bims-flamet 2025-01-12 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–01–12
35 papers selected by
Peio Azcoaga, Biodonostia HRI

Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and their targeting in cancer therapy.
The Emerging Role of Schwann Cells in the Tumor Immune Microenvironment and Its Potential Clinical Application.
The multi-faceted roles of cancer-associated fibroblasts in pancreatic cancer.
Metabolic Crossroad Between Macrophages and Cancer Cells: Overview of Hepatocellular Carcinoma.
Glucose Metabolism Reprogramming of Immune Cells in the Microenvironment of Pancreatic and Hepatobiliary Cancers.
Metabolic adaptation of myeloid cells in the glioblastoma microenvironment.
The bidirectional interplay between T cell-based immunotherapies and the tumor microenvironment.
Involvement of the ubiquitin-proteasome system in the regulation of the tumor microenvironment and progression.
The Therapeutic Potential of Physical Exercise in Cancer: The Role of Chemokines.
Tumor metabolic regulators: key drivers of metabolic reprogramming and the promising targets in cancer therapy.
CD36 as a Therapeutic Target in Tumor Microenvironment and Lipid Metabolism.
Fungi, immunosenescence and cancer.
Progress in understanding the regulatory mechanisms of immune checkpoint proteins PD-1 and PD-L1 expression.
Cancer immunotherapy in progress-an overview of the past 130 years.
The role of cisplatin in modulating the tumor immune microenvironment and its combination therapy strategies: a new approach to enhance anti-tumor efficacy.
Metabolic Fitness of NAC1-Deficient Regulatory T Cells in the Tumor Microenvironment Fuels Tumor Growth.
Magnesium peroxide-based biomimetic nanoigniter degrades extracellular matrix to awake T cell-mediated cancer immunotherapy.
Tumor Metabolic Reprogramming and Ferroptosis: The Impact of Glucose, Protein, and Lipid Metabolism.
Unleashing the Power of immune Checkpoints: A new strategy for enhancing Treg cells depletion to boost antitumor immunity.
Rbfox3 Promotes Transformation of MDSC-Like Tumor Cells to Shape Immunosuppressive Microenvironment.
Boosting CAR-T cell therapy through vaccine synergy.
Estrogens increase cancer cell efferocytosis to establish an immunosuppressive tumor microenvironment.
Unveiling the Tumor Microenvironment Through Fibroblast Activation Protein Targeting in Diagnostic Nuclear Medicine: A Didactic Review on Biological Rationales and Key Imaging Agents.
Intra-tumoral sphingobacterium multivorum promotes triple-negative breast cancer progression by suppressing tumor immunosurveillance.
Application of tumor organoids simulating the tumor microenvironment in basic and clinical research of tumor immunotherapy.
Mutant p53-Mediated Tumor Secretome: Bridging Tumor Cells and Stromal Cells.
Single-Cell Profiling Reveals Global Immune Responses during the Progression of Murine Epidermal Neoplasms.
Targeting Cancer: Microenvironment and Immunotherapy Innovations.
Sustained inhibition of CSF1R signaling augments antitumor immunity through inhibiting tumor-associated macrophages.
Tumor Microenvironment Targeted by Polysaccharides in Cancer Prevention: Expanding Roles of Gut Microbiota and Metabolites.
Innovative Nanomedicine Delivery: Targeting Tumor Microenvironment to Defeat Drug Resistance.
SQLE-mediated squalene metabolism promotes tumor immune evasion in pancreatic cancer.
Therapeutic Significance of NLRP3 Inflammasome in Cancer: Friend or Foe?
Targeting Perineural Invasion in Pancreatic Cancer.
Metabolic-Immune Suppression Mediated by the SIRT1-CX3CL1 Axis Induces Functional Enhancement of Regulatory T Cells in Colorectal Carcinoma.

Mol Cancer. 2025 Jan 08. 24(1): 5

Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and their targeting in cancer therapy.

Shuyan He, Lu Zheng, Chunjian Qi.

  The advent of immunotherapy represents a significant breakthrough in cancer treatment, with immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 demonstrating remarkable therapeutic efficacy. However, patient responses to immunotherapy vary significantly, with immunosuppression within the tumor microenvironment (TME) being a critical factor influencing this variability. Immunosuppression plays a pivotal role in regulating cancer progression, metastasis, and reducing the success rates of immunotherapy. Myeloid-derived suppressor cells (MDSCs), due to their potent immunosuppressive capabilities, emerged as major negative regulators within the TME, facilitating tumor immune evasion by modulating various immune cells. In addition to their immunosuppressive functions, MDSCs also promote tumor growth and metastasis through non-immunological mechanisms, such as angiogenesis and the formation of pre-metastatic niches. Consequently, MDSCs in the TME are key regulators of cancer immune responses and potential therapeutic targets in cancer treatment. This review describes the origins and phenotypes of MDSCs, their biological roles in tumor progression, and regulatory mechanisms, with a focus on current therapeutic approaches targeting tumor-associated MDSCs. Furthermore, the synergistic effects of targeting MDSCs in combination with immunotherapy are explored, aiming to provide new insights and directions for cancer therapy.

