bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–05–11
29 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Metabolic reprogramming of tumor-associated neutrophils in tumor treatment and therapeutic resistance.
  2. LncRNAs as behind-the-scenes molecules in cancer progression through regulating tumor-associated innate immune system cells.
  3. Role of the tumor microenvironment in cancer therapy: unveiling new targets to overcome drug resistance.
  4. Editorial: NK cells in the tumor microenvironment: immunosuppressive mechanisms and therapeutic opportunities.
  5. A novel exploration of COL11A1's role in regulating myeloid-derived suppressor cell activation within the colon cancer microenvironment.
  6. The mechanism of action and therapeutic potential of tumor-associated macrophages in tumor immune evasion.
  7. Interactions between cancer cells and tumor-associated macrophages in tumor microenvironment.
  8. Role of the RAB27/SYTL Axis in Tumor Microenvironment Construction.
  9. Nivolumab resistance in head and neck squamous cell carcinoma patients and future perspectives.
  10. Protein lipidation in the tumor microenvironment: enzymology, signaling pathways, and therapeutics.
  11. Exosome-mediated ferroptosis in the tumor microenvironment: from molecular mechanisms to clinical application.
  12. CircRNAs in the tumor microenvironment: new frontiers in cancer progression and therapy.
  13. A review of the role of tumor-derived exosomes in cancers treatment and progression.
  14. Subtypes of tumor-associated neutrophils and their roles in cancer immunotherapy.
  15. Advancing Breast Cancer Treatment: The Role of Immunotherapy and Cancer Vaccines in Overcoming Therapeutic Challenges.
  16. An immunomechanical checkpoint PYK2 governs monocyte-to-macrophage differentiation in pancreatic cancer.
  17. Tumor Microenvironment Lactate: Is It a Cancer Progression Marker, Immunosuppressant, and Therapeutic Target?
  18. Dual role of Metrnl: exercise-induced benefits and potential cancer implications.
  19. Corrigendum: Unraveling the enigma of tumor-associated macrophages: challenges, innovations, and the path to therapeutic breakthroughs.
  20. The role of macrophage polarization in ovarian cancer: from molecular mechanism to therapeutic potentials.
  21. Regulating the fate of tumor-associated macrophages.
  22. Editorial: The role of ubiquitination in disease development, progression, and prognosis.
  23. Intratumoral Immunotherapy in Breast Cancer.
  24. Breaking Barriers in Oncology: Harnessing Sonodynamic Therapy for Enhanced Tumor Metabolism Regulation.
  25. Role of Exosome in Solid Cancer Progression and Its Potential Therapeutics in Cancer Treatment.
  26. The Roles of Natural Killer Cells in Breast Cancer Pathobiology and their Regulation by Estrogens.
  27. Prognostic significance of cancer-associated fibroblasts and tumor-associated macrophages in the tongue squamous cell carcinoma and their correlation with tumor budding.
  28. One Step Ahead: Preventing Tumor Adaptation to Immune Therapy.
  29. Roles of macrophages and monocytes in resistance to immunotherapy in breast cancers.
  1. Front Cell Dev Biol. 2025 ;13 1584987
    Metabolic reprogramming of tumor-associated neutrophils in tumor treatment and therapeutic resistance.
    Jun Lin, Xian-Lu He, Wei-Wei Zhang, Chun-Fen Mo.
      Tumor-associated neutrophils (TANs), pivotal immune cells within the tumor microenvironment (TME), exhibit dual potential in both pro- and anti-tumorigenic effects. These cells display remarkable heterogeneity and plasticity within the TME, adapting to hypoxic and nutrient-deprived conditions through metabolic reprogramming while critically influencing tumor progression, metastasis, and immune evasion. The metabolic reprogramming of TANs not only modulates their functional phenotypes but also reshapes tumor biological behaviors and therapeutic responses by regulating metabolic intermediates and cellular interactions within the TME. Therefore, elucidating the mechanisms underlying TANs metabolic reprogramming has significant implications for deciphering the molecular basis of tumorigenesis, identifying novel therapeutic targets, and optimizing immunotherapeutic strategies. This review systematically summarizes current knowledge regarding metabolic reprogramming mechanisms of TANs in the TME and their impact on tumor progression. We particularly focus on: 1) TAN-specific alterations in glucose, lipid, and amino acid metabolism within the TME; 2) Emerging immunotherapeutic strategies targeting TANs metabolic pathways; 3) Recent advances in understanding TAN-mediated immune evasion and therapy resistance. Furthermore, this review discusses potential challenges and corresponding solutions in targeting TANs metabolic reprogramming for therapeutic intervention, aiming to provide novel insights for advancing cancer immunotherapy.
    Keywords:  immunotherapy; metabolic reprogramming; therapeutic resistance; tumor microenvironment; tumor-associated neutrophils
    DOI:  https://doi.org/10.3389/fcell.2025.1584987
  2. Mol Biol Rep. 2025 May 08. 52(1): 449
    LncRNAs as behind-the-scenes molecules in cancer progression through regulating tumor-associated innate immune system cells.
    Mohammad Reza Moghaddasnejad, Ali Keshavarz, Amirhossein Mardi, Negar Sadat Sherafat, Leili Aghebati-Maleki, Mohammad Hossein Mohammadi.
      Long non-coding RNAs (lncRNAs) have emerged as critical regulators in cancer biology, particularly in the modulation of innate immune cells within the tumor microenvironment. These lncRNAs significantly influence the phenotype and function of immune cells, such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), natural killer cells (NK), neutrophils, and γδT cells. Thus, lncRNAs emerge as pivotal molecules in cancer development due to their capacity to modulate the innate immune system. Understanding the intricate mechanisms by which lncRNAs influence tumor-associated immune cells can pave the way for novel therapeutic strategies to restore effective anti-tumor immunity. This review highlights the diverse roles of lncRNAs in regulating the differentiation, activation, and effector functions of innate immune cells within the complex tumor microenvironment.
