. We discuss innovative combinations of immunotherapy, cellular therapies, and metabolic interventions that could optimize the efficacy of existing treatment protocols.
    Keywords:  CP: Cancer; CP: Metabolism; antitumor activity of immune cells; cancer; metabolism; therapeutic strategies; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2024.115206
  2. Biochim Biophys Acta Rev Cancer. 2025 Jan 09. pii: S0304-419X(25)00001-0. [Epub ahead of print] 189259
    Targeting lipid metabolism in regulatory T cells for enhancing cancer immunotherapy.
    Liu Yang, Xingyue Wang, Shurong Wang, Jing Shen, Yaling Li, Shengli Wan, Zhangang Xiao, Zhigui Wu.
      As immunosuppressive cells, Regulatory T cells (Tregs) exert their influence on tumor immune escape within the tumor microenvironment (TME) by effectively suppressing the activity of other immune cells, thereby significantly impeding the anti-tumor immune response. In recent years, the metabolic characteristics of Tregs have become a focus of research, especially the important role of lipid metabolism in maintaining the function of Tregs. Consequently, targeted interventions aimed at modulating lipid metabolism in Tregs have been recognized as an innovative and promising approach to enhance the effectiveness of tumor immunotherapy. This review presents a comprehensive overview of the pivotal role of lipid metabolism in regulating the function of Tregs, with a specific focus on targeting Tregs lipid metabolism as an innovative approach to augment anti-tumor immune responses. Furthermore, we discuss potential opportunities and challenges associated with this strategy, aiming to provide novel insights for enhancing the efficacy of cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Lipid metabolism; Regulatory T cells; Tumor immune evasion; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189259
  3. Bioeng Transl Med. 2025 Jan;10(1): e10698
    Insights into the mechanisms, regulation, and therapeutic implications of extracellular matrix stiffness in cancer.
    Ximo Zhang, Abdullah Al-Danakh, Xinqing Zhu, Dan Feng, Linlin Yang, Haotian Wu, Yingying Li, Shujing Wang, Qiwei Chen, Deyong Yang.
      The tumor microenvironment (TME) is critical for cancer initiation, growth, metastasis, and therapeutic resistance. The extracellular matrix (ECM) is a significant tumor component that serves various functions, including mechanical support, TME regulation, and signal molecule generation. The quantity and cross-linking status of ECM components are crucial factors in tumor development, as they determine tissue stiffness and the interaction between stiff TME and cancer cells, resulting in aberrant mechanotransduction, proliferation, migration, invasion, angiogenesis, immune evasion, and treatment resistance. Therefore, broad knowledge of ECM dysregulation in the TME might aid in developing innovative cancer therapies. This review summarized the available information on major ECM components, their functions, factors that increase and decrease matrix stiffness, and related signaling pathways that interplay between cancer cells and the ECM in TME. Moreover, mechanotransduction alters during tumorogenesis, and current drug therapy based on ECM as targets, as well as future efforts in ECM and cancer, are also discussed.
    Keywords:  ECM stiffness; cancer; extracellular matrix; signaling pathways; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.1002/btm2.10698
  4. Int J Nanomedicine. 2025 ;20 483-503
    Drug Delivery System Targeting Cancer-Associated Fibroblast for Improving Immunotherapy.
    Zhongsong Zhang, Rong Wang, Long Chen.
      Cancer-associated fibroblasts (CAFs) are a heterogeneous population of non-malignant cells that play a crucial role in the tumor microenvironment, increasingly recognized as key contributors to cancer progression, metastasis, and treatment resistance. So, targeting CAFs has always been considered an important part of cancer immunotherapy. However, targeting CAFs to improve the efficacy of tumor therapy is currently a major challenge. Nanomaterials show their unique advantages in the whole process. At present, nanomaterials have achieved significant accomplishments in medical applications, particularly in the field of cancer-targeted therapy, showing enormous potential. It has been confirmed that nanomaterials can not only directly target CAFs, but also interact with the tumor microenvironment (TME) and immune cells to affect tumorigenesis. As for the cancer treatment, nanomaterials could enhance the therapeutic effect in many ways. Therefore, in this review, we first summarized the current understanding of the complex interactions between CAFs and TME, immune cells, and tumor cells. Next, we discussed common nanomaterials in modern medicine and their respective impacts on the TME, CAFs, and interactions with tumors. Finally, we focus on the application of nano drug delivery system targeting CAFs in cancer therapy.