Keywords:  Immunosuppression; Immunotherapy; MDSCs; TME; Therapeutic targets

DOI:  https://doi.org/10.1186/s12943-024-02208-3
Int J Mol Sci. 2024 Dec 23. pii: 13722. [Epub ahead of print]25(24):

The Emerging Role of Schwann Cells in the Tumor Immune Microenvironment and Its Potential Clinical Application.

Shan Zhang, Jing Chen, Fanjun Cheng, Fang Zheng.

  As the primary glial cells in the peripheral nervous system (PNS), Schwann cells (SCs) have been proven to influence the behavior of cancer cells profoundly and are involved in cancer progression through extensive interactions with cancer cells and other stromal cells. Indeed, the tumor microenvironment (TME) is a critical factor that can significantly limit the efficacy of immunotherapeutic approaches. The TME promotes tumor progression in part by reshaping an immunosuppressive state. The immunosuppressive TME is the result of the crosstalk between the tumor cells and the different immune cell subsets, including macrophages, natural killer (NK) cells, dendritic cells (DCs), lymphocytes, myeloid-derived suppressor cells (MDSCs), etc. They are closely related to the anti-tumor immune status and the clinical prognosis of cancer patients. Increasing research demonstrates that SCs influence these immune cells and reshape the formation of the immunosuppressive TME via the secretion of various cytokines, chemokines, and other effector molecules, eventually facilitating immune evasion and tumor progression. In this review, we summarize the SC reprogramming in TME, the emerging role of SCs in tumor immune microenvironment, and the underlying mechanisms involved. We also discuss the possible therapeutic strategies to selectively target SCs, providing insights and perspectives for future research and clinical studies involving SC-targeted treatment.

Keywords:  Schwann cells; immunocytes; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms252413722
Cell Signal. 2025 Jan 03. pii: S0898-6568(24)00560-6. [Epub ahead of print] 111584

The multi-faceted roles of cancer-associated fibroblasts in pancreatic cancer.

John Y Kwon, Renzo E Vera, Martin E Fernandez-Zapico.

  The tumor microenvironment (TME) has been linked with the pathogenesis of pancreatic ductal adenocarcinoma (PDAC), the most common histological subtype of pancreatic cancer. A central component of the TME are cancer-associated fibroblasts (CAFs), which can either suppress or promote tumor growth in a context-dependent manner. In this review, we will discuss the multi-faceted roles of CAFs in tumor-stroma interactions influencing cancer initiation, progression and therapeutic response.

Keywords:  Cancer associated fibroblasts; PDAC; Stroma; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cellsig.2024.111584
Biomedicines. 2024 Nov 25. pii: 2684. [Epub ahead of print]12(12):

Metabolic Crossroad Between Macrophages and Cancer Cells: Overview of Hepatocellular Carcinoma.

Anna Santarsiero, Paolo Convertini, Dominga Iacobazzi, Vittoria Infantino, Simona Todisco.

  The metabolic interplay between macrophages and cancer cells mirrors the plasticity of both kinds of cells, which adapt to the microenvironment by sustaining cell growth and proliferation. In this way, cancer cells induce macrophage polarization, and, on the other hand, tumor-associated macrophages (TAMs) contribute to the survival of cancer cells. In a simplified manner, macrophages can assume two opposite subtypes: M1, pro-inflammatory and anti-tumor phenotype, and M2, anti-inflammatory and protumor phenotype. How do cancer cells induce macrophage polarization? Any actor involved in tumor growth, including the mitochondria, releases molecules into the tumor microenvironment (TME) that trigger a subtype transition. These metabolic changes are the primary cause of this polarization. Hepatocellular carcinoma (HCC), the prevalent type of liver primary tumor, is characterized by cells with extensive metabolic adaptions due to high flexibility in different environmental conditions. This review focuses on the main metabolic features of M1 and M2 macrophages and HCC cells underlying their metabolic behavior in response to TME.

Keywords:  cancer cells; cellular signals; hepatocellular carcinoma; macrophages; metabolic reprogramming; mitochondria

DOI:  https://doi.org/10.3390/biomedicines12122684
J Gastroenterol Hepatol. 2025 Jan 08.

Glucose Metabolism Reprogramming of Immune Cells in the Microenvironment of Pancreatic and Hepatobiliary Cancers.

Yongqing Zhao, Weixiong Zhu, Shi Dong, Hui Zhang, Wence Zhou.