    Keywords:  Innate immune cells; LncRNA; Tumor microenvironment; miRNAs
    DOI:  https://doi.org/10.1007/s11033-025-10513-3
  3. Med Oncol. 2025 May 07. 42(6): 202
    Role of the tumor microenvironment in cancer therapy: unveiling new targets to overcome drug resistance.
    Sri Sathya Sandilya Garemilla, Siri Chandana Gampa, Sireesha Garimella.
      Cancer is a leading cause of death globally, with resistance to therapy representing a major obstacle to effective treatment. The tumor microenvironment (TME), comprising a complex network to cellular and non-cellular components including cancer-associated fibroblasts, immune cells, the extracellular matrix and region of hypoxia, is integral to cancer progression and therapeutic resistance. This review delves into the multifaceted interactions within the TME that contribute to tumor growth, survival and immune evasion. Key elements such as the role of cancer- associated fibroblasts in remodeling the extracellular matrix and promoting angiogenesis, the influence of immune cells such as tumor-associated macrophages in creating an immunosuppressive milieu and the impact of hypoxia conditions on metabolic adaptation and therapy resistance are thoroughly examined. This review evaluates current and emerging TME-targeted therapeutic strategies, including inhibitors of extracellular matrix components, modulators of immune cell activity and approached to alleviate hypoxia. Combination therapies that integrate TME-targeted agents with conventional treatments such as chemotherapy and immunotherapy are also discussed for their potential to enhance treatment efficacy and circumvent resistance mechanisms. By synthesising recent advances in TME research and therapeutic innovation, this paper aims to underscore the importance of TME in cancer therapy and highlight promising avenues for improving patient outcomes through targeted intervention.
    Keywords:  Cancer-associated fibroblasts (CAFs); Extracellular matrix (ECM); Hypoxia; Immune cells; Therapeutic resistance; Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1007/s12032-025-02754-w
  4. Front Immunol. 2025 ;16 1606236
    Editorial: NK cells in the tumor microenvironment: immunosuppressive mechanisms and therapeutic opportunities.
    Jose M Ayuso, Jorrit De Waele.
      
    Keywords:  Natural Killer cells; cancer immunotherapy; cell adoptive therapy; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1606236
  5. J Pharm Anal. 2025 Apr;15(4): 101181
    A novel exploration of COL11A1's role in regulating myeloid-derived suppressor cell activation within the colon cancer microenvironment.
    Wei Niu, Xiaxia Du, Yang Song, Lianyi Guo, Baohai Liu, Xin Tong.
      This study aimed to elucidate the role of collagen type XI alpha 1 (COL11A1)-positive cancer-associated fibroblasts (CAFs) in modifying the tumor microenvironment of colon cancer (CC) and facilitating immune evasion through interactions with myeloid-derived suppressor cells (MDSCs). Using single-cell transcriptomic sequencing, we analyzed the interplay between COL11A 1-positive CAFs and MDSCs in the CC microenvironment, focusing on how COL11A1 impacts MDSC differentiation and activation. The results demonstrate that COL11A1 expression in fibroblasts significantly enhances matrix metalloproteinase (MMP)3 and MMP13 expression, leading to paracrine induction of MDSC differentiation and activation, which promotes immune evasion and tumor growth. Additionally, we observed that COL11A1 knockout (COL11A1KO) suppresses tumor growth and hinders immune evasion. These findings underscore the essential role of COL11A 1-positive CAFs in establishing an immunosuppressive tumor microenvironment conducive to CC progression. By elucidating the molecular pathway through which COL11A1 influences MDSC activity, this research suggests new therapeutic avenues for targeting the tumor microenvironment in CC, particularly through modulating COL11A1 expression in CAFs.
    Keywords:  COL11A1; Cancer-associated fibroblasts; Colon cancer; MMP13; MMP3; Myeloid-derived suppressor cells
    DOI:  https://doi.org/10.1016/j.jpha.2024.101181
  6. Front Immunol. 2025 ;16 1545928
    The mechanism of action and therapeutic potential of tumor-associated macrophages in tumor immune evasion.
    Kehua Wang, Xu Zhang, Aiqin Li, Xia Qiao, Yanan Xu.
      Tumor-associated macrophages (TAMs) play a multifaceted role in tumor progression. As specialized immune cells, macrophages are capable of phagocytosis and digesting foreign substances, as well as removing harmful substances including cellular debris and tumor cells. Under specific pathological conditions, circulating monocytes can be recruited into the tumor microenvironment and differentiate into TAMs. Macrophages are generally polarized into two distinct subpopulations: classically activated macrophages (M1) and alternatively activated macrophages (M2). TAMs constitute a significant proportion of the mononuclear leukocyte population in solid tumors, exhibiting a complex and dualistic relationship with tumor cells. Substantial evidence indicates that TAMs can interact with tumor cells, facilitating their immune evasion while promoting invasion and metastasis. This review focuses on the mechanism and regulation of macrophages in the immune response to tumor cells, as well as various macrophage-based tumor-targeted therapeutic strategies. It will provide a reference for research on macrophage-centered therapy strategies and their application in clinical practice.
    Keywords:  TAMs; cytokines; macrophage; regulation of immunity; tumor
    DOI:  https://doi.org/10.3389/fimmu.2025.1545928
  7. Biochim Biophys Acta Rev Cancer. 2025 May 07. pii: S0304-419X(25)00086-1. [Epub ahead of print] 189344
    Interactions between cancer cells and tumor-associated macrophages in tumor microenvironment.
    Lu Liu, Yafei Li, Bo Li.
