bims-flamet 2025-09-21 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–09–21
25 papers selected by
Peio Azcoaga, Biodonostia HRI

PKM2 orchestrates tumor progression via metabolic reprogramming and MDSCs-mediated immune suppression in the tumor microenvironment.
Role of Circular RNAs in Regulating Tumor Microenvironment, Epithelial Mesenchymal Transition, and Resistance to Cancer Therapy.
Advance in therapies targeting tumor-associated macrophages in ovarian cancer.
Mitochondrial lipid metabolism in tumor immunosurveillance and evasion.
'Smelling' lipid cues: chemosensory receptors tune tumor-associated macrophage behavior.
Role of tumor microenvironment in cancer promotion, development of drug resistance and cancer treatment.
Enhancing T cell infiltration in glioblastoma: a review article on challenges and therapeutic strategies.
The emerging roles of the urea cycle in tumor microenvironment and therapies.
Modeling bistable dynamics arising from macrophage-tumor interactions in the tumor microenvironment.
Lactate metabolic checkpoint in immuno-oncology: mechanisms and therapeutic implications.
Optimizing mitochondria function in immune cells: implications for cancer immunotherapy.
Microbiome-macrophage crosstalk in the tumor microenvironment: implications for oral squamous cell carcinoma progression and therapy.
Breaking barriers: enhancing CAR-armored T cell therapy for solid tumors through microenvironment remodeling.
CAR-T cells in solid tumors: Challenges and breakthroughs.
Fueling Prostate Cancer: The Central Role of Glutamine/Glutamate Metabolic Reprogramming.
Targeting the tumor microenvironment in triple-negative breast cancer: Biological insights and therapeutic opportunities.
Revisiting Tregs in cancer and beyond: immunological control and therapeutic potential.
Lactate and lactylation in tumor immunity.
Precision engineering of macrophage reprogramming with RNA interference-loaded lipid nanoparticles: a game-changer in cancer immunotherapy.
Activated B cells modulate the maturation of MDSCs via CD36-dependent MHC-II transfer to orchestrate CD4+ Th1-dominant antitumor immunity after cryo-thermal therapy.
Current status of chimeric antigen receptor T cell therapy and its exhaustion mechanism.
Next-generation oncology: integrative therapeutic frontiers at the crossroads of precision genomics, immuno-engineering, and tumor microenvironment modulation.
Angiocrine and pericrine signaling: how endothelial cells and pericytes drive cancer progression and therapy resistance.
TNFSF15 alleviates myeloid-derived suppressor cell-mediated cancer immunosuppression in mice.
Metabolism at the core of melanoma: From bioenergetics to immune escape and beyond.

Front Immunol. 2025 ;16 1588019

PKM2 orchestrates tumor progression via metabolic reprogramming and MDSCs-mediated immune suppression in the tumor microenvironment.

Wenxi Liu, Jiaqi Wu, Xinran Zhang, Yanhua Zhang, Xianqin Zeng, Xiaochun Peng.

  The tumor microenvironment (TME) is a complex system, in which the energy metabolism of tumor cells plays a key role in the occurrence, development and metastasis of tumors. In the TME, the energy supply of tumor cells mainly comes from glycolysis. This metabolic reprogramming phenomenon is usually called the Warburg effect. Despite the abundance of oxygen, tumor cells still preferentially utilize the glycolytic pathway to meet their bioenergetic demands. Pyruvate kinase (PK), as a key enzyme in glycolysis, plays an important role in the regulation of energy metabolism in tumor cells. Among them, pyruvate kinase M2 (PKM2) is highly expressed in tumors and promotes the release of cytokines by tumor cells, thereby recruiting myeloid-derived suppressor cells (MDSCs). These cytokines bind to the surface receptors of MDSCs, activate related signaling pathways, and up-regulate the expression of cathepsin cysteine proteases. This process subsequently inhibits the activity of T cells, thereby affecting tumor development.

Keywords:  T cell; cathepsins; cysteinecathepsins; glycolysis; myeloid-derived suppressor cells; pyruvate kinase M2 type; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1588019
Crit Rev Oncol Hematol. 2025 Sep 13. pii: S1040-8428(25)00330-0. [Epub ahead of print] 104942

Role of Circular RNAs in Regulating Tumor Microenvironment, Epithelial Mesenchymal Transition, and Resistance to Cancer Therapy.

Md Abdus Samad, Iftikhar Ahmad, Mohd Suhail, Fahad Al-Abbasi, Shams Tabrez.

  Circular RNAs (circRNAs) is a type of non-coding RNAs abundantly found in eukaryotic cells, have gained increasing attention in cancer research lately. They act as mediators in several signaling pathways by facilitating communication between different cell types. Aberrant expression of circRNAs has been observed in numerous cancer types, where they contribute to tumor initiation and progression. They can also influence the tumor microenvironment (TME) by regulating the function of various immune cells, such as T-cells, B-cells, natural killer (NK) cells, and macrophages, as well as other crucial components that include cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), and extracellular matrix (ECM). Furthermore, circRNAs are also implicated in regulating the epithelial-mesenchymal transition (EMT) through their interactions with the zinc finger E-box binding (ZEB), Twist, Snail, Slug proteins, and transforming growth factor-beta (TGF-β) including the development of resistance to cancer therapies. They can also modulate immune checkpoints and can reduce the effectiveness of immune checkpoint inhibitors (ICIs). In this review, we focused on the pivotal roles of circRNAs in cancer biology with special emphasis on their involvement in the TME, EMT, and therapeutic resistance. We have also explored translational potential of circRNAs, identified the current challenges and limitations they encounter, and potential strategies to overcome these obstacles. This article underscores the significant potential of circRNAs in the realm of cancer biology; however, further studies are required to exploit different circRNAs as prognostic, diagnostic, and therapeutic markers against various cancer types.