   BACKGROUND AND AIM: Pancreatic and hepatobiliary cancers are increasing in prevalence and contribute significantly to cancer-related mortality worldwide. Emerging therapeutic approaches, particularly immunotherapy, are gaining attention for their potential to harness the patient's immune system to combat these tumors. Understanding the role of immune cells in the tumor microenvironment (TME) and their metabolic reprogramming is key to developing more effective treatment strategies. This review aims to explore the relationship between immune cell function and glucose metabolism in the TME of pancreatic and hepatobiliary cancers.
METHODS: This review synthesizes current research on the metabolic adaptations of immune cells, specifically focusing on glucose metabolism within the TME of pancreatic and hepatobiliary cancers. We examine the mechanisms by which immune cells influence tumor progression through metabolic reprogramming and how these interactions can be targeted for therapeutic purposes.
RESULTS: Immune cells in the TME undergo significant metabolic changes, with glucose metabolism playing a central role in modulating immune responses. These metabolic shifts not only affect immune cell function but also influence tumor behavior and progression. The unique metabolic features of immune cells in pancreatic and hepatobiliary cancers provide new opportunities for targeting immune responses to combat these malignancies more effectively.
CONCLUSION: Understanding the complex relationship between immune cell glucose metabolism and tumor progression in the TME of pancreatic and hepatobiliary cancers offers promising therapeutic strategies. By modulating immune responses through targeted metabolic interventions, it may be possible to improve the efficacy of immunotherapies and better combat these aggressive cancers.

Keywords:  glucose metabolism; immune cell; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1111/jgh.16873
Front Immunol. 2024 ;15 1431112

Metabolic adaptation of myeloid cells in the glioblastoma microenvironment.

Nora Essakhi, Alexandre Bertucci, Nathalie Baeza-Kallee, Carole Colin, Rosario Lavignolle-Heguy, Paulina Garcia-Gonzalez, Rafael J Argüello, Aurélie Tchoghandjian, Emeline Tabouret.

  In recent decades, immunometabolism in cancers has emerged as an interesting target for treatment development. Indeed, the tumor microenvironment (TME) unique characteristics such as hypoxia and limitation of nutrients availability lead to a switch in metabolic pathways in both tumor and TME cells in order to support their adaptation and grow. Glioblastoma (GBM), the most frequent and aggressive primary brain tumor in adults, has been extensively studied in multiple aspects regarding its immune population, but research focused on immunometabolism remains limited. Here, we provide an overview of immunometabolism adaptation of myeloid cells in cancers with a specific focus on GBM and other brain tumors, before describing current therapeutic strategies targeting metabolic pathways. The main myeloid cells composing the GBM TME include tumor-associated macrophages (TAMs), which comprise both peripheral macrophages and local microglia, as well as myeloid-derived suppressor cells. The metabolic pathways involved in myeloid cell remodeling encompass the tricarboxylic acid cycle (TCA cycle), the lipid, glucose and amino acid metabolism and hypoxia. Developing treatments that target these metabolic pathways in tumor growth and its TME is a promising and increasing field. It includes both drug-repurposing and the development of innovative metabolic therapies. We finally provide an overview of all clinical trials in neuro-oncology involving treatments modifying cell metabolism and provide the preclinical rationale for both drugs already evaluated within clinical trials and potential candidates for future trials.

Keywords:  TCA cycle; glioblastoma; glycolysis; lipid metabolism; metabolism; myeloid cells

DOI:  https://doi.org/10.3389/fimmu.2024.1431112
Cancer Immunol Res. 2025 Jan 09.

The bidirectional interplay between T cell-based immunotherapies and the tumor microenvironment.

Alfredo Pherez-Farah, Gioia Boncompagni, Aleksey Chudnovskiy, Giulia Pasqual.

T cell-based therapies, including Tumor Infiltrating Lymphocyte Therapy (TIL), T cell receptor engineered T cells (TCR T), and Chimeric Antigen Receptor T cells (CAR T), are powerful therapeutic approaches for cancer treatment. While these therapies are primarily known for their direct cytotoxic effects on cancer cells, accumulating evidence indicates that they also influence the tumor microenvironment (TME), by altering the cytokine milieu and recruiting additional effector populations to help orchestrate the antitumor immune response. Conversely, the TME itself can modulate the behaviour of these therapies within the host by either supporting or inhibiting their activity. In this review we provide an overview of clinical and preclinical data on the bidirectional influences between T cell therapies and the TME. Unravelling the interactions between T cell-based therapies and the TME is critical for a better understanding of their mechanisms of action, resistance, and toxicity, with the goal of optimizing efficacy and safety.

DOI: https://doi.org/10.1158/2326-6066.CIR-24-0857
Genes Dis. 2025 Mar;12(2): 101240

Involvement of the ubiquitin-proteasome system in the regulation of the tumor microenvironment and progression.

Yulan Huang, Yuan Gao, Zhenghong Lin, Hongming Miao.