      Tumor microenvironment (TME) refers to the local environment in which various cancer cells grow, encompassing tumor cells, adjacent non-tumor cells, and associated non-cellular elements, all of which collectively promote cancer occurrence and progression. As a principal immune component in the TME, tumor-associated macrophages (TAMs) exert a considerable influence on cancer behaviors via their interactions with cancer cells. The interactive loops between cancer cells and TAMs, including secretory factors derived from both cancer cells and TAMs, are crucial for the proliferation, stemness, drug resistance, invasion, migration, metastasis, and immune escape of various cancers. Cancer cells release paracrine proteins (HMGB1, AREG etc.), cytokines (IL-6, CCL2 etc.), RNAs (miR-21-5p, circPLEKHM1, LINC01812 etc.), and metabolites (lactic acid, succinate etc.) to regulate the polarization phenotype, mediator secretion and function of TAMs. In turn, mediators (TGF-β, IL-10, IL-6 etc.) from TAMs promote cancer progression. This review summarizes recent advancements in the interactive loops between cancer cells and TAMs in TME. Inhibiting the recruitment and M2 polarization of TAMs, reprogramming TAMs from M2 to M1 phenotype, blocking TAMs-mediated immunosuppression and immune escape, and combining with existing immunotherapy can target TAMs to overcome immunotherapy resistance in various cancers. The new breakthroughs lie in identifying effective targets for drug development, improving the drug delivery system to enhance the drug delivery efficiency, and adopting combined therapy. Interventions targeting secretory factors, cell surface receptors, and intracellular signaling pathways and metabolic modulation in the interactive loops between cancer cells and TAMs are expected to suppress cancer progression and improve therapeutic effects.
    Keywords:  Cancer cell; Cytokine; Interaction; Mediator; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189344
  8. Cancer Sci. 2025 May 04.
    Role of the RAB27/SYTL Axis in Tumor Microenvironment Construction.
    Miwa Tanaka, Takuro Nakamura.
      Crosstalk between cancer cells and the tumor microenvironment (TME) is a key event in malignant progression and metastasis. The secretion of bioactive substances by cancer cells remodels the TME, affecting the activities of its components, including blood vessels, mesenchymal cells, and immune cells. These substances are effectively delivered through intracellular trafficking and exocytosis of cytoplasmic vesicles. The small guanosine triphosphatase (GTPase) RAB27 and its effectors, synaptotagmin-like (SYTL) family proteins, play essential roles in vesicle trafficking. Our recent research demonstrates the upregulation of RAB27A/B and SYTL1/2 in alveolar soft part sarcoma and acute myeloid leukemia. This enhanced trafficking promotes angiogenesis and the occupation of leukemia cells in the bone marrow niche. This review focuses on the role of the RAB27/SYTL axis in various cancer types associated with TME modifications, with a discussion on its importance as a therapeutic target.
    Keywords:  RAB27; SYTL; angiogenesis; trafficking; tumor microenvironment
    DOI:  https://doi.org/10.1111/cas.70096
  9. Contemp Oncol (Pozn). 2025 ;29(1): 22-27
    Nivolumab resistance in head and neck squamous cell carcinoma patients and future perspectives.
    Karolina Buchajska, Anna Mydlak, Jakub Zwoliński, Kinga Wojtaszczyk, Bartosz Spławski.
      Head and neck cancer (HNC) cases are increasing globally, with resistance to immunotherapies such as nivolumab posing a significant challenge. This systematic review examines the mechanisms of nivolumab resistance in HNC, with a focus on intrinsic tumor factors, the immunosuppressive tumor microenvironment (TME), and immune checkpoint dysregulation. Intrinsic mechanisms, such as mutations that impair antigen presentation and MYC amplification, reshape the TME to promote immune evasion. The tumor microenvironment, enriched with immunosuppressive cells such as tumor-associated macrophages and myeloid-derived suppressor cells, further compromises nivolumab's effectiveness. Moreover, cancer cells exploit immune checkpoints, including programmed death-ligand 1 (PD-L1), T-cell immunoglobulin and mucin domain-3, and LAG-3, to evade immune surveillance. Identifying predictive biomarkers, such as MYC amplification and PD-L1 expression, is essential for developing personalized treatments. This review underscores the complex nature of nivolumab resistance and the urgent need for comprehensive therapeutic strategies to improve outcomes in HNC patients.
    Keywords:  PD-1/PD-L1 pathway; emerging therapies in HNSCC; future perspectives in immunotherapy; head and neck squamous cell carcinoma (HNSCC); immunotherapy in HNSCC; mechanisms of drug resistance; nivolumab resistance; overcoming immunotherapy resistance
    DOI:  https://doi.org/10.5114/wo.2025.149237
  10. Mol Cancer. 2025 May 07. 24(1): 138
    Protein lipidation in the tumor microenvironment: enzymology, signaling pathways, and therapeutics.
    Mengke Xu, Bo Xu.
      Protein lipidation is a pivotal post-translational modification that increases protein hydrophobicity and influences their function, localization, and interaction network. Emerging evidence has shown significant roles of lipidation in the tumor microenvironment (TME). However, a comprehensive review of this topic is lacking. In this review, we present an integrated and in-depth literature review of protein lipidation in the context of the TME. Specifically, we focus on three major lipidation modifications: S-prenylation, S-palmitoylation, and N-myristoylation. We emphasize how these modifications affect oncogenic signaling pathways and the complex interplay between tumor cells and the surrounding stromal and immune cells. Furthermore, we explore the therapeutic potential of targeting lipidation mechanisms in cancer treatment and discuss prospects for developing novel anticancer strategies that disrupt lipidation-dependent signaling pathways. By bridging protein lipidation with the dynamics of the TME, our review provides novel insights into the complex relationship between them that drives tumor initiation and progression.
    Keywords:   N-myristoylation; S-palmitoylation; S-prenylation; Lipidation; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12943-025-02309-7
  11. Cell Death Discov. 2025 May 06. 11(1): 221
    Exosome-mediated ferroptosis in the tumor microenvironment: from molecular mechanisms to clinical application.