Keywords:  Circular RNA; EMT; Hypoxia; TME; Therapeutic resistance

DOI:  https://doi.org/10.1016/j.critrevonc.2025.104942
Front Immunol. 2025 ;16 1677839

Advance in therapies targeting tumor-associated macrophages in ovarian cancer.

Man Li, Yue Ma, Tinggeng Dai, Yongxin Wang, Ying Yue.

  Ovarian cancer remains the deadliest gynecologic malignancy, with its aggressive progression and therapeutic resistance heavily influenced by the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), the predominant immune infiltrates in OC, play pivotal roles in metastasis, immunosuppression, and chemoresistance by adopting a pro-tumoral M2 phenotype. Despite promising preclinical results, clinical translation faces challenges, such as on-target toxicity and incomplete understanding of TAM ontogeny in humans. This review summarizes the origins, heterogeneity, and functional plasticity of TAMs, emphasizing their mechanistic contributions to OC progression through epithelial-mesenchymal transition (EMT), angiogenesis, and immune evasion. We outline the emerging evidence that TAMs drive platinum resistance via exosomal signaling and metabolic reprogramming, underscoring TAMs as central mediators of OC pathogenesis and treatment paradigms.

Keywords:  TAM polarization; chemoresistance; epithelial-mesenchymal transition; ovarian cancer; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1677839
Trends Immunol. 2025 Sep 16. pii: S1471-4906(25)00215-7. [Epub ahead of print]

Mitochondrial lipid metabolism in tumor immunosurveillance and evasion.

Ana Belén Plata-Gómez, Weixin Chen, Ping-Chih Ho, Guang Sheng Ling.

  Mitochondrial lipid metabolism plays a pivotal role in tumor immunosurveillance and immune evasion. This review explores how mitochondrial regulation shapes immune cell metabolism within the tumor microenvironment (TME), focusing on the antitumor effects of the mitochondrial-fueled immune response and the detrimental impact of impaired mitochondrial function on immune cell cytotoxicity. Although current studies support this dual role, critical gaps remain, including how immune cells adapt differently to the lipid-rich TME, and how therapies can target lipid metabolism without harming immune memory. By synthesizing current findings and highlighting these uncertainties, this review highlights mitochondrial lipid metabolism as a promising therapeutic axis in cancer immunotherapy.

Keywords:  immunometabolism; lipid metabolism; mitochondria; tumor metabolic reprogramming

DOI:  https://doi.org/10.1016/j.it.2025.08.005
Trends Immunol. 2025 Sep 12. pii: S1471-4906(25)00218-2. [Epub ahead of print]

'Smelling' lipid cues: chemosensory receptors tune tumor-associated macrophage behavior.

Martina Farber, Serena Vegna.

  Tumor-associated macrophages (TAMs) are key regulators of the tumor microenvironment (TME), but their heterogeneity, driven by tumor-derived cues, poses challenges for therapeutic targeting and underscores the need for precise macrophage reprogramming strategies. Through a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen, Marelli et al. identified chemosensors as lipid-sensing regulators of macrophage activity, revealing new therapeutic avenues.

Keywords:  chemosensory receptors; genome-wide CRISPR screening; lipidomics; palmitic acid; prostate cancer; tumor microenvironment (TME); tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.1016/j.it.2025.08.008
J Egypt Natl Canc Inst. 2025 Sep 15. 37(1): 59

Role of tumor microenvironment in cancer promotion, development of drug resistance and cancer treatment.

Duaa E Fathah, Samina Ejaz.

  Cancer is a multifactorial disease and the second leading cause of death worldwide after cardiovascular disease. Initially, it was considered a genetic disease or gene expression disorder, but now it is regarded as a tumor microenvironment (TME) disease. The TME consists of cancer cells, endothelial cells, fibroblasts, and immune cells that interact with each other. These interactions support tumor growth by providing nutrients via altered metabolic mechanisms such as glutamine metabolism, aerobic glycolysis, and fatty acid metabolism. The by-products of these altered metabolic pathways interfere with the function of surrounding cells and thus lead to cancer progression. The role of metabolic crosstalk highlights the intricate relationship between the cancer cells and their TME. This review comprehensively analyzes recent studies to enhance understanding of the metabolic crosstalk in TME. It highlights how tumor-associated macrophages and fibroblasts reprogram lipid and glucose metabolism to create an immunosuppressive environment. This review also provides information about the role of hypoxia-induced HIF-1α signaling in the promotion of lactate accumulation. This factor in turn ensures tumor cells' survival and makes them resistant to anti-cancer drugs. Further, we have discussed therapeutic approaches targeting TME, including use of PD-1, PD-L1 inhibitors, CAR-T cell therapy, and oncolytic viruses to improve patient outcomes. Besides this, clinical studies involving the estimation of lactate, GLUT1, and HIF-1α levels may help to recognize high-risk patients and develop guidance for personalized metabolism-targeting therapies. In the long run, such studies can ultimately improve patient outcomes and thus reduce disease burden.