  The tumor microenvironment is a complex environment comprising tumor cells, non-tumor cells, and other critical non-cellular components. Some studies about tumor microenvironment have recently achieved remarkable progress in tumor treatment. As a substantial part of post-translational protein modification, ubiquitination is a crucial player in maintaining protein stability in cell signaling, cell growth, and a series of cellular life activities, which are also essential for regulating tumor cells or other non-tumor cells in the tumor microenvironment. This review focuses on the role and function of ubiquitination and deubiquitination modification in the tumor microenvironment while discussing the prospect of developing inhibitors targeting ubiquity-related enzymes, thereby providing ideas for future research in cancer therapy.

Keywords:  Adipose cells; Deubiquitination; Immunity; Tumor microenvironment; Tumor-associated fibroblasts; Ubiquitination

DOI:  https://doi.org/10.1016/j.gendis.2024.101240
Int J Mol Sci. 2024 Dec 23. pii: 13740. [Epub ahead of print]25(24):

The Therapeutic Potential of Physical Exercise in Cancer: The Role of Chemokines.

Glenda B B Buzaglo, Guilherme D Telles, Rafaela B Araújo, Gilmar D S Junior, Olivia M Ruberti, Marina L V Ferreira, Sophie F M Derchain, Felipe C Vechin, Miguel S Conceição.

  The global increase in cancer cases and mortality has been associated with inflammatory processes, in which chemokines play crucial roles. These molecules, a subfamily of cytokines, are essential for the migration, adhesion, interaction, and positioning of immune cells throughout the body. Chemokines primarily originate in response to pathogenic stimuli and inflammatory cytokines. They are expressed by lymphocytes in the bloodstream and are divided into four classes (CC, CXC, XC, and CX3C), playing multifaceted roles in the tumor environment (TME). In the TME, chemokines regulate immune behavior by recruiting cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), which promote tumor survival. Additionally, they directly influence tumor behavior, promoting pathological angiogenesis, invasion, and metastasis. On the other hand, chemokines can also induce antitumor responses by mobilizing CD8+ T cells and natural killer (NK) cells to the tumor, reducing pro-inflammatory chemokines and enhancing essential antitumor responses. Given the complex interaction between chemokines, the immune system, angiogenic factors, and metastasis, it becomes evident how important it is to target these pathways in therapeutic interventions to counteract cancer progression. In this context, physical exercise emerges as a promising strategy due to its role modulating the expression of anti-inflammatory chemokines and enhancing the antitumor response. Aerobic and resistance exercises have been associated with a beneficial inflammatory profile in cancer, increased infiltration of CD8+ T cells in the TME, and improvement of intratumoral vasculature. This creates an environment less favorable to tumor growth and supports the circulation of antitumor immune cells and chemokines. Therefore, understanding the impact of exercise on the expression of chemokines can provide valuable insights for therapeutic interventions in cancer treatment and prevention.

Keywords:  cancer; chemokine receptors; chemokines; physical exercise

DOI:  https://doi.org/10.3390/ijms252413740
Mol Cancer. 2025 Jan 09. 24(1): 7

Tumor metabolic regulators: key drivers of metabolic reprogramming and the promising targets in cancer therapy.

Kun Huang, Ying Han, Yihong Chen, Hong Shen, Shan Zeng, Changjing Cai.

  Metabolic reprogramming within the tumor microenvironment (TME) is a hallmark of cancer and a crucial determinant of tumor progression. Research indicates that various metabolic regulators form a metabolic network in the TME and interact with immune cells, coordinating the tumor immune response. Metabolic dysregulation creates an immunosuppressive TME, impairing the antitumor immune response. In this review, we discuss how metabolic regulators affect the tumor cell and the crosstalk of TME. We also summarize recent clinical trials involving metabolic regulators and the challenges of metabolism-based tumor therapies in clinical translation. In a word, our review distills key regulatory factors and their mechanisms of action from the complex reprogramming of tumor metabolism, identified as tumor metabolic regulators. These regulators provide a theoretical basis and research direction for the development of new strategies and targets in cancer therapy based on tumor metabolic reprogramming.

Keywords:  Cancer therapy; Metabolic regulators; Metabolic reprogramming; TME

DOI:  https://doi.org/10.1186/s12943-024-02205-6
Anticancer Agents Med Chem. 2025 Jan 01.

CD36 as a Therapeutic Target in Tumor Microenvironment and Lipid Metabolism.

Jiaxuan Li, Jiaqi Chen, Guang Yang, Shulin Zhang, Peiyao Li, Lan Ye.