    Keywords:  cancer immunotherapy; cancer-associated fibroblasts; drug delivery; nanomedicine; tumor microenvironment
    DOI:  https://doi.org/10.2147/IJN.S500591
  5. Cancers (Basel). 2024 Dec 29. pii: 66. [Epub ahead of print]17(1):
    Modulation of Tumor-Associated Macrophages to Overcome Immune Suppression in the Hepatocellular Carcinoma Microenvironment.
    Mahmoud Singer, Zhuoli Zhang, Farshid Dayyani, Zigeng Zhang, Vahid Yaghmai, April Choi, Jennifer Valerin, David Imagawa, Nadine Abi-Jaoudeh.
      Hepatocellular carcinoma (HCC) is a major global health issue characterized by poor prognosis and complex tumor biology. One of the critical components of the HCC tumor microenvironment (TME) is tumor-associated macrophages (TAMs), which play a pivotal role in modulating tumor growth, immune evasion, and metastasis. Macrophages are divided into two major subtypes: pro-inflammatory M1 and anti-inflammatory M2, both of which may exist in TME with altered function and proportion. The anti-inflammatory M2 macrophages are further subdivided into four distinct immune suppressive subsets. TAMs are generally counted as M2-like macrophages with altered immune suppressive functions that exert a significant influence on both cancer progression and the ability of tumors to escape immune surveillance. Their involvement in modulating immune responses via different mechanisms at the local and systemic levels has made them a key target for therapeutic interventions seeking to enhance treatment outcomes. How TAMs' depletion influences immune responses in cancer is the primary interest in cancer immunotherapies. The purpose of this review is to delve into the recent progress made in TAM-targeting therapies. We will explore the current theories, benefits, and challenges associated with TAMs' depletion or inhibition. The manuscript concludes with future directions and potential implications for clinical practice.
    Keywords:  HCC; TAMs; depletion; immunotherapy; liver cancer; macrophages; suppression TME; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3390/cancers17010066
  6. Cancer Drug Resist. 2024 ;7 53
    Ovarian tumor microenvironment contributes to tumor progression and chemoresistance.
    Adriana Ponton-Almodovar, Samuel Sanderson, Ramandeep Rattan, Jamie J Bernard, Sachi Horibata.
      Ovarian cancer is one of the deadliest gynecologic cancers affecting the female reproductive tract. This is largely attributed to frequent recurrence and development of resistance to the platinum-based drugs cisplatin and carboplatin. One of the major contributing factors to increased cancer progression and resistance to chemotherapy is the tumor microenvironment (TME). Extracellular signaling from cells within the microenvironment heavily influences progression and drug resistance in ovarian cancer. This is frequently done through metabolic reprogramming, the process where cancer cells switch between biochemical pathways to increase their chances of survival and proliferation. Here, we focus on how crosstalk between components of the TME and the tumor promotes resistance to platinum-based chemotherapy. We highlight the role of cancer-associated fibroblasts, immune cells, adipocytes, and endothelial cells in ovarian tumor progression, invasion, metastasis, and chemoresistance. We also highlight recent advancements in targeting components of the TME as a novel therapeutic avenue to combat chemoresistance in ovarian cancer.
    Keywords:  Ovarian cancer; chemoresistance; tumor microenvironment
    DOI:  https://doi.org/10.20517/cdr.2024.111
  7. Transl Cancer Res. 2024 Dec 31. 13(12): 6995-7001
    Slamming hepatocellular carcinoma: targeting immunosuppressive macrophages via SLAMF7 reprograms the tumor microenvironment.
    Alix Bruneau, Linda Hammerich.
      Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and one of the leading causes of cancer-related deaths worldwide due to limited treatment options. The tumor microenvironment (TME), which is usually immunosuppressive in HCC, appears to be a decisive factor for response to immunotherapy and strategies aimed at inducing a more inflamed TME hold promise to overcome resistance to immunotherapy. Within the TME, the interplay of various cell types determines whether immunotherapy is successful. Liver macrophages, in particular tumor associated macrophages (TAMs), are known to play a crucial role in tumor progression and represent potential future therapeutic targets. The presence of C-C motif chemokine receptor 2 (CCR2) expressing macrophages is known to be associated with pathogenic angiogenesis and bad prognosis for HCC patients. A recent study published in Cancer Research describes how immunosuppressive macrophages in the TME can be repolarized through targeting Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7)-regulated CC-chemokine ligand 2 (CCL2) signaling, which sensitizes HCC tumors to immunotherapy in a mouse model. This mini-review gives a brief overview about the current knowledge on SLAMF7 in the context of anti-cancer immunity and how the recent findings could be integrated into new therapeutic strategies for HCC.