Keywords:  Angiogenesis; CAR-T cell therapy; Cancer; PD-1/PD-L1; Tumor microenvironment

DOI:  https://doi.org/10.1186/s43046-025-00317-8
Cancer Treat Res Commun. 2025 Sep 09. pii: S2468-2942(25)00135-2. [Epub ahead of print]45 100999

Enhancing T cell infiltration in glioblastoma: a review article on challenges and therapeutic strategies.

Mohammad Amin Habibi, Negar Nejati, Majed Bahri Najafi, Alireza Khodadadiyan, Mohsen Dashti, Parsa Lorestani, Zahra Karimizadeh, Mahsa Ahmadpour, Amirali Kalantari, Armita Jokar-Derisi, Faezeh Maghsood, Behrouz Robat-Jazi, Elaheh Ebrahimi, Sajjad Ahmadpour, Soheil Tavakolpour.

  This review focuses on enhancing T-cell infiltration in glioblastoma (GBM) while overcoming its immunosuppressive tumor microenvironment (TME). Key strategies include targeting myeloid-derived suppressor cells (MDSCs) to reduce immunosuppression and repolarizing tumor-associated macrophages (TAMs) from an M2 (immunosuppressive) phenotype to an M1 (proinflammatory) phenotype to increase T-cell function. Administering chemokines can help attract more effector T cells to the tumor site. Combining immune checkpoint inhibitors (ICIs) with other treatments can further increase T cell activity. To make immunotherapy more effective in GBM, it is also essential to address the immunosuppressive signals in the TME, such as transforming growth factor beta (TGF-β) and interleukin-10 (IL-10).

Keywords:  Blood–brain barrier; CAR-T cell; Glioblastoma; Immunosuppressive microenvironment; Immunotherapy; Tumor microenvironment; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.ctarc.2025.100999
Trends Cancer. 2025 Sep 12. pii: S2405-8033(25)00205-5. [Epub ahead of print]

The emerging roles of the urea cycle in tumor microenvironment and therapies.

Jiawen Zhou, Xuan Sun, Peng Jiang.

  The urea cycle (UC) is a vital metabolic pathway that is responsible for the disposal of nitrogen and the production of metabolites necessary for biosynthesis. UC dysregulation is common in various cancers and impacts on cellular metabolism and the tumor microenvironment (TME). In this review we explore alterations in the expression of UC genes and metabolites in tumors, focusing on their roles in tumor progression, the TME, and cancer therapies. We discuss the effects of the UC on immune responses involving T cells and immunosuppressive cells, as well as on stromal cells and angiogenesis. We highlight the impact of arginine and polyamine metabolism in the TME. Although therapeutic strategies targeting the UC show promise, including arginine deprivation therapy (ADT), they face challenges such as drug resistance and toxicity. It will be essential to elucidate the specific functions of UC enzymes in tumorigenesis to devise more effective, personalized tumor therapies. Future studies should focus on combination therapies and personalized medicine to improve efficacy and patient prognosis.

Keywords:  arginine deprivation therapy; metabolic reprogramming and sensing; tumor cell metabolism; tumor microenvironment; urea cycle (UC)

DOI:  https://doi.org/10.1016/j.trecan.2025.08.007
Math Biosci. 2025 Sep 16. pii: S0025-5564(25)00160-9. [Epub ahead of print] 109534

Modeling bistable dynamics arising from macrophage-tumor interactions in the tumor microenvironment.

Hwayeon Ryu, Susanna Röblitz, Kamila Larripa, Anna-Simone Frank.

  Macrophages in the tumor microenvironment (TME), known as tumor-associated macrophages (TAMs), originate primarily from circulating monocytes that differentiate under the influence of tumor-derived signals. Within the TME, naïve macrophages can adopt either a pro-inflammatory, anti-tumor (M1-like) or anti-inflammatory, pro-tumor (M2-like) phenotype. These phenotypic shifts significantly affect tumor progression, making TAMs attractive targets for therapeutic intervention aimed at blocking recruitment, promoting anti-tumor polarization, or disrupting tumor-macrophage interactions. In this study, we develop a mathematical model capturing the temporal dynamics of tumor volume alongside populations of naïve, M1-like, M2-like, and mixed (M1/M2) phenotype TAMs. The model incorporates the bidirectional influence between tumor development and macrophage polarization. Through numerical simulations with different parameter sets, our tumor-macrophage population model exhibits the emergence of bistability, demonstrating the system becomes more controllable, responsive to perturbations, and sensitive to immunotherapy. We conduct the bifurcation as well as global sensitivity analyses to identify regions of bistability for tumor dynamics in the parameter space and the impact of sensitive parameters on TME. These results are then linked to treatment strategies that may effectively induce transitions from high to low tumor burden.

Keywords:  Bifurcation; Bistability; Macrophage polarization; Mathematical modeling; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.mbs.2025.109534
Cancer Lett. 2025 Sep 11. pii: S0304-3835(25)00608-1. [Epub ahead of print]633 218038

Lactate metabolic checkpoint in immuno-oncology: mechanisms and therapeutic implications.

Zhe Wang, Ziyan Gu, Wendi Mo, Haijun Zhang.