  Dysregulated lipid metabolism within the tumor microenvironment (TME) is a critical hallmark of cancer progression, with lipids serving as a major energy source for tumor cells. Beyond their role in cell membrane synthesis, lipids also provide essential substrates for biomolecule production and activate signaling pathways that regulate various cellular processes. Aberrant lipid metabolism impacts not only function but also alters the behavior of immune and stromal cells within the TME. CD36, a key lipid transporter, plays a crucial role in regulating fatty acid sensing and lipid metabolism, and its dysregulated expression has been associated with poor prognosis in several cancers. Studies have demonstrated that elevated CD 36 expression in the TME is closely linked to abnormal lipid metabolism, promoting tumor growth, migration, and metastasis. In recent years, significant progress has been made in developing CD36-targeted therapies, including small-molecule inhibitors, antibodies, and nanoparticle-based drugs, with many entering experimental or preclinical stages. This review comprehensively summarizes the latest advances in understanding the role of CD36 in the TME, focusing on its metabolic regulatory mechanisms in tumor cells, immune cells, and stromal cells. Additionally, it highlights the contribution of CD36 to immune evasion, drug resistance, and cancer stem cell maintenance while discussing several therapeutic strategies targeting CD36, including novel therapies currently in clinical trials. By exploring the therapeutic potential of CD36, this review provides critical insights for the future development of CD36-targeted cancer therapies.

Keywords:  CD36; cancer stem cells.; lipid metabolism; targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.2174/0118715206353634241111113338
Semin Cancer Biol. 2025 Jan 07. pii: S1044-579X(25)00002-1. [Epub ahead of print]

Fungi, immunosenescence and cancer.

Bin Xu, Zan Luo, Xing Niu, Zhi Li, Yeping Lu, Junyu Li.

  Fungal microbes are a small but immunoreactive component of the human microbiome, which may influence cancer development, progression and therapeutic response. Immunosenescence is a process of immune dysfunction that occurs with aging, including lymphoid organ remodeling, contributing to alterations in the immune system in the elderly, which plays a critical role in many aspects of cancer. There is evidence for the interactions between fungi and immunosenescence in potentially regulating cancer progression and remodeling the tumor microenvironment (TME). In this review, we summarize potential roles of commensal and pathogenic fungi in modulating cancer-associated processes and provide more-detailed discussions on the mechanisms of which fungi affect tumor biology, including local and distant regulation of the TME, modulating antitumor immune responses and interactions with neighboring bacterial commensals. We also delineate the features of immunosenescence and its influence on cancer development and treatment, and highlight the interactions between fungi and immunosenescence in cancer. We discuss the prospects and challenges for harnessing fungi and immunosenescence in cancer diagnosis and/or treatment. Considering the limited understanding and techniques in conducting such research, we also provide our view on how to overcome challenges faced by the exploration of fungi, immunosenescence and their interactions on tumor biology.

Keywords:  cancer; fungi; immunosenescence; treatment; tumor microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2025.01.002
Clin Transl Oncol. 2025 Jan 08.

Progress in understanding the regulatory mechanisms of immune checkpoint proteins PD-1 and PD-L1 expression.

Xuanxuan Wu, Zengjun Zhu, Jian Zhang, Maojin Tian, Peiqing Zhao.

  Programmed Death Protein-1 (PD-1) is a cell surface receptor that serves as a checkpoint for T cells, playing a pivotal role in regulating T-cell apoptosis. The binding of PD-1 to its ligand, Programmed Death Ligand 1 (PD-L1), inhibits anti-tumor immunity by suppressing T-cell activation signals. Indeed, the PD-1/PD-L1 pathway governs the induction and maintenance of immune tolerance within the tumor microenvironment. Consequently, the regulation of PD-1/PD-L1 immune checkpoint expression is of paramount importance. This review summarizes the mechanisms governing PD1/PD-L1 expression at various stages, including transcription, post-transcription (mRNA processing), and post-translation (protein modifications), as well as immunotherapy targeting PD1/PD-L1, aiming to further explore novel strategies for tumor immunotherapy.

Keywords:  PD-L1; PD1; Post-translational modifications; Transcriptional regulation

DOI:  https://doi.org/10.1007/s12094-024-03835-4
Int Immunol. 2025 Jan 10. pii: dxaf002. [Epub ahead of print]

Cancer immunotherapy in progress-an overview of the past 130 years.

Hiroaki Ikeda.

  Since the first approval of an immune-checkpoint inhibitor, we have witnessed the clinical success of cancer immunotherapy. Adoptive T-cell therapy with chimeric antigen-receptor T (CAR-T) cells has shown remarkable efficacy in hematological malignancies. Concurrently with these successes, the cancer immunoediting concept that refined the cancer immunosurveillance concept underpinned the scientific mechanism and reason for past failures, as well as recent breakthroughs in cancer immunotherapy. Now, we face the next step of issues to be solved in this field, such as tumor heterogeneity, the tumor microenvironment, the metabolism of tumors and the immune system, and personalized approaches for patients, aiming to expand the population benefitted by the therapies.