    Na Liu, Tianqing Wu, Guohu Han, Minbin Chen.
      Ferroptosis in the tumor microenvironment (TME) plays a crucial role in the development, metastasis, immune escape, and drug resistance of various types of cancer. A better understanding of ferroptosis in the TME could illuminate novel aspects of this process and promote the development of targeted therapies. Compelling evidence indicates that exosomes are key mediators in regulating the TME. In this respect, it is now understood that exosomes can deliver biologically functional molecules to recipient cells, influencing cancer progression by reprogramming the metabolism of cancer cells and their surrounding stromal cells through ferroptosis. In this review, we focus on the role of exosomes in the TME and describe how they contribute to tumor reprogramming, immunosuppression, and the formation of pre-metastatic niches through ferroptosis. In addition, we highlight exosome-mediated ferroptosis as a potential target for cancer therapy and discuss strategies employing exosomes in ferroptosis treatment. Finally, we outline the current applications and challenges of targeted exosome-mediated ferroptosis therapy in tumor immunotherapy and chemotherapy. Our aim is to advance research on the link between exosomes and ferroptosis in the TME, and we pose questions to guide future studies in this area.
    DOI:  https://doi.org/10.1038/s41420-025-02484-y
  12. Crit Rev Oncol Hematol. 2025 May 02. pii: S1040-8428(25)00142-8. [Epub ahead of print]212 104754
    CircRNAs in the tumor microenvironment: new frontiers in cancer progression and therapy.
    Yipei Guo, Yuanxun Gong, Man Wu, Mengjia Ji, Fei Xie, Hao Chen, Haitao Niu, Chao Tang.
      The tumor microenvironment (TME), a dynamic ecosystem which including immune cells, cancer-associated fibroblasts (CAFs), endothelial cells, pericytes and acellular components, is orchestrating cancer progression through crosstalk between malignant cells and stromal components and increasingly recognized as a therapeutic frontier. Within this intricate network, circular RNAs (circRNAs) have emerged as pivotal regulators due to their unique covalently closed structures, which confer exceptional stability and multifunctional capabilities. This regulation is mediated through multiple mechanisms, such as acting as microRNA (miRNA) sponges, interacting with proteins, and, in certain instances, encoding functional peptides. The interaction between circRNAs and the TME not only affects cancer growth and metastasis but also influences immune evasion and therapeutic resistance. Elucidating the mechanisms by which circRNAs orchestrate these interactions is essential for identifying novel diagnostic biomarkers and developing effective therapeutic strategies. Such insights are expected to bridge gaps in current cancer biology, offering promising avenues for precision oncology and ultimately improving clinical outcomes for cancer patients.
    Keywords:  CircRNA; Immune Modulation; Precision Oncology; Therapeutic Resistance; Tumor Microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104754
  13. Int Immunopharmacol. 2025 May 06. pii: S1567-5769(25)00772-6. [Epub ahead of print]157 114782
    A review of the role of tumor-derived exosomes in cancers treatment and progression.
    Wajida Ataallah Khidr, Karar H Alfarttoosi, Waam Mohammed Taher, Mariem Alwan, Ali M Ali Al-Nuaimi, Mahmood Jasem Jawad.
      Tumor cells (TCs) produce exosomes (EXOs), nanovesicles formed in endosomes. Tumor-derived exosomes (TDEs) are tiny, bubble-shaped structures formed by TCs that include microRNAs (miRNA), proteins, enzymes, and copies of DNA and RNA. Many different kinds of cancer rely on TDEs. For instance, TDEs play a large role in the tumor microenvironment (TME) and promote tumor spread via many pathways. Furthermore, TDEs impact the efficacy of cancer treatments. Additionally, because of their low immunogenicity, high biocompatibility, and low toxicity, TDEs have been extensively used as drug delivery vehicles for cancer immunotherapy. Consequently, future cancer treatments may benefit from focusing on both the therapeutic function and the tumorigenic pathways of TDEs. Consequently, in this work, we have examined the roles of TDEs in cancer development, such as tumor angiogenesis, immune system evasion, and tumor metastasis. Then, we reviewed TDEs used to transport anticancer medicines, including chemotherapeutic medications, therapeutic compounds (including miRNA), and anticancer nanoparticles. We have concluded by outlining the challenges of clinical translation, including carcinogenicity and medication resistance, and by offering some suggestions for addressing these issues.
    Keywords:  Cancers; Drug delivery systems; Metastasis; Tumor-derived exosomes; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.intimp.2025.114782
  14. Crit Rev Oncol Hematol. 2025 May 05. pii: S1040-8428(25)00151-9. [Epub ahead of print] 104763
    Subtypes of tumor-associated neutrophils and their roles in cancer immunotherapy.
    Xinyun Chu, Ning Pu, Xue Yang, Yuqi Xie, Liang Liu, Yun Jin.
      Neutrophils are essential components of the innate immune system. Tumor-associated neutrophils (TANs) are shaped by tumor microenvironment (TME), leading to significant heterogeneity in biological characteristics and functions. Recent advances in single-cell sequencing have revealed a wide array of TAN subtypes, while a comprehensive classification system is still lacking. This review aims to summarize the alterations observed in TAN subgroups following cancer immunotherapy, and identify the distinctions and commonalities between pro-tumor and anti-tumor subgroups. Current progress of preclinical and clinical studies is also highlighted, involving novel therapies targeting TANs.
    Keywords:  Cancer Immunotherapy; Clinical translation; Reprogram; Subgroups; Tumor-associated neutrophils
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104763
  15. Vaccines (Basel). 2025 Mar 24. pii: 344. [Epub ahead of print]13(4):
    Advancing Breast Cancer Treatment: The Role of Immunotherapy and Cancer Vaccines in Overcoming Therapeutic Challenges.