    Keywords:  Hepatocellular carcinoma (HCC); Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7); combination therapy; tumor microenvironment (TME); tumor-associated macrophages (TAMs)
    DOI:  https://doi.org/10.21037/tcr-24-876
  8. Am J Cancer Res. 2024 ;14(12): 5999-6011
    The role and research progress of tumor-associated macrophages in cervical cancer.
    Dan Wang, Xue Han, Hui-Ling Liu.
      Tumor-associated macrophages (TAMs) are important immune cells in the tumor micro-environment (TME) and play a key role in the occurrence and development of cervical cancer. Besides, targeting TAMs can significantly inhibit cervical cancer tumor growth, invasion, metastasis, and angiogenesis as well as affect immune regulation. This review summarizes the correlation between TAM and tumors, the mechanism of action of TAM in cervical cancer, and the potential application of TAM in the treatment of cervical cancer. Therefore, this study may provide new ideas and targets for the development of further treatment strategies for cervical cancer patients.
    Keywords:  Cervical cancer; immunotherapy; polarization; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.62347/FFXL7288
  9. Mol Cancer. 2025 Jan 11. 24(1): 11
    AXL: shapers of tumor progression and immunosuppressive microenvironments.
    Yihui Liu, Lei Xu, Yuanyao Dou, Yong He.
      As research progresses, our understanding of the tumor microenvironment (TME) has undergone profound changes. The TME evolves with the developmental stages of cancer and the implementation of therapeutic interventions, transitioning from an immune-promoting to an immunosuppressive microenvironment. Consequently, we focus intently on the significant role of the TME in tumor proliferation, metastasis, and the development of drug resistance. AXL is highly associated with tumor progression; however, previous studies on AXL have been limited to its impact on the biological behavior of cancer cells. An increasing body of research now demonstrates that AXL can influence the function and differentiation of immune cells, mediating immune suppression and thereby fostering tumor growth. A comprehensive analysis to identify and overcome the causes of immunosuppressive microenvironments represents a novel approach to conquering cancer. In this review, we focus on elucidating the role of AXL within the immunosuppressive microenvironments, discussing and analyzing the effects of AXL on tumor cells, T cells, macrophages, natural killer (NK) cells, fibroblasts, and other immune-stromal cells. We aim to clarify the contributions of AXL to the progression and drug resistance of cancer from its functional role in the immune microenvironment.
    Keywords:  AXL; Drug resistance; Immunosuppressive microenvironment; TME; Tumor progression
    DOI:  https://doi.org/10.1186/s12943-024-02210-9
  10. Trends Cancer. 2025 Jan 09. pii: S2405-8033(24)00288-7. [Epub ahead of print]
    Recent developments in myeloid immune modulation in cancer therapy.
    Sepideh Parvanian, Xinying Ge, Christopher S Garris.
      Myeloid cells play a crucial dual role in cancer progression and response to therapy, promoting tumor growth, enabling immune suppression, and contributing to metastatic spread. The ability of these cells to modulate the immune system has made them attractive targets for therapeutic strategies aimed at shifting their function from tumor promotion to fostering antitumor immunity. Therapeutic approaches targeting myeloid cells focus on modifying their numbers, genetics, metabolism, and interactions within the tumor microenvironment. These strategies aim to reverse their suppressive functions and redirect them to support antitumor immune responses by inhibiting immunosuppressive pathways, targeting specific receptors, and promoting their differentiation into less immunosuppressive phenotypes. Here, we discuss recent approaches to clinically target tumor myeloid cells, focusing on reprogramming myeloid cells to promote antitumor immunity.
    Keywords:  cancer immunotherapy; dendritic cell; immune agonist; macrophage; myeloid
    DOI:  https://doi.org/10.1016/j.trecan.2024.12.003
  11. Cancers (Basel). 2025 Jan 06. pii: 155. [Epub ahead of print]17(1):
    Metabolic Signaling in the Tumor Microenvironment.
    Ryan Clay, Kunyang Li, Lingtao Jin.