  Immuno-Oncology has transformed cancer therapeutics, yet its clinical efficacy remains limited by the immunosuppressive tumor microenvironment (TME). Once considered merely a metabolic byproduct of glycolysis, lactate is now recognized as a critical regulator of immune TME through both direct metabolic effects and its derivative modification, histone lysine lactylation (Kla). Within the TME, lactate and Kla reprogram signaling pathways that impair immune function, thereby facilitating tumor immune escape. This review synthesizes emerging evidence positioning lactate metabolism and histone Kla as pivotal immunosuppressive modulators within the TME. Tumor-derived lactate, produced through the Warburg effect, acidifies the TME and disrupts immune cell function via two interconnected mechanisms: direct metabolic interference and epigenetic reprogramming via Kla. Histone Kla represents a novel post-translational modification that drives immunosuppressive signaling in immune cells, serving as a prognostic biomarker across multiple cancers. Moreover, we highlight therapeutic strategies targeting lactate metabolism, which show considerable promise in overcoming the current limitations of immunotherapy and enhancing its clinical efficacy.

Keywords:  Immunotherapy; Lactate; Lactylation; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.218038
Trends Cancer. 2025 Sep 16. pii: S2405-8033(25)00204-3. [Epub ahead of print]

Optimizing mitochondria function in immune cells: implications for cancer immunotherapy.

Huiyu Li, Wenyi Jin, Junhong Liu, Yundong Zhou, Xiaoli Shan, Yubiao Zhang, Yongliang Kou, Chunyan Deng, Cheng Jin, Junjie Kuang, Yui-Leung Lau, João Conde, Baozhen Huang, Queran Lin.

  The tumor microenvironment (TME) imposes profound metabolic and functional constraints on immune cells, with mitochondrial dysfunction emerging as a pivotal driver of immunosuppression. While mitochondrial metabolism is well recognized for its role in energy production and cellular homeostasis, its dynamic regulation of immune cell activation, differentiation, and exhaustion within the TME remains underexplored. In this review we summarize insights into how TME stressors such as hypoxia, nutrient competition, and metabolic byproducts subvert mitochondrial dynamics, redox balance, and mitochondrial DNA (mtDNA) signaling in T cells, natural killer (NK) cells, and macrophages, thereby directly impairing their antitumor efficacy. We emphasize that the restoration of mitochondrial fitness in immune cells, achieved by targeting metabolites in the TME and mitochondrial quality control, represents a pivotal axis for adoptive cell therapies (ACTs) and TME reprogramming.

Keywords:  ROS; chimeric antigen receptor (CAR); metabolism; mitochondria; tumor immunotherapy

DOI:  https://doi.org/10.1016/j.trecan.2025.08.006
Front Immunol. 2025 ;16 1651837

Microbiome-macrophage crosstalk in the tumor microenvironment: implications for oral squamous cell carcinoma progression and therapy.

Xin Deng, Shaohong Huang.

  Oral squamous cell carcinoma (OSCC) remains a formidable malignancy with persistently poor clinical outcomes. Recent research has underscored the pivotal role of the innate immune system, particularly tumor-associated macrophages (TAMs), a key component of the myeloid lineage, in orchestrating the tumor microenvironment (TME) and shaping disease progression. As professional phagocytes of the innate immune system, macrophages not only mediate pathogen recognition and inflammatory responses but also undergo functional polarization in response to local cues. In OSCC, dysbiosis of the oral microbiota, marked by the overrepresentation of species such as Fusobacterium nucleatum and Porphyromonas gingivalis-acts as a chronic inflammatory trigger that promotes epithelial-mesenchymal transition (EMT), immune evasion, and tumor growth. These pathogenic bacteria actively engage innate immune signaling pathways such as TLRs and CSF-1R, skewing macrophages toward an immunosuppressive M2 phenotype. M2-like TAMs then contribute to tumor progression by secreting anti-inflammatory cytokines (IL-10, TGF-β), promoting angiogenesis, and expressing immune checkpoint ligands such as PD-L1. This review summarizes current knowledge on the bidirectional crosstalk between dysbiotic microbiota and innate immune macrophages in OSCC, highlighting key receptor-mediated pathways and their implications for immune suppression, metastasis, and therapy resistance. Targeting microbiota modulation or innate immune reprogramming represents a promising strategy for restoring anti-tumor immunity and enhancing therapeutic efficacy in OSCC.

Keywords:  chemokine receptors; immune suppression; inflammation; microbiota; oral squamous cell carcinoma; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2025.1651837
Front Immunol. 2025 ;16 1638186

Breaking barriers: enhancing CAR-armored T cell therapy for solid tumors through microenvironment remodeling.

Tereza Andreou, Constantina Neophytou, Maria Kalli, Fotios Mpekris, Triantafyllos Stylianopoulos.

  Whilst chimeric antigen receptor (CAR) T cell therapy has emerged as a revolutionary immunotherapeutic approach for hematological malignancies in recent years, several challenges remain to potentiate the efficacy of CAR T cell therapies for solid tumors. Here, we focus on the obstacles posed by the tumor microenvironment that hinder the effective trafficking, infiltration and precise tumor targeting by engineered cells. We discuss how the tumor microenvironment presents a physical barrier that needs to be surpassed for effective cell therapies and ongoing efforts in designing innovative CAR T cell therapies with enhanced tumor-targeting precision, improved stability, and overcoming on-target off-tumor toxicity are presented. We focus on recent advances in clinical and preclinical settings to reprogram the immunosuppressive tumor microenvironment, including stroma and blood vessel normalization strategies that can be leveraged to improve the tumor-homing and tumor-targeting potential of engineered therapeutic cells for immuno-oncology applications. As the endeavors for innovative CAR designs continue, we are entering an exciting era in the field of personalized cell therapies offering renewed hope to patients with hard-to-treat solid tumors.