    Marco Palma.
      Breast cancer (BC) remains a significant global health challenge due to its complex biology, which complicates both diagnosis and treatment. Immunotherapy and cancer vaccines have emerged as promising alternatives, harnessing the body's immune system to precisely target and eliminate cancer cells. However, several key factors influence the selection and effectiveness of these therapies, including BC subtype, tumor mutational burden (TMB), tumor-infiltrating lymphocytes (TILs), PD-L1 expression, HER2 resistance, and the tumor microenvironment (TME). BC subtypes play a critical role in shaping treatment responses. Triple-negative breast cancer (TNBC) exhibits the highest sensitivity to immunotherapy, while HER2-positive and hormone receptor-positive (HR+) subtypes often require combination strategies for optimal outcomes. High TMB enhances immune responses by generating neoantigens, making tumors more susceptible to immune checkpoint inhibitors (ICIs); whereas, low TMB may indicate resistance. Similarly, elevated TIL levels are associated with better immunotherapy efficacy, while PD-L1 expression serves as a key predictor of checkpoint inhibitor success. Meanwhile, HER2 resistance and an immunosuppressive TME contribute to immune evasion, highlighting the need for multi-faceted treatment approaches. Current breast cancer immunotherapies encompass a range of targeted treatments. HER2-directed therapies, such as trastuzumab and pertuzumab, block HER2 dimerization and enhance antibody-dependent cellular cytotoxicity (ADCC), while small-molecule inhibitors, like lapatinib and tucatinib, suppress HER2 signaling to curb tumor growth. Antibody-drug conjugates (ADCs) improve tumor targeting by coupling monoclonal antibodies with cytotoxic agents, minimizing off-target effects. Meanwhile, ICIs, including pembrolizumab, restore T-cell function, and CAR-macrophage (CAR-M) therapy leverages macrophages to reshape the TME and overcome immunotherapy resistance. While immunotherapy, particularly in TNBC, has demonstrated promise by eliciting durable immune responses, its efficacy varies across subtypes. Challenges such as immune-related adverse events, resistance mechanisms, high costs, and delayed responses remain barriers to widespread success. Breast cancer vaccines-including protein-based, whole-cell, mRNA, dendritic cell, and epitope-based vaccines-aim to stimulate tumor-specific immunity. Though clinical success has been limited, ongoing research is refining vaccine formulations, integrating combination therapies, and identifying biomarkers for improved patient stratification. Future advancements in BC treatment will depend on optimizing immunotherapy through biomarker-driven approaches, addressing tumor heterogeneity, and developing innovative combination therapies to overcome resistance. By leveraging these strategies, researchers aim to enhance treatment efficacy and ultimately improve patient outcomes.
    Keywords:  HER2-positive; breast cancer; cancer vaccines; immunotherapy; triple-negative breast cancer; tumor microenvironment
    DOI:  https://doi.org/10.3390/vaccines13040344
  16. Cancer Discov. 2025 May 09.
    An immunomechanical checkpoint PYK2 governs monocyte-to-macrophage differentiation in pancreatic cancer.
    Wenyan Xie, Xin Yu, Qingxin Yang, Nengwen Ke, Ping Wang, Hao Kong, Xiangji Wu, Panpan Ma, Lang Chen, Jie Yang, Xiuqin Feng, Yuan Wang, Hubing Shi, Lu Chen, Yun-Hua Liu, Bi-Sen Ding, Qiang Wei, Hong Jiang.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic, stiff tumor microenvironment (TME), where tumor-associated macrophages (TAMs) drive ECM remodeling, progression, and immune evasion. The contribution of mechanical cues to monocyte differentiation into TAMs remains largely unexplored. Here we show that mechanical force is required for monocyte-to-macrophage differentiation. PYK2, as an innovative immunomechanical checkpoint, de facto governs this differentiation process. We demonstrated that PYK2 senses mechanical signals via Piezo1 and integrins, triggering F-actin polymerization and translocating to the nucleus to regulate mechanotransduction and differentiation genes (e.g., ACTR3, RELA). Targeted deletion of PYK2 impairs the differentiation and polarization of monocyte-derived macrophages, reshapes the PDAC microenvironment, and enhances the efficacy of anti-PD-1 immunotherapy. These findings underscore the critical role of mechanical cues in monocyte differentiation and suggest that targeting PYK2 is a promising strategy to modulate TAM function and improve immunotherapy outcomes in patients with PDAC.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1712
  17. Molecules. 2025 Apr 15. pii: 1763. [Epub ahead of print]30(8):
    Tumor Microenvironment Lactate: Is It a Cancer Progression Marker, Immunosuppressant, and Therapeutic Target?
    Eugene Y Kim, Joyce Abides, Chandler R Keller, Steve R Martinez, Weimin Li.
      The "Warburg effect" is a term coined a century ago for the preferential use of glycolysis over aerobic respiration in tumor cells for energy production, even under aerobic conditions. Although this is a less efficient mechanism of generating energy from glucose, aerobic glycolysis, in addition to the canonical anaerobic glycolysis, is an effective means of lactate production. The abundant waste product, lactate, yielded by the dual glycolysis in a tumor, has been discovered to be a major biomolecule that drives cancer progression. Lactate is a metabolic energy source that, via cell membrane lactate transporters, shuttles in and out of cancer cells as well as cancer cell-associated stromal cells and immune cells within the tumor microenvironment (TME). Additionally, lactate serves as a pH tuner, signaling ligand and transducer, epigenetic and gene transcription regulator, TME modifier, immune suppressor, chemoresistance modulator, and prognostic marker. With such broad functionalities, the production-consumption-reproduction of TME lactate fuels tumor growth and dissemination. Here, we elaborate on the lactate sources that contribute to the pool of lactate in the TME, the functions of TME lactate, the influence of the TME lactate on immune cell function and local tissue immunity, and anticancer therapeutic approaches adopting lactate manipulations and their efficacies. By scrutinizing these properties of the TME lactate and others that have been well addressed in the field, it is expected that a better weighing of the influence of the TME lactate on cancer development, progression, prognosis, and therapeutic efficacy can be achieved.