Keywords:  CAR-T therapy; immune checkpoint inhibitor; tumor heterogeneity; tumor immunology

DOI:  https://doi.org/10.1093/intimm/dxaf002
Ann Med. 2025 Dec;57(1): 2447403

The role of cisplatin in modulating the tumor immune microenvironment and its combination therapy strategies: a new approach to enhance anti-tumor efficacy.

Guandu Li, Xiangyu Che, Shijin Wang, Dequan Liu, Deqian Xie, Bowen Jiang, Zunwen Zheng, Xu Zheng, Guangzhen Wu.

  Cisplatin is a platinum-based drug that is frequently used to treat multiple tumors. The anti-tumor effect of cisplatin is closely related to the tumor immune microenvironment (TIME), which includes several immune cell types, such as the tumor-associated macrophages (TAMs), cytotoxic T-lymphocytes (CTLs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and natural killer (NK) cells. The interaction between these immune cells can promote tumor survival and chemoresistance, and decrease the efficacy of cisplatin monotherapy. Therefore, various combination treatment strategies have been devised to enhance patient responsiveness to cisplatin therapy. Cisplatin can augment anti-tumor immune responses in combination with immune checkpoint blockers (such as PD-1/PD-L1 or CTLA4 inhibitors), lipid metabolism disruptors (like FASN inhibitors and SCD inhibitors) and nanoparticles (NPs), resulting in better outcomes. Exploring the interaction between cisplatin and the TIME will help identify potential therapeutic targets for improving the treatment outcomes in cancer patients.

Keywords:  Cisplatin; combination therapy; immune therapy; lipid metabolism disruptors; tumor immune microenvironment

DOI:  https://doi.org/10.1080/07853890.2024.2447403
JCI Insight. 2025 Jan 07. pii: e186000. [Epub ahead of print]

Metabolic Fitness of NAC1-Deficient Regulatory T Cells in the Tumor Microenvironment Fuels Tumor Growth.

Anil Kumar, Jugal Das, Hao-Yun Peng, Liqing Wang, Darby Ballard, Yijie Ren, Xiaofang Xiong, Xingcong Ren, Jin-Ming Yang, Paul de Figueiredo, Jianxun Song.

  The nucleus accumbens-associated protein-1 (NAC1) has recently emerged as a pivotal factor in oncogenesis by promoting glycolysis. Deletion of NAC1 in regulatory T cells (Tregs) has been shown to enhance FoxP3 stability, a suppressor of glycolysis. This study delves into the intriguing dual role of NAC1, uncovering that Tregs-specific deletion of NAC1 fosters metabolic fitness in Tregs, thereby promoting tumorigenesis. Our results unveil that NAC1-deficient Tregs exhibit prolonged survival and heightened function, particularly in acidic environments. Mechanistically, we find that NAC1-deficient Tregs adapt to adverse conditions by upregulating FoxP3 expression, engaging in CD36-mediated lipid metabolism, and enhancing PGC-1α-regulated mitochondrial function. In mouse tumor xenograft models, NAC1-deficient mice demonstrate increased susceptibility to tumor growth. Notably, Tregs lacking NAC1 not only display elevated lipid metabolism and mitochondrial fitness but also exhibit enhanced tumoral infiltration. Adoptive Treg transfer experiments further underscore the supportive role of NAC1-deficient Tregs in tumor growth. These findings suggest that modulating NAC1 expression in FoxP3+ Tregs could serve as a promising approach to augment antitumor immunity. Understanding the intricate interplay between NAC1 and Tregs opens avenues for potential therapeutic strategies targeting the tumor microenvironment (TME).

Keywords:  Cancer; Immunology

DOI:  https://doi.org/10.1172/jci.insight.186000
Biomaterials. 2024 Dec 27. pii: S0142-9612(24)00579-9. [Epub ahead of print]317 123043

Magnesium peroxide-based biomimetic nanoigniter degrades extracellular matrix to awake T cell-mediated cancer immunotherapy.

Huisong Hao, Shengjie Sun, Yanan Fu, Simin Wen, Yingfei Wen, Yunfei Yi, Zhangwen Peng, Yixuan Fang, Jia Tang, Tianqi Wang, Meiying Wu.

  As the elite force of our immune system, T cells play a determining role in the effectiveness of cancer immunotherapy. However, the clever tumor cells construct a strong immunosuppressive tumor microenvironment (TME) fortress to resist the attack of T cells. Herein, a magnesium peroxide (MP)-based biomimetic nanoigniter loaded with doxorubicin (DOX) and metformin (MET) is rationally designed (D/M-MP@LM) to awake T cell-mediated cancer immunotherapy via comprehensively destroying the strong TME fortress. The nanoigniter not only effectively initiate CD8+ T cell-mediated immune response by promoting the presentation of tumor antigens, but also greatly facilitate the infiltration of T cells by degrading rigid extracellular matrix (ECM). More importantly, the nanoigniter significantly augment the effector functions of infiltrated CD8+ T cells by Mg2+-mediated metalloimmunotherapy and avoid the exhaustion of CD8+ T cells by improving the acidic TME. Thus, the nanoigniter comprehensively awakes T cells and achieves remarkable tumor inhibition efficacy.