      Cancer cells must reprogram their metabolism to sustain rapid growth. This is accomplished in part by switching to aerobic glycolysis, uncoupling glucose from mitochondrial metabolism, and performing anaplerosis via alternative carbon sources to replenish intermediates of the tricarboxylic acid (TCA) cycle and sustain oxidative phosphorylation (OXPHOS). While this metabolic program produces adequate biosynthetic intermediates, reducing agents, ATP, and epigenetic remodeling cofactors necessary to sustain growth, it also produces large amounts of byproducts that can generate a hostile tumor microenvironment (TME) characterized by low pH, redox stress, and poor oxygenation. In recent years, the focus of cancer metabolic research has shifted from the regulation and utilization of cancer cell-intrinsic pathways to studying how the metabolic landscape of the tumor affects the anti-tumor immune response. Recent discoveries point to the role that secreted metabolites within the TME play in crosstalk between tumor cell types to promote tumorigenesis and hinder the anti-tumor immune response. In this review, we will explore how crosstalk between metabolites of cancer cells, immune cells, and stromal cells drives tumorigenesis and what effects the competition for resources and metabolic crosstalk has on immune cell function.
    Keywords:  cancer metabolism; immune response; oncometabolite; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers17010155
  12. Curr Res Transl Med. 2024 Dec 31. pii: S2452-3186(24)00053-9. [Epub ahead of print]73(2): 103491
    Optimizing CAR-T cell function in solid tumor microenvironment: insights from culture media additives.
    Wenwen Chen, Luxia Xu, Zhigang Guo, Muya Zhou.
      Cancer remains one of the most pressing health challenges worldwide. Recently, chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising approach for treating hematological cancers. However, the translation of CAR-T cell therapy to solid tumors faces formidable obstacles, notably the immunosuppressive tumor microenvironment. Within solid tumors, CAR-T cells encounter a hostile milieu that promotes exhaustion and diminishes their long-term effectiveness against cancer cells. Optimizing the manufacturing process is paramount to ensuring the efficacy of CAR-T cell therapy in solid tumors. A critical aspect of this optimization lies in refining the composition of cell culture media. By supplementing basic culture media with specific additives, researchers aim to improve the behavior and functionality of CAR-T cells, thereby enhancing their therapeutic potential. This review delves into the culture media additives that have been investigated or show promise in modulating CAR-T cell phenotypes and enhancing their anti-tumor efficacy. We explore various types of additives and their mechanisms of action to mitigate exhaustion and augment persistence within the challenging solid tumor microenvironment. By shedding light on the latest advancements in culture media optimization for CAR-T cell therapy, this review aims to provide insights into novel strategies for overcoming the hurdles posed by solid tumors. Ultimately, these insights hold the potential to enhance the effectiveness of CAR-T cell therapy and improve outcomes for cancer patients.
    Keywords:  CAR-T cell therapy; Culture media additives; Memory phenotype; T cell exhaustion; immunotherapy
    DOI:  https://doi.org/10.1016/j.retram.2024.103491
  13. Ann Gastroenterol. 2025 Jan-Feb;38(1):38(1): 1-11
    Landscape of B lymphocytes and plasma cells in digestive tract carcinomas.
    Konstantina Dimopoulou, Dina Tiniakos, Nikolaos Arkadopoulos, Periklis G Foukas.
      Digestive tract carcinomas are the most commonly occurring cancers worldwide, but their prognosis with traditional treatments remains poor. T lymphocytes are well-recognized as crucial components of effective anti-tumor immunity, and current immunotherapeutic strategies concentrate mainly on T-cell-mediated immunity reinforcement, whereas the role of B lymphocytes and plasma cells (PCs) has been neglected in the past, and it is only recently that these cells have been considered as key players in the tumor microenvironment (TME). In this review, we describe the complex dual role of B lymphocytes and PCs in promoting and inhibiting tumor progression in the TME of digestive tract carcinomas, and we demonstrate their prognostic value. Furthermore, we highlight their controversial function in cancer and nominate them as additional therapeutic targets for the development of new treatment interventions that might alter the dismal prognosis of digestive tract tumors.
    Keywords:  B lymphocytes; digestive tract carcinomas; plasma cells
    DOI:  https://doi.org/10.20524/aog.2024.0936
  14. Semin Immunol. 2025 Jan 09. pii: S1044-5323(25)00001-6. [Epub ahead of print]77 101929
    Beyond the Norm: The emerging interplay of complement system and extracellular matrix in the tumor microenvironment.
    Andrea Balduit, Chiara Agostinis, Roberta Bulla.