    Keywords:  cell metabolism; immune regulation; lactate; posttranslational modification; signaling and gene regulation; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/molecules30081763
  18. J Immunother Cancer. 2025 May 07. pii: e011666. [Epub ahead of print]13(5):
    Dual role of Metrnl: exercise-induced benefits and potential cancer implications.
    Hamid Alizadeh.
      Metrnl (Meteorin-like), a protein elevated by exercise, supports metabolic regulation, inflammation reduction and glucose homeostasis. While exercise is a cornerstone of cancer prevention and management, recent findings suggest that Metrnl plays a dual role, potentially impairing T-cell function in the tumor microenvironment. This commentary explores the interplay between Metrnl's systemic benefits and its local immunosuppressive effects in cancer. Despite these concerns, exercise remains broadly advantageous for patients with cancer, though further research is essential to understand Metrnl's context-specific impacts.
    Keywords:  Cytokine; T-Lymphocytes; Tumor infiltrating lymphocyte - TIL; Tumor microenvironment - TME
    DOI:  https://doi.org/10.1136/jitc-2025-011666
  19. Front Immunol. 2025 ;16 1606194
    Corrigendum: Unraveling the enigma of tumor-associated macrophages: challenges, innovations, and the path to therapeutic breakthroughs.
    Shengwen Shao, Huilai Miao, Wenxue Ma.
      [This corrects the article DOI: 10.3389/fimmu.2023.1295684.].
    Keywords:  cancer immunotherapy; clinical trials; phenotypic diversity; regulatory signaling pathways; tumor microenvironment (TME); tumor-associated macrophages (TAM)
    DOI:  https://doi.org/10.3389/fimmu.2025.1606194
  20. Front Immunol. 2025 ;16 1543096
    The role of macrophage polarization in ovarian cancer: from molecular mechanism to therapeutic potentials.
    Chenchen Xu, Jiyu Chen, Mi Tan, Qingqing Tan.
      Ovarian cancer (OC) remains the most lethal gynecological malignancy, primarily due to its late-stage diagnosis, frequent recurrence, and resistance to conventional chemotherapy. A critical factor contributing to OC's aggressiveness is the tumor microenvironment (TME), particularly the presence and polarization of tumor-associated macrophages (TAMs). TAMs, often skewed toward an immunosuppressive M2-like phenotype, facilitate tumor growth, angiogenesis, metastasis, and resistance to therapy. This comprehensive review delves into the multifaceted regulation of macrophage polarization in OC, highlighting key molecular pathways such as PTEN loss, Wnt/β-catenin signaling, NF-κB, Myc, STAT3, and JNK, among others. Additionally, it explores the role of chemokines, non-coding RNAs, and various proteins in modulating TAM phenotypes. Emerging evidence underscores the significance of extracellular vesicles (EVs) and ovarian cancer stem cells (CSCs) in promoting M2 polarization, thereby enhancing tumor progression and therapy resistance. The review also identifies critical biomarkers associated with macrophage polarization, including CD163, LILRB1, MUC2, and others, which hold prognostic and therapeutic potential. Therapeutic strategies targeting TAMs are extensively discussed, encompassing oncolytic viruses, engineered EVs, immunotherapies, nanoparticles, targeted therapies, and natural products. These approaches aim to reprogram TAMs from a pro-tumorigenic M2 state to an anti-tumorigenic M1 phenotype, thereby enhancing immune responses and overcoming resistance to treatments such as chemotherapy and immune checkpoint inhibitors. Furthermore, the review addresses the interplay between macrophage polarization and therapy resistance, emphasizing the need for novel interventions to modulate the TME effectively. By synthesizing current knowledge on macrophage polarization in ovarian cancer, this study underscores the potential of targeting TAMs to improve clinical outcomes and personalize treatment strategies for OC patients. Continued research in this domain is essential to develop robust therapeutic frameworks that can mitigate the immunosuppressive TME and enhance the efficacy of existing and novel cancer therapies.
    Keywords:  biomarkers; extracellular vesicles; immunotherapy; macrophage polarization; ovarian cancer; therapy resistance; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2025.1543096
  21. Cancer Cell. 2025 Apr 27. pii: S1535-6108(25)00165-5. [Epub ahead of print]
    Regulating the fate of tumor-associated macrophages.
    Elina Timosenko, Dmitry I Gabrilovich.
      Tumor-associated macrophages (TAMs) are key players in tumor progression, yet their role in this process remains only partially understood. In this issue of Cancer Cell, Sheban et al. demonstrate that zinc finger E-box-binding homeobox 2 (ZEB2) acts as a master regulator that reprograms TAMs toward a pro-tumor phenotype and that therapeutic targeting of ZEB2 exhibits anti-tumor activity.
    DOI:  https://doi.org/10.1016/j.ccell.2025.04.006
  22. Front Immunol. 2025 ;16 1595755
    Editorial: The role of ubiquitination in disease development, progression, and prognosis.
    Mingyang Xue, Wenyi Jin.
      
    Keywords:  disease development; disease progression; immune regulation; tumor cells; tumor microenvironment; ubiquitination
    DOI:  https://doi.org/10.3389/fimmu.2025.1595755
  23. Vaccines (Basel). 2025 Apr 19. pii: 429. [Epub ahead of print]13(4):
    Intratumoral Immunotherapy in Breast Cancer.
    Camille C Baumrucker, Nicole Harris, Susan Hoover, Brian J Czerniecki.