Keywords:  Biomimetic nanomedicine; Cancer therapy; Magnesium peroxide; Metalloimmunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.biomaterials.2024.123043
Int J Mol Sci. 2024 Dec 14. pii: 13413. [Epub ahead of print]25(24):

Tumor Metabolic Reprogramming and Ferroptosis: The Impact of Glucose, Protein, and Lipid Metabolism.

Keyu Zhu, Yuang Cai, Lan Lan, Na Luo.

  Ferroptosis, a novel form of cell death discovered in recent years, is typically accompanied by significant iron accumulation and lipid peroxidation during the process. This article systematically elucidates how tumor metabolic reprogramming affects the ferroptosis process in tumor cells. The paper outlines the basic concepts and physiological significance of tumor metabolic reprogramming and ferroptosis, and delves into the specific regulatory mechanisms of glucose metabolism, protein metabolism, and lipid metabolism on ferroptosis. We also explore how complex metabolic changes in the tumor microenvironment further influence the response of tumor cells to ferroptosis. Glucose metabolism modulates ferroptosis sensitivity by influencing intracellular energetic status and redox balance; protein metabolism, involving amino acid metabolism and protein synthesis, plays a crucial role in the initiation and progression of ferroptosis; and the relationship between lipid metabolism and ferroptosis primarily manifests in the generation and elimination of lipid peroxides. This review aims to provide a new perspective on how tumor cells regulate ferroptosis through metabolic reprogramming, with the ultimate goal of offering a theoretical basis for developing novel therapeutic strategies targeting tumor metabolism and ferroptosis.

Keywords:  ferroptosis; glucose metabolism; lipid metabolism; protein metabolism; tumor metabolic reprogramming

DOI:  https://doi.org/10.3390/ijms252413413
Int Immunopharmacol. 2025 Jan 06. pii: S1567-5769(24)02474-3. [Epub ahead of print]147 113952

Unleashing the Power of immune Checkpoints: A new strategy for enhancing Treg cells depletion to boost antitumor immunity.

Guoxin Li, Siqi Li, Yilin Jiang, Tao Chen, Zhengwen An.

  Regulatory T (Treg) cells, immunosuppressive CD4+ T cells, can impede anti-tumor immunity, complicating cancer treatment. Since their discovery, numerous studies have been dedicated to understand Treg cell biology, with a focus on checkpoint pathways' role in their generation and function. Immune checkpoints, such as PD-1/PD-L1, CTLA-4, TIGIT, TIM-3, and OX40, are pivotal in controlling Treg cell expansion and activity in the tumor microenvironment (TME), affecting their ability to suppress immune responses. This review examines the complex relationship between these checkpoints and Tregs in the TME, and how they influence tumor immunity. We also discuss the therapeutic potential of targeting these checkpoints to enhance anti-tumor immunity, including the use of immune checkpoint blockade (ICB) therapies and novel approaches such as CCR8-targeted therapies. Understanding the interaction between immune checkpoints and Treg cells can lead to more effective immunotherapeutic strategies, such as combining CCR8-targeted therapies with immune checkpoint inhibitors, to improve patient outcomes in cancer treatment.

Keywords:  CCR-8; Immune checkpoint blockade; Immunotherapy; Regulatory T cells; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2024.113952
Adv Sci (Weinh). 2025 Jan 07. e2404585

Rbfox3 Promotes Transformation of MDSC-Like Tumor Cells to Shape Immunosuppressive Microenvironment.

Zhiyang Li, Zhuangzhuang Feng, Mengzhan Chen, Xinxiu Shi, Bijia Cui, Yujie Sun, Heng Zhang, Yinan Li, Caihong Chen, Yiqian Feng, Jingxia Han, Xuewu Xing, Huijuan Liu, Tao Sun.

  Myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME) contribute to the malignant progression of tumors by exerting immunosuppressive effects. Bacterial lipopolysaccharides (LPS) have been widely demonstrated in various types of solid tumors. LPS can promote the malignant progression of tumors, which mechanism has not yet been fully elucidated. In this study, a type of MDSC-like tumor cells (MLTCs) is found in tumor tissues induced by low-dose and long-term LPS stimulation. MLTCs can simultaneously express tumor cell and MDSCs markers. Similar to MDSCs, MLTCs can produce arginine, nitric oxide, and reactive oxygen species and inhibit the activity of NK and T cells to promote the formation of an immunosuppressive microenvironment. MLTCs can also promote tumor cell proliferation and vasculogenic mimicry formation. CRISPR-Cas9 activity screening studies identified RNA-binding Fox-1 homolog 3 (Rbfox3) as a critical protein for MLTCs formation after LPS treatment. Rbfox3 can transcriptionally regulate the expression of Ass1 in the form of phase-separated particles. Crocin can inhibit the generation of MLTCs by disrupting phase-separated particles of Rbfox3 and enhance the anti-tumor effects of immune checkpoint inhibitors (ICIs).