Keywords:  CAR T cell; cell therapy; extracellular matrix normalization; solid tumors; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1638186
Cell Rep Med. 2025 Sep 12. pii: S2666-3791(25)00426-4. [Epub ahead of print] 102353

CAR-T cells in solid tumors: Challenges and breakthroughs.

Giulia Escobar, Trisha R Berger, Marcela V Maus.

  Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies, but its efficacy in solid tumors is limited by several challenges. Key obstacles include insufficient CAR-T cell trafficking to tumors, limited expansion and persistence, tumor relapse due to antigen loss or heterogeneity, and an immunosuppressive tumor microenvironment (TME) that dampens CAR-T cell functions. In this review, we discuss insights from recent successful clinical trials in advanced solid tumors and highlight groundbreaking strategies integrating synthetic biology and gene engineering to enhance CAR-T cell fitness, potency, and persistence, activate host immunity, reprogram the TME, and enable multi-antigen targeting. We examine strengths and weaknesses of current preclinical models for assessing the efficacy and safety of CAR-T cell therapies, including human xenografts in immunodeficient mice and humanized or syngeneic models. The array of cutting-edge approaches employed in next-generation CAR-T cell therapies is expected to transform the treatment landscape of solid tumors.

Keywords:  CAR-T cells; CRISPR-screens; armored CAR-T cells; solid tumors; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2025.102353
Asian Pac J Cancer Prev. 2025 Sep 01. pii: 91865. [Epub ahead of print]26(9): 3157-3174

Fueling Prostate Cancer: The Central Role of Glutamine/Glutamate Metabolic Reprogramming.

Ahmed S Alhallaq, Nadeen S Sultan.

  Metabolic reprogramming induced by the glutamine/glutamate (Gln/Glu) metabolic pathway is a key mechanism in ATP production, precursor biosynthesis, and redox homeostasis, promoting prostate cancer (PCa) growth and proliferation. This evolutionarily acquired hallmark of cancers enables malignant cells to adapt their bioenergetic and biosynthetic pathways in response to microenvironmental stresses. Therefore, Gln/Glu metabolism orchestrates epigenetic regulation, metastatic capacity, and oxidative homeostasis in PCa, supporting the survival of PCa tumors. Fluctuations in Glu metabolite levels and oxygen tension shape the PCa epigenome by facilitating Glu-derived α-ketoglutarate (α-KG) activation of TET and KDM enzymes, which drive histone and DNA demethylation. Furthermore, tumor progression toward metastatic castration-resistant PCa is characterized by heightened Gln/Glu dependency and increased Gln uptake. Within the tumor microenvironment (TME), a dynamic tug-of-war occurs between tumor and immune cells, competing for Gln metabolites. Gln/Glu converges on critical oncogenic signaling axes, including NF-κB/Nrf2, c-Myc/androgen receptor, MAPK/ERK, and PI3K/AKT/mTOR. Additionally, extracellular Glu release via SLC7A11 and PSMA triggers metabotropic glutamate receptor (mGluR) signaling, further potentiating oncogenic programs. Targeting this Gln/Glu metabolic network thus presents a promising therapeutic approach against PCa. In this review, we summarize the role of Gln/Glu in PCa progression based on the compartmentalization of the Gln/Glu metabolic pathway to elucidate why PCa cells manifest dependence on Gln/Glu. Eventually, we highlight potential therapeutic targets that can be exploited for PCa treatment.

Keywords:  Glutamine; Metabolic Reprogramming; Prostate Cancer; Tumor Microenvironment; glutamate

DOI:  https://doi.org/10.31557/APJCP.2025.26.9.3157
Pathol Res Pract. 2025 Sep 10. pii: S0344-0338(25)00419-4. [Epub ahead of print]275 156226

Targeting the tumor microenvironment in triple-negative breast cancer: Biological insights and therapeutic opportunities.

Teresa Maria Martorana, Gabriele Ricciardi, Pietro Tralongo, Vincenzo Fiorentino, Cristina Pizzimenti, Mariausilia Franchina, Maria Adele Marino, Mariacarmela Santarpia, Giovanni Tuccari, Antonio Ieni, Guido Fadda, Maurizio Martini, Valeria Zuccalà.

  Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression. Despite initial chemosensitivity, TNBC often relapses, and nearly half of patients develop distant metastases, particularly to visceral organs and the brain. In recent years, growing attention has been given to the tumor microenvironment (TME) as a critical driver of disease progression, immune evasion, and therapeutic resistance. TME is composed of a dynamic network of immune and stromal cells, extracellular matrix components, and soluble mediators that influence tumor behavior and shape response to treatment. In this review, we provide a comprehensive overview of the cellular and molecular composition of the TME in TNBC, highlight key prognostic and predictive markers, and discuss emerging therapeutic strategies aimed at targeting TME components. Understanding the complex crosstalk between the tumor and its microenvironment is essential for developing effective, personalized approaches to managing TNBC in the future.

Keywords:  Biomarkers; Immunotherapy; Triple-negative breast cancer; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.prp.2025.156226
Front Immunol. 2025 ;16 1581093

Revisiting Tregs in cancer and beyond: immunological control and therapeutic potential.

Lei Zheng, Dan Wu, Hongwei Xie, Hai Zhao.