      Ground-breaking awareness has been reached about the intricate and dynamic connection between developing tumors and the host immune system. Being a powerful arm of innate immunity and a functional bridge with adaptive immunity, the complement system (C) has also emerged as a pivotal player in the tumor microenvironment (TME). Its "double-edged sword" role in cancer can find an explanation in the controversial relationship between C capability to mediate tumor cell cytolysis or, conversely, to sustain chronic inflammation and tumor progression by enhancing cell invasion, angiogenesis, and metastasis to distant organs. However, comprehensive knowledge about the actual role of C in cancer progression is impaired by several limitations of the currently available studies. In the current review, we aim to bring a fresh eye to the controversial role of C in cancer by analyzing the interplay between C and extracellular matrix (ECM) components as potential orchestrators of the TME. The interaction of C components with specific ECM components can determine C activation or inhibition and promote specific non-canonical functions, which can, in the tumor context, favor or limit progression based on the cancer setting. An in-depth and tumor-specific characterization of TME composition in terms of C components and ECM proteins could be essential to determine their potential interactions and become a key element for improving drug development, prognosis, and therapy response prediction in solid tumors.
    Keywords:  Complement system; Extracellular matrix; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.smim.2025.101929
  15. MedComm (2020). 2025 Jan;6(1): e70048
    The crosstalk between senescence, tumor, and immunity: molecular mechanism and therapeutic opportunities.
    Zehua Wang, Chen Chen, Jiaoyu Ai, Yaping Gao, Lei Wang, Shurui Xia, Yongxu Jia, Yanru Qin.
      Cellular senescence is characterized by a stable cell cycle arrest and a hypersecretory, proinflammatory phenotype in response to various stress stimuli. Traditionally, this state has been viewed as a tumor-suppressing mechanism that prevents the proliferation of damaged cells while activating the immune response for their clearance. However, senescence is increasingly recognized as a contributing factor to tumor progression. This dual role necessitates a careful evaluation of the beneficial and detrimental aspects of senescence within the tumor microenvironment (TME). Specifically, senescent cells display a unique senescence-associated secretory phenotype that releases a diverse array of soluble factors affecting the TME. Furthermore, the impact of senescence on tumor-immune interaction is complex and often underappreciated. Senescent immune cells create an immunosuppressive TME favoring tumor progression. In contrast, senescent tumor cells could promote a transition from immune evasion to clearance. Given these intricate dynamics, therapies targeting senescence hold promise for advancing antitumor strategies. This review aims to summarize the dual effects of senescence on tumor progression, explore its influence on tumor-immune interactions, and discuss potential therapeutic strategies, alongside challenges and future directions. Understanding how senescence regulates antitumor immunity, along with new therapeutic interventions, is essential for managing tumor cell senescence and remodeling the immune microenvironment.
    Keywords:  SASP; cancer treatment; cellular senescence; immunity; tumor microenvironment; tumor progression
    DOI:  https://doi.org/10.1002/mco2.70048
  16. Eur J Pharmacol. 2025 Jan 11. pii: S0014-2999(25)00021-4. [Epub ahead of print] 177268
    Role of exosomal miRNAs and macrophage polarization in gastric cancer: a novel therapeutic strategy.
    Yun Zhang, Baozhen Wang, Jing Chen, Tao Li.
      Gastric cancer (GC) is one of the most common gastrointestinal cancers worldwide, with consistently high morbidity and mortality rates and poor prognosis. Most patients are diagnosed at an advanced stage due to the lack of specific presentation in the early stages. Exosomes are a class of extracellular vesicles (EVs) widely found in body fluids and can release genetic material or multiple proteins to facilitate intercellular communication. In recent years, exosomal miRNAs have gained attention for their role in various cancers. These exosomal miRNAs can impact GC development and progression by targeting specific genes or influencing signaling pathways and cytokines involved in Angiogenesis, epithelial-mesenchymal transition (EMT), drug resistance, and immune regulation. They show great potential in terms of diagnosis, prognosis, and treatment of GC. Notably, the gastrointestinal tract has the largest number of macrophages, which play a significant role in GC progression. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and can influence macrophage programming through various mediators, including macrophage polarization. Macrophage polarization is involved in inflammatory responses and significantly impacts the GC process.
    Keywords:  Gastric cancer; exosomes; macrophages; microRNA; treatment
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177268
  17. Cancer Lett. 2025 Jan 11. pii: S0304-3835(25)00018-7. [Epub ahead of print] 217454
    Interrogation of the Tumor Microenvironment by Nanoparticles.