      Breast cancer remains the most frequently diagnosed cancer and the second highest cause of cancer death in females. Metastatic recurrence that is resistant to traditional therapies presents a major challenge, necessitating the development of an innovative treatment strategy. Immunotherapy has gained popularity in the treatment of cancer, particularly melanoma, lung cancer, and more recently breast cancer. Major developments in immunotherapy have been made with a better understanding of the tumor microenvironment and how the microenvironment can be manipulated to induce an anti-tumor immune response. Intratumorally delivered immunotherapy can be used to create a local immune response. This review provides a comprehensive overview of intratumoral immunotherapy for breast cancer and its resultant changes in the tumor microenvironment. The discussed immunotherapeutics include oncolytic viruses, nucleic acids, innate immune agonists, bacteria, chimeric antigen receptor T cells, and dendritic cells. The review also evaluates completed clinical trials using these therapies. Lastly, the review offers future perspectives in the development of breast cancer immunotherapy.
    Keywords:  breast cancer; dendritic cell vaccines; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3390/vaccines13040429
  24. Small. 2025 May 02. e2502323
    Breaking Barriers in Oncology: Harnessing Sonodynamic Therapy for Enhanced Tumor Metabolism Regulation.
    Yangmengfan Chen, Kun Li, Hao Du, Yangcheng Yao, Dong Xie, Zongke Zhou.
      The recent booming development of sonometabolism regulation in controlling the tumor microenvironment (TME) has opened a new research area to identify innovative approaches against cancer. The aim of this review is to highlight the potentials and advantages of sonodynamic therapy (SDT) in antitumor nanotherapies, specifically, delineating the progress made in SDT concerning the regulation of TME metabolism which encompasses factors such as hypoxia, redox balance, autophagy, immunosuppression, ion homeostasis, and other metabolic processes. By focusing on both tumor cell metabolism and TME dynamics, a wide range of SDT strategies that have demonstrated great therapeutic effectiveness by targeting the metabolic functions inherent to TME are summarized. In conclusion, this review offers valuable insights for researchers involved in SDT-based antitumor therapeutic strategies, with the aim of advancing the development of antitumor SDT methodologies in future research.
    Keywords:  Metabolic regulations; Nanomedicine; Sonodynamic therapies; Tumor microenvironments
    DOI:  https://doi.org/10.1002/smll.202502323
  25. Cancer Med. 2025 May;14(9): e70941
    Role of Exosome in Solid Cancer Progression and Its Potential Therapeutics in Cancer Treatment.
    Nada Aakel, Rawdhah Mohammed, Assela Fathima, Rabia Kerzabi, Atiyeh Abdallah, Wisam Nabeel Ibrahim.
       BACKGROUND: Exosomes are extracellular vesicles ranging from 40 to 100 nm in diameter that mediate intercellular communication by transferring proteins, lipids, nucleic acids, and other metabolites. In the context of cancer, exosomes influence the tumor microenvironment by carrying regulatory RNAs such as miRNA, circRNA, and lncRNA. They originate from various cells, including adipocytes, fibroblasts, and hepatocellular carcinoma (HCC) cells, and can either promote or inhibit cancer progression through pathways like MAPK and PI3K-Akt.
    AIM: This review aims to explore the role of exosomes in the progression of solid cancers, emphasizing their self-induced activation mechanisms and how they modulate tumor behavior.
    METHODOLOGY: A comprehensive review of recent literature was conducted, focusing on studies that investigated the biological functions of exosomes in solid tumor progression, including their molecular cargo, cellular origin, and involvement in signaling pathways.
    RESULTS: Findings from multiple studies indicate that cancer-derived exosomes contribute to tumor proliferation, metastasis, and therapy resistance by enhancing communication within the tumor microenvironment. These vesicles activate oncogenic pathways and can serve as biomarkers or therapeutic targets due to their role in disease modulation.
    CONCLUSION: Exosomes play a pivotal role in solid cancer progression and offer significant potential in advancing our understanding of tumor biology. Their capacity to influence key signaling pathways and facilitate intercellular communication makes them promising candidates for novel diagnostic and therapeutic strategies.
    Keywords:  cancer biology; cancer progression; exosomes; extracellular vesicles; molecular signaling; solid tumors; therapeutic targets; tumor microenvironment
    DOI:  https://doi.org/10.1002/cam4.70941
  26. Endocr Rev. 2025 May 09. pii: bnaf014. [Epub ahead of print]
    The Roles of Natural Killer Cells in Breast Cancer Pathobiology and their Regulation by Estrogens.
    Jovita Byemerwa, Ching-Yi Chang, Donald P McDonnell.
      Breast cancer remains the most commonly diagnosed malignancy among women worldwide. While breast cancer treatment outcomes have improved in recent years there remains an unmet medical need for therapeutics that can be used with curative intent in the most aggressive breast cancer subtypes and for those cancers that have metastasized. In recent years, the success of T-cell-based therapies and other technologies that boost anti-tumor activities of immune cells have increased interest in using natural killer (NK) cell-based immunotherapies to treat solid tumors. These innate lymphoid cells can identify and eliminate tumor cells through their intrinsic cytotoxic activities and their ability to modulate the immune response through cytokine production. Owing to their lack of T-cell receptors, NK cells can also be used in the allogeneic setting and strategies to develop and establish NK cells as therapeutics in breast cancer are currently being explored. In this review, we will describe NK cell biology as it relates to breast cancer pathobiology and treatment outcomes and discuss how NK cell biology can be exploited and manipulated in the development of new therapeutics for breast cancer. Additionally, we review the role of estrogens in regulating NK cell activity and discuss how endocrine therapies targeting the estrogen receptor signaling axis could be employed as an approach to increase tumor immunity and the efficacy of NK-cell-directed immunotherapies.