  Tregs play a crucial role in maintaining immune homeostasis, but their involvement in cancer and other diseases has made them a focus of intense research. Tregs contribute to immune evasion by tumors and can affect responses to therapies. Understanding their mechanisms and the potential to manipulate them therapeutically is critical for improving cancer treatment strategies. This review aims to provide an updated perspective on the role of Tregs in cancer and beyond, with a focus on their immunological control mechanisms and therapeutic potential. We examine the recent advances in understanding Treg biology, their interaction with the tumor microenvironment, and the strategies developed to target Tregs for cancer immunotherapy. The review highlights the dual role of Tregs in promoting immune tolerance and in facilitating tumor progression. It discusses the various markers, transcription factors, and signaling pathways involved in Treg differentiation and function. Moreover, we explore the potential of targeting Tregs using novel therapeutic approaches, including monoclonal antibodies, checkpoint inhibitors, and gene editing. The review emphasizes emerging strategies for modulating Treg function in a way that enhances anti-tumor immunity while minimizing systemic autoimmunity.

Keywords:  angiogenesis; cancer immunotherapy; immune suppression; metabolic regulation; regulatory T cells; tissue repair and regeneration

DOI:  https://doi.org/10.3389/fimmu.2025.1581093
Front Med. 2025 Sep 20.

Lactate and lactylation in tumor immunity.

Liu Song, Lingjuan Sun, Song Chen, Peixiang Lan.

  The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metastasis. This process is accompanied by the massive production and accumulation of lactate both intracellularly and extracellularly. The resulting acidic microenvironment impairs the normal physiological functions of immune cells and promotes tumor progression. An increasing number of studies indicate that lactate, a key metabolite in the tumor microenvironment (TME), acts as a pivotal immunosuppressive signaling molecule that modulates immune cell function. This review aims to comprehensively examine lactate's role as an immunosuppressive molecule in TME. It focuses on mechanisms such as membrane receptor binding, functional reshaping of immune cells via lactate shuttle transport, epigenetic regulation of gene expression through histone lactylation, and modulation of protein structure and function through nonhistone lactylation, emphasizing lactate's importance in immune regulation within the TME. Ultimately, this review offers novel insights into immunosuppressive therapies aimed at targeting lactate function.

Keywords:  TME; immunosuppressive immune cells; lactate; lactylation; tumor immunity

DOI:  https://doi.org/10.1007/s11684-025-1148-0
Drug Deliv Transl Res. 2025 Sep 18.

Precision engineering of macrophage reprogramming with RNA interference-loaded lipid nanoparticles: a game-changer in cancer immunotherapy.

Sezen Gül, Juliette Vergnaud, François Fay, Elias Fattal.

  Tumor-associated macrophages (TAMs) represent solid tumors' most prevalent immune cell subset. These cells primarily adopt an immunosuppressive phenotype in the tumor microenvironment, promoting tumor initiation and progression. Their ability to shift between distinct activation states identifies TAMs as ideal targets for cancer treatment. Consequently, reprogramming TAMs from an immunosuppressive to an immunostimulatory state has emerged as a promising therapeutic approach to fight cancer. RNA interference has gained significant attention as a therapeutic modality due to its potential to selectively inhibit the expression of one or several critical proteins for the pro-tumorous activities of TAMs. However, the efficiency of RNA interference is limited by its susceptibility to nuclease degradation, rapid clearance from the body, and poor cellular uptake. These limitations necessitate the development of delivery systems to enhance their therapeutic potential. Among the nanocarriers we discuss in this review, lipid nanoparticles (LNPs) have been widely recognized as the most effective for siRNA or miRNA, providing stability, high gene silencing efficiency, and biocompatibility. The clinical application of LNPs has been further advanced by recent progress in microfluidics, enabling reproducible and scalable production of LNPs with high encapsulation efficiency. The increasing number of preclinical studies shows the growing interest in cancer immunotherapy using RNA interference-LNPs. In this review, we summarize the current knowledge on macrophage biology and its role in cancer, explore advancements in RNA interference-LNP technology, review ongoing research efforts, and discuss key translational challenges that must be addressed for the clinical success of RNA interference-LNP-based macrophage reprogramming.

Keywords:  Lipid nanoparticles; RNA interference; Reprogramming; Tumor-associated macrophages

DOI:  https://doi.org/10.1007/s13346-025-01970-1
Int J Biol Sci. 2025 ;21(12): 5547-5562

Activated B cells modulate the maturation of MDSCs via CD36-dependent MHC-II transfer to orchestrate CD4+ Th1-dominant antitumor immunity after cryo-thermal therapy.

Zelu Zhang, Shicheng Wang, Junjun Wang, Yichen Yao, Yuankai Hao, Yue Lou, Ping Liu, Lisa X Xu.

  Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has shown great success in treating various cancer types. However, the therapeutic efficacy of ICIs remains unsatisfactory because of the immunosuppressive tumor microenvironment. Cryo-thermal therapy (CTT), a novel tumor ablation approach developed by our laboratory, transforms the tumor immunosuppressive environment into an immunostimulatory environment by activating both innate and adaptive immunity. CTT promotes the differentiation of myeloid-derived suppressor cells (MDSCs) into mature dendritic cells and macrophages, activates antigen-presenting cells and natural killer (NK) cells, and induces Th1-dominant CD4+ T-cell-mediated antitumor immunity in numerous highly metastatic tumor models. However, the role of B cells in CTT-induced antitumor immunity remains unclear despite their critical function in adaptive immunity. Here, in vivo B-cell depletion with anti-CD20 monoclonal antibodies in multiple tumor models revealed that B cells play a crucial role in suppressing tumor metastasis and extending survival. More interestingly, CTT-activated B cells reprogram MDSCs to a mature phenotype through CD36-dependent major histocompatibility complex class II (MHC-II) transfer, resulting in enhanced Th1-dominant CD4+ T-cell responses and CD8+ T-cell cytotoxicity. These findings reveal a novel mechanism of B-cell-mediated modulation of the tumor microenvironment and provide insights into enhancing the efficacy of immunotherapy strategies.