    Prasanta Panja, Upender Manne, Vibhudutta Awasthy, Resham Bhattacharya, Priyabrata Mukherjee.
      The tumor microenvironment (TME) plays a pivotal role in cancer progression by fostering intricate multicellular crosstalk among cancer cells, stromal cells, and immune cells. This review explores the emerging paradigm of utilizing nanoparticles to disrupt this crosstalk within the TME as a therapeutic strategy. Nanoparticles are engineered with precise physicochemical properties to target specific cell types and deliver therapeutic payloads, thereby inhibiting critical signaling pathways involved in tumor growth, invasion, and metastasis. The mechanisms involved include modulation of the immune response, interference with growth factor signaling, and induction of programmed cell death in cancer cells. Challenges such as biocompatibility, efficient delivery, and potential development of resistance are discussed alongside promising advancements in nanoparticle design. Moving forward, integration of nanoparticle-based therapies with existing treatment modalities holds great potential for enhancing therapeutic efficacy and personalized medicine in cancer therapy.
    Keywords:  Cancer Therapy; Multicellular Crosstalk; Nanomedicine; Targeting; Tumor Microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2025.217454
  18. Oncoimmunology. 2025 Dec;14(1): 2451444
    Calpain 2 regulates IL-1α secretion and inhibits tumor development via modulating calpain 1 expression in the tumor microenvironment.
    Zuhairah Binte Hanafi, Yu Mei, Huey Yee Teo, Ying Zhu, Chew Chin Yong Lionel, Jing Wen Chiu, Jinhua Lu, Haiyan Liu.
      Tumor-promoting inflammation significantly impacts cancer progression, and targeting inflammatory cytokines has emerged as a promising therapeutic approach in clinical trials. Interleukin (IL)-1α, a member of the IL-1 cytokine family, plays a crucial role in both inflammation and carcinogenesis. How IL-1α is secreted in the tumor microenvironment has been poorly understood, and we previously showed that calpain 1 cleaves pro-IL-1α for mature IL-1α secretion, which exacerbates hepatocellular carcinoma by recruiting myeloid-derived suppressor cells. In this study, we report that calpain 2 also modulates IL-1α secretion. Notably, a deficiency in calpain 2 resulted in enhanced hepatocellular carcinoma development within an IL-1α-enriched tumor microenvironment. Further investigations revealed that calpain 2 deficiency increased calpain 1 expression, implying a compensatory mechanism between the two calpains. Mechanistically, calpain 2 deficiency led to increased expression of FoxO3, which is a forkhead transcription factor that promotes calpain 1 expression. Collectively, these results suggest that calpain 2 modulates calpain 1 expression, and therefore IL-1α secretion through the induction of FoxO3, offering novel potential therapeutic targets for cancer treatment.
    Keywords:  Calpain 2; IL-1α; MDSCs; hepatocellular carcinoma; tumor microenvironment
    DOI:  https://doi.org/10.1080/2162402X.2025.2451444
  19. Chin J Cancer Res. 2024 Dec 30. 36(6): 652-668
    Fatty acid metabolism: A new target for nasopharyngeal carcinoma therapy.
    Juan Li, Pengbin Ping, Yanhua Li, Xiaoying Xu.
      Lipid metabolic reprogramming is considered one of the most prominent metabolic abnormalities in cancer, and fatty acid metabolism is a key aspect of lipid metabolism. Recent studies have shown that fatty acid metabolism and its related lipid metabolic pathways play important roles in the malignant progression of nasopharyngeal carcinoma (NPC). NPC cells adapt to harsh environments by enhancing biological processes such as fatty acid metabolism, uptake, production, and oxidation, thereby accelerating their growth. In addition, the reprogramming of fatty acid metabolism plays a central role in the tumor microenvironment (TME) of NPC, and the phenotypic transformation of immune cells is closely related to fatty acid metabolism. Moreover, the reprogramming of fatty acid metabolism in NPC contributes to immune escape, which significantly affects disease treatment, progression, recurrence, and metastasis. This review explores recent advances in fatty acid metabolism in NPC and focuses on the interconnections among metabolic reprogramming, tumor immunity, and corresponding therapies. In conclusion, fatty acid metabolism represents a potential target for NPC treatment, and further exploration is needed to develop strategies that target the interaction between fatty acid metabolic reprogramming and immunotherapy.