    Keywords:  17β-Estradiol (E2); Breast cancer; CAR-NK; Natural Killer cells; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1210/endrev/bnaf014
  27. Oral Oncol. 2025 May 05. pii: S1368-8375(25)00124-1. [Epub ahead of print]165 107295
    Prognostic significance of cancer-associated fibroblasts and tumor-associated macrophages in the tongue squamous cell carcinoma and their correlation with tumor budding.
    Yuki Oikawa, Michinobu Umakoshi, Kenichiro Suzuki, Yukitsugu Kudo-Asabe, Ken Miyabe, Kei Koyama, Makoto Yoshida, Masamitsu Tanaka, Hiroshi Nanjo, Masayuki Fukuda, Takechiyo Yamada, Akiteru Goto.
       BACKGROUND: Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy of the oral cavity and is characterized by a high propensity for invasion and a poor prognosis. Recent studies have highlighted the critical roles of cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in tumor progression, particularly within the tumor microenvironment (TME).
    OBJECTIVE: This study aimed to investigate the correlation between CAFs, TAMs, and tumor budding in tongue squamous cell carcinoma (TSCC), and evaluate their impact on prognostic factors.
    METHODS: A total of 88 cases of surgically resected TSCC were analyzed. Immunohistochemical staining was performed using markers of CAFs (fibroblast activation protein, FAP) and TAMs (CD163). The correlation between CAF and TAM scores, tumor budding, and various clinicopathological factors was assessed. TAM scores were evaluated for the number of TAMs in the intratumoral areas (TAM-t) and the invasive front (TAM-fr). CAF scores were evaluated for cancer cells in the intratumoral area (cCAF-t), stromal cells in the intratumoral area (sCAF-t), stromal cells in the invasive front (sCAF-fr), and the infiltration pattern of CAF (IPC).
    RESULTS: The IPC score was significantly associated with the tumor budding scores (p < 0.001) and poor DFS (p < 0.01). In the multivariate analysis, cCAF-t, sCAF-t, and IPC scores emerged as independent prognostic factors (p < 0.05) for early-stage TSCC. CAFs may play a pivotal role in tumor invasion.
    CONCLUSION: These findings indicate that CAFs significantly influence the invasive characteristics of TSCC and are correlated with tumor budding and a poor prognosis. These results underscore the potential of targeting CAFs as a therapeutic strategy for improving OSCC outcome.
    Keywords:  Cancer-associated fibroblast; Epithelial‐to‐mesenchymal transition; Tongue squamous cell carcinoma; Tumor budding; Tumor microenvironment; Tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.oraloncology.2025.107295
  28. Am Soc Clin Oncol Educ Book. 2025 Jun;45(3): e481556
    One Step Ahead: Preventing Tumor Adaptation to Immune Therapy.
    Erica L Braverman, Giuliana P Mognol, Andy J Minn, Dario A A Vignali, Judith A Varner.
      Immune checkpoint inhibitors are cancer therapeutics that have shown remarkable success in extending lives in many cancers, including melanoma, MSI-high cancers, and other cancers. However, these therapeutics have not shown benefit for many patients with cancer, especially those with advanced cancer diagnoses. In addition, many patients develop resistance to these therapeutics and/or life-altering adverse events that can include cardiotoxicity, pneumonitis, thyroiditis, pancreatitis, and hepatitis. Extensive efforts to improve cancer care by uncovering mechanisms of resistance to immune therapy in solid tumors have led to identification of new sources of resistance and to the development of new approaches to activate or sustain antitumor immunity. Chronic stimulation of T cells by tumors and by checkpoint inhibitors can lead to a progressive state of T-cell exhaustion. Chronic T-cell activation by the tumor microenvironment (TME) or immune therapeutics can upregulate the expression and function of alternate checkpoints, including the T-cell protein LAG-3. Persistent interferon signaling in the TME can drive epigenetic changes in cancer cells that enable tumors to counter immune activation and disrupt tumor cell elimination. In addition, immune-suppressive macrophages can flood tumors in response to signals from dying tumor cells, further preventing effective immune responses. New clinical developments and/or approvals for therapies that target alternate immune checkpoints, such as the T-cell checkpoint LAG-3; myeloid cell proteins, such as the kinase phosphoinositide 3-kinase gamma isoform; and chronic interferon signaling, such as Jak 1 inhibitors, have been approved for cancer care or shown promise in recent clinical trials.
    DOI:  https://doi.org/10.1200/EDBK-25-481556
  29. Postgrad Med J. 2025 May 06. pii: qgaf065. [Epub ahead of print]
    Roles of macrophages and monocytes in resistance to immunotherapy in breast cancers.
    Siyuan Liu, Lihong Hu, Jiejie Hu, Chengdong Qin, Chuner Jiang, Yang Yu.
       BACKGROUND: Immunotherapy is increasingly integral to breast cancer treatment, yet a subset develops resistance, partly mediated by macrophages and monocytes in the tumor immune microenvironment. While macrophages play essential roles in phagocytosis and pathogen clearance, their dual role in breast cancer-acting as both barriers to therapy and potential therapeutic targets-complicates treatment efficacy.
    STRATEGY: Tumor-associated macrophages, polarized by tumor-derived signals, promote cancer progression and metastasis. Monocytes, subdivided into CD14+CD16- and CD14+CD16+ subsets, exhibit distinct functional profiles in cytokine secretion, antigen presentation, and migration. Modulating monocyte subset dynamics and functionality may enhance immunotherapy responsiveness.
    CONCLUSION: A multimodal strategy targeting macrophages, monocytes, and complementary immunotherapies offers promising avenues to overcome resistance. Further research into the heterogeneity and regulatory mechanisms of these cells is critical for developing optimized, safe immunotherapeutic protocols. This review underscores the necessity of combination immunotherapies to improve outcomes in breast cancer.
    Keywords:  TAMs; breast cancer; immunotherapy resistance; macrophages and monocytes
    DOI:  https://doi.org/10.1093/postmj/qgaf065
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