Keywords:  B cells; CD36; Cryo-thermal therapy; MDSCs; MHC-II; antitumor immunity

DOI:  https://doi.org/10.7150/ijbs.115232
Immunotherapy. 2025 Sep 15. 1-19

Current status of chimeric antigen receptor T cell therapy and its exhaustion mechanism.

Huiwen Zhang, Juwei Gao, Zipeng Zhang, Bo Zhang.

  With the rapid advancements in oncology, immunology, and molecular biology, immunotherapy has emerged as a cornerstone of anti-tumor treatment, complementing traditional modalities such as surgery, radiotherapy, and chemotherapy. Among the many immunotherapy strategies, adoptive cell therapy (ACT) is the most representative one. A key technology within ACT is chimeric antigen receptor (CAR) T-cell therapy, a precision-targeted treatment that leverages genetic engineering to modify T cells, enabling them to express antigen-specific receptors independent of major histocompatibility complex (MHC) restrictions. In recent years, continuous optimization of CAR-T therapy has been leading to remarkable clinical outcomes in oncology. However, its efficacy is significantly compromised by T-cell exhaustion, characterized by reduced proliferative capacity, attenuated anti-tumor activity, and limited persistence. Notably, CAR-T cell exhaustion is primarily driven by repeated tumor antigen stimulation, sustained autonomous activation of CAR constructs, and the immunosuppressive tumor microenvironment (TME), collectively contributing to disease relapse in hematologic malignancies and limited efficacy in solid tumors. Therefore, it is important to elucidate and inhibit the mechanism of CAR-T cell dysfunction to improve its efficacy. Overcoming these challenges will facilitate the development of CAR-T cells with sustained proliferative potential and tumor clearance.

Keywords:  CAR-T cell exhaustion; Chimeric antigen receptor T cells; adoptive cell therapy; cancer immunotherapy; tumor immune microenvironment

DOI:  https://doi.org/10.1080/1750743X.2025.2560798
Med Oncol. 2025 Sep 20. 42(11): 482

Next-generation oncology: integrative therapeutic frontiers at the crossroads of precision genomics, immuno-engineering, and tumor microenvironment modulation.

Ahmad M Alamri, Abdullah A Assiri, Bushra Khan, Najeeb Ullah Khan.

  The landscape of oncology is undergoing a paradigm shift, transitioning from conventional cytotoxic therapies to an integrative, intelligence-driven framework that combines precision genomics, immunoengineering, and modulation of the tumor microenvironment (TME). This review explores how cancer, as a complex adaptive system (CAS), evolves through genetic, epigenetic, and microenvironmental interactions, necessitating dynamic, multi-dimensional therapeutic strategies. Review highlights the limitations of mono-targeted therapies and the emergence of synergistic approaches, including AI-guided adaptive dosing, synthetic biology-enhanced CAR-T cells, and metabolic reprogramming of the tumor microenvironment (TME). Breakthroughs in molecular cartography, quantum biology, synthetic oncology, and dark genome mining are expanding therapeutic frontiers. Meanwhile, immuno-engineering innovations-such as next-generation checkpoint modulators, logic-gated CAR-T cells, and neoantigen vaccines-are redefining immune-oncology. Additionally, TME-targeted strategies, including stromal remodeling, hypoxia modulation, and microbiome engineering, are helping to overcome treatment resistance. The convergence of multi-omics profiling, combinatorial therapeutics, and computational oncology (e.g., digital twins) is enabling real-time, personalized interventions. Despite these advances, challenges persist-therapeutic resistance, toxicity, accessibility, and ethical concerns-demanding interdisciplinary collaboration and equitable innovation. The future lies in adaptive, autonomous oncology, integrating AI, closed-loop therapies, and modular mRNA platforms to deliver precision medicine at scale. This review underscores the imperative for a unified, systems-based approach to transform cancer into a manageable condition.

Keywords:  Computational Oncology; Immuno-Engineering; Precision Genomics; Synthetic Oncology; Tumor Microenvironment (TME)

DOI:  https://doi.org/10.1007/s12032-025-03042-3
Physiol Rev. 2026 Jan 01. 106(1): 87-119

Angiocrine and pericrine signaling: how endothelial cells and pericytes drive cancer progression and therapy resistance.

Alexander M Jordan, Rebecca J G Drake, Kairbaan M Hodivala-Dilke.

  The emergence of treatment resistance and metastasis are significant challenges that need to be addressed to improve cancer patient outcomes. Greater insight into the mechanisms regulating these processes is needed to identify novel targets for the development of effective treatments. The importance of blood vessel interactions, including endothelial angiocrine and pericyte pericrine signals, with surrounding tissues, has been well established in regulating several normal physiological functions, including angiogenesis, metabolism, wound healing, and development. They have also been implicated in the mechanisms of cancer growth, metastatic dissemination, regulation of the immune microenvironment, and therapeutic resistance. This review provides an overview of the angiocrine and pericrine processes that regulate cancer, the tumor microenvironment, and therapy responses. It highlights that endothelial cells and pericytes are not only important in maintaining blood vessel structure in cancer but that their signaling roles are a pivotal regulatory element harnessed by tumors, some of which could be targeted for alternative cancer treatment strategies. Here, we summarize current research targeting angiocrine and pericrine signaling in cancer and propose new approaches for thorough exploration of these networks to further disentangle the intricate mechanisms at play.