    Keywords:  Nasopharyngeal carcinoma; fatty acid metabolism; immunity; lipid metabolism; treatment
    DOI:  https://doi.org/10.21147/j.issn.1000-9604.2024.06.05
  20. Exp Cell Res. 2025 Jan 13. pii: S0014-4827(25)00020-5. [Epub ahead of print]445(1): 114424
    Cancer-associated fibroblast-derived exosomes in cancer progression: A focus on hepatocellular carcinoma.
    Chou-Yi Hsu, Abdulrahman T Ahmed, Safia Obaidur Rab, Subasini Uthirapathy, Suhas Ballal, Rishiv Kalia, Renu Arya, Deepak Nathiya, Muthena Kariem, Abed J Kadhim.
      The tumor microenvironment (TME) has drawn much interest recently in the search for innovative cancer therapeutics, especially in light of the growing body of evidence supporting the efficacy of immune checkpoint inhibitors (ICIs). The TME comprises various cell types within the extracellular matrix (ECM), such as immune cells, endothelial cells, and cancer-associated fibroblasts (CAFs). Throughout the malignancy, these cells interact with cancerous cells and with one another. Inside the TME, CAFs are predominant and diverse cell types essential in regulating immune escape, angiogenesis, chemotherapeutic resistance, and cancer cells to invade and metastasize. Extracellular vesicles (EVs) and soluble substances are secreted by CAFs, which also remodel the extracellular matrix to partially coordinate their actions. A subclass of EVs called exosomes comprises proteins, lipids, and nucleic acids. Exosomes contain macromolecules that can transfer from one cell to another, changing the recipient cell's activity. Since exosomes are also circulating, it is possible to investigate their composition as potential biomarkers for cancer patient's diagnosis and prognosis. In this review, we focus on the function of exosomes derived from CAFs in the communications between CAFs and other TME cells and cancerous cells. Initially, we explain the various roles of CAFs in carcinogenesis. Subsequently, we address the processes by which CAFs interact with hepatocellular carcinoma (HCC) cells and other cells within the TME, with a special focus on the function of exosomes. We then go into greater detail regarding the processes by which exosomes derived from CAFs aid in the development of HCC, in addition to the clinical implications of exosomes. Finally, we address facets of exosomes that warrant additional research, such as novel discoveries regarding the enhancement of immune checkpoint inhibitor blockade therapy.
    Keywords:  Cancer progression; Cancer-associated fibroblasts; Exosomes; Extracellular vesicles; Hepatocellular carcinoma
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114424
  21. Adv Exp Med Biol. 2025 ;1464 347-370
    Metabolic Reprogramming and Adaption in Breast Cancer Progression and Metastasis.
    Qianying Zuo, Yibin Kang.
      Recent evidence has revealed that cancer is not solely driven by genetic abnormalities but also by significant metabolic dysregulation. Cancer cells exhibit altered metabolic demands and rewiring of cellular metabolism to sustain their malignant characteristics. Metabolic reprogramming has emerged as a hallmark of cancer, playing a complex role in breast cancer initiation, progression, and metastasis. The different molecular subtypes of breast cancer exhibit distinct metabolic genotypes and phenotypes, offering opportunities for subtype-specific therapeutic approaches. Cancer-associated metabolic phenotypes encompass dysregulated nutrient uptake, opportunistic nutrient acquisition strategies, altered utilization of glycolysis and TCA cycle intermediates, increased nitrogen demand, metabolite-driven gene regulation, and metabolic interactions with the microenvironment. The tumor microenvironment, consisting of stromal cells, immune cells, blood vessels, and extracellular matrix components, influences metabolic adaptations through modulating nutrient availability, oxygen levels, and signaling pathways. Metastasis, the process of cancer spread, involves intricate steps that present unique metabolic challenges at each stage. Successful metastasis requires cancer cells to navigate varying nutrient and oxygen availability, endure oxidative stress, and adapt their metabolic processes accordingly. The metabolic reprogramming observed in breast cancer is regulated by oncogenes, tumor suppressor genes, and signaling pathways that integrate cellular signaling with metabolic processes. Understanding the metabolic adaptations associated with metastasis holds promise for identifying therapeutic targets to disrupt the metastatic process and improve patient outcomes. This chapter explores the metabolic alterations linked to breast cancer metastasis and highlights the potential for targeted interventions in this context.
    Keywords:  Breast cancer; Circulating tumor cells (CTCs); Epithelial-mesenchymal transition (EMT); Metabolism; Metastasis; Metastatic colonization
    DOI:  https://doi.org/10.1007/978-3-031-70875-6_17
  22. World J Gastrointest Oncol. 2025 Jan 15. 17(1): 97831
    Interleukin-17A facilitates tumor progression via upregulating programmed death ligand-1 expression in hepatocellular carcinoma.
    Zhong-Xia Yang, Li-Ting Zhang, Xiao-Jun Liu, Xue-Bin Peng, Xiao-Rong Mao.
       BACKGROUND: Hepatocellular carcinoma (HCC) is an inflammation-associated tumor with a dismal prognosis. Immunotherapy has become an important treatment strategy for HCC, as immunity is closely related to inflammation in the tumor microenvironment. Inflammation regulates the expression of programmed death ligand-1 (PD-L1) in the immunosuppressive tumor microenvironment and affects immunotherapy efficacy. Interleukin-17A (IL-17A) is involved in the remodeling of the tumor microenvironment and plays a protumor or antitumor role in different tumors. We hypothesized that IL-17A participates in tumor progression by affecting the level of immune checkpoint molecules in HCC.
    AIM: To investigate the effect and mechanism of action of IL-17A on PD-L1 expression and to identify attractive candidates for the treatment of HCC.
    METHODS: The upregulation of PD-L1 expression in HCC cells by IL-17A was assessed by reverse transcription PCR, western blotting, and flow cytometry. Mechanistic studies were conducted with gene knockout models and pathway inhibitors. The function of IL-17A in immune evasion was explored through coculture of T cells and HCC cells. The effects of IL-17A on the malignant biological behaviors of HCC cells were evaluated in vitro, and the antitumor effects of an IL-17A inhibitor and its synergistic effects with a PD-L1 inhibitor were studied in vivo.
    RESULTS: IL-17A upregulated PD-L1 expression in HCC cells in a dose-dependent manner, whereas IL-17A receptor knockout or treatment with a small mothers against decapentaplegic 2 inhibitor diminished the PD-L1 expression induced by IL-17A. IL-17A enhanced the survival of HCC cells in the coculture system. IL-17A increased the viability, G2/M ratio, and migration of HCC cells and decreased the apoptotic index. Cyclin D1, VEGF, MMP9, and Bcl-1 expression increased after IL-17A treatment, whereas BAX expression decreased. The combination of IL-17A and PD-L1 inhibitors showed synergistic antitumor efficacy and increased cluster of differentiation 8 + T lymphocyte infiltration in an HCC mouse model.
    CONCLUSION: IL-17A upregulates PD-L1 expression via the IL-17A receptor/phosphorylation-small mothers against decapentaplegic 2 signaling pathway in HCC cells. Blocking IL-17A enhances the therapeutic efficacy of PD-L1 antibodies in HCC in vivo.
    Keywords:  Hepatocellular carcinoma; Immunotherapy; Interleukin-17A; Interleukin-17A receptor; Programmed death ligand-1; Small mothers against decapentaplegic 2
    DOI:  https://doi.org/10.4251/wjgo.v17.i1.97831
  23. Cancers (Basel). 2024 Dec 28. pii: 59. [Epub ahead of print]17(1):
    Synergistic Potential of Antibiotics with Cancer Treatments.
    Giuseppe Nardo, Pan Pantziarka, Matteo Conti.
      Intratumoral microbiota, the diverse community of microorganisms residing within tumor tissues, represent an emerging and intriguing field in cancer biology. These microbial populations are distinct from the well-studied gut microbiota, offering novel insights into tumor biology, cancer progression, and potential therapeutic interventions. Recent studies have explored the use of certain antibiotics to modulate intratumoral microbiota and enhance the efficacy of cancer therapies, showing promising results. Antibiotics can alter intratumoral microbiota's composition, which may have a major role in promoting cancer progression and immune evasion. Certain bacteria within tumors can promote immunosuppression and resistance to therapies. By targeting these bacteria, antibiotics can help create a more favorable environment for chemotherapy, targeted therapy, and immunotherapy to act effectively. Some bacteria within the tumor microenvironment produce immunosuppressive molecules that inhibit the activity of immune cells. The combination of antibiotics and other cancer therapies holds significant promise for creating a synergistic effect and enhancing the immune response against cancer. In this review, we analyze several preclinical studies that have been conducted to demonstrate the synergy between antibiotics and other cancer therapies and discuss possible clinical implications.
    Keywords:  antibiotics; chemotherapy; immunotherapy; microbiome; microbiota; radiotherapy
    DOI:  https://doi.org/10.3390/cancers17010059
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