Keywords:  angiocrine; endothelial cells and pericytes; pericrine; therapy resistance; tumor microenvironment

DOI:  https://doi.org/10.1152/physrev.00046.2024
Acta Pharmacol Sin. 2025 Sep 19.

TNFSF15 alleviates myeloid-derived suppressor cell-mediated cancer immunosuppression in mice.

Yi-Pan Zhu, Jing Sun, Xin-Yu Cao, Xin-Yu Ding, Yu-Ying Wang, Qiu-Ju Han, Jing-Ying Wang, Lu-Yuan Li, Zhi-Song Zhang.

  Myeloid-derived suppressor cells (MDSCs) are a category of immature myeloid cells that have an important function in suppressing immune responses in a variety of pathological settings. Thus, MDSCs are the subject of intensive studies regarding their recruitment, expulsion, deactivation, and maturation promotion. Tumor necrosis factor superfamily member 15 (TNFSF15) is produced largely by vascular endothelial cells in mature blood vessels with expression also observed in tumor-associated macrophages (TAMs) and dendritic cells (DCs) within the tumor stroma. In addition to inhibiting the proliferation of vascular endothelial cells and the differentiation of bone marrow-derived endothelial cell progenitors, TNFSF15 is able to promote the maturation of DC, as well as to modulate the polarization of naive M2-macrophages into M1-macrophages capable of eliminating cancer cells, and activate T-cell. In this study, we investigated whether a recombinant TNFSF15 results in a substantial reduction of MDSC accumulation in Lewis lung cancer (LLC) tumor-bearing mice. LLC allograft model mice were administered recombinant TNFSF15 (5 mg·kg-1·d-1, i.p.) for 7 consecutive days. The tumor, bone marrow and spleen were retrieved on Day 8 and analyzed using flow cytometry or immunofluorescence staining. We showed that TNFSF15 treatment significantly inhibited the tumor growth, and caused a substantial reduction of MDSC accumulation in the tumors. The proportions of MDSC in the bone marrows and the spleens were also reduced. The diminished MDSC was mainly the monocyte-like MDSC (M-MDSC) subtype. Additionally, the reduction in M-MDSC population was accompanied by an increase of the proportions of macrophages and DCs in the tumors. We demonstrated that TNFSF15 promoted M-MDSC differentiation by activating the JAK1/STAT3 signaling pathway. Moreover, the treatment gave rise to a markedly escalated accumulation of cytotoxic T cells in the tumors, attributing to tumor growth inhibition. Our results support the view that TNFSF15-driven differentiation of M-MDSC into DCs and macrophages, and the subsequent activation of T cells, may contribute partially to reinstitution of immunity in the tumor microenvironment.

Keywords:  Lewis lung cancer; MDSC; T-cell; TNFSF15; dendritic cell; differentiation; macrophages

DOI:  https://doi.org/10.1038/s41401-025-01663-y
Semin Oncol. 2025 Sep 12. pii: S0093-7754(25)00105-8. [Epub ahead of print]52(6): 152413

Metabolism at the core of melanoma: From bioenergetics to immune escape and beyond.

Chou-Yi Hsu, Yasmeen Kateb Ahmed, Shaker Mohammed, Mohammad A Alghamdi, Hasan S Al-Ghamdi, Jaafaru Sani Mohammed, Mohammed Abed Jawad, Salim B Alsaadi.

  Melanoma is a particularly aggressive type of skin cancer due to its rapid growth and capacity to metastasize. There is substantial metabolic reprogramming in melanoma that is linked to its malignant characteristics, including therapeutic resistance. This review intended to provide a detailed overview of the central metabolic pathways reprogrammed in melanoma, including the Warburg effect and the complex interactions between glycolysis and oxidative phosphorylation, which ultimately influence energy production, biosynthesis, and adaptation to the tumor microenvironment. We also discuss the molecular pathways that regulate these metabolic pathways and the effect these metabolic processes have on crucial elements of melanoma progression, including invasion, metastasis, and survival during nutrient deprivation and hypoxia. Furthermore, we discuss the importance of metabolism beyond glucose, including glutamine metabolism, changes in lipid metabolism, and alterations in one-carbon and nucleotide biosynthesis, as well as mechanisms critical for the proliferation and survival of melanoma cells. An emphasis is placed on the active metabolic crosstalk between melanoma cells and the immune system within the tumor microenvironment, where melanoma cells utilize nutrient competition and the production of immunosuppressive metabolites to alter and block the function of anti-tumor immune cells, thereby facilitating immune evasion and therapy resistance. Lastly, we critically assess developments targeting melanoma metabolism, including pharmacological inhibition of key metabolic enzymes and pathways, as well as metabolic modulation to enhance the efficacy of conventional and immunotherapies. Although promising, this area is complex and subject to contextual effects and metabolic heterogeneity, indicating that we still have a way to go in annotating robust and clinically relevant metabolic targets. We sought to consolidate current knowledge about melanoma metabolism and highlight the challenges, future directions, and complexity of a potential therapeutic vulnerability in the rapidly evolving field of cancer research.

Keywords:  Bioenergetics; Melanoma; Metabolism; Pathogenesis; Therapy

DOI:  https://doi.org/10.1016/j.seminoncol.2025.152413