Keywords:  MDSC‐like tumor cells; Rbfox3; immunosuppressive tumor microenvironment; phase‐separated particles

DOI:  https://doi.org/10.1002/advs.202404585
Trends Pharmacol Sci. 2025 Jan 03. pii: S0165-6147(24)00270-0. [Epub ahead of print]

Boosting CAR-T cell therapy through vaccine synergy.

Yan-Ruide Li, Zibai Lyu, Xinyuan Shen, Ying Fang, Lili Yang.

  Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for hematological cancers. However, achieving comparable success in solid tumors remains challenging. Factors contributing to these limitations include the scarcity of tumor-specific antigens (TSAs), insufficient CAR-T cell infiltration, and the immunosuppressive tumor microenvironment (TME). Vaccine-based strategies are emerging as potential approaches to address these challenges, enhancing CAR-T cell expansion, persistence, and antitumor efficacy. In this review, we explore diverse vaccine modalities, including mRNA, peptide, viral vector, and dendritic cell (DC)-based vaccines, and their roles in augmenting CAR-T cell responses. Special focus is given to recent clinical advancements combining mRNA-based vaccines with CAR-T therapy for the treatment of genitourinary cancers. In addition, we discuss crucial considerations for optimizing vaccine dosing, scheduling, and delivery to maximize CAR-T synergy, aiming to refine this combination strategy to improve treatment efficacy and safety.

Keywords:  CAR-engineered T (CAR-T) cell therapy; chimeric antigen receptor (CAR); dendritic cell-based vaccines; immunotherapy; mRNA vaccines; peptide vaccines; solid tumor therapy; tumor microenvironment; vaccine synergy; viral vector vaccines

DOI:  https://doi.org/10.1016/j.tips.2024.12.004
bioRxiv. 2024 Dec 26. pii: 2024.12.26.630419. [Epub ahead of print]

Estrogens increase cancer cell efferocytosis to establish an immunosuppressive tumor microenvironment.

Binita Chakraborty, Prabuddha Chakraborty, Michael C Brown, Daniel Crowder, Aditi Goyal, Rachid Safi, Sandeep Artham, Megan Kirkland, Alessandro Racioppi, Patrick Juras, Debarati Mukherjee, Felicia Lim, Jovita Byemerwa, Kiana Gunn, Scott R Floyd, Georgia Beasley, Suzanne Wardell, Ching-Yi Chang, Donald P McDonnell.

Phagocytic clearance of apoptotic cancer cells (efferocytosis) by tumor-associated macrophages (TAMs) contributes in a substantial manner to the establishment of an immunosuppressive tumor microenvironment. This puts in context our observation that the female steroid hormone 17β-estradiol (E2) facilitates tumor immune resistance through cancer cell extrinsic Estrogen Receptor (ERalpha;) signaling in TAMs. Notable was the finding that E2 induces the expression of CX3CR1 in TAMs to enable efferocytosis of apoptotic cancer cells which results in the suppression of type I interferon (IFN) signaling. Mechanistically, E2 facilitates calcium-dependent activation of the transcription factor NFATC1, which in turn induces CX3CR1 expression. This drives macrophage polarization towards an immune-suppressive state, increasing the ability of TAMs to engulf pro-inflammatory apoptotic cancer cells. Genetic or pharmacological inhibition of the E2/ER/CX3CR1 axis reversed the efferocytic activity of TAMs, rescued E2-dependent suppression of type I IFN signaling, and potentiated intratumoral adaptive immune cell function. Efferocytosis following radiation-induced cancer cell apoptosis limits the efficacy of radiation therapy. Importantly, we determined that preconditioning with either ER-directed endocrine therapies or CX3CR1 inhibition enhanced the antitumor efficacy of radiation therapy by reversing macrophage suppression and reviving intratumoral T cell activation. Our work defines the mechanisms by which E2 increases the efferocytotic activity of TAMs to establish an immunosuppressive tumor microenvironment and demonstrates how this process can be reversed with endocrine therapies which target ERalpha.

DOI: https://doi.org/10.1101/2024.12.26.630419
Biology (Basel). 2024 Nov 24. pii: 967. [Epub ahead of print]13(12):

Unveiling the Tumor Microenvironment Through Fibroblast Activation Protein Targeting in Diagnostic Nuclear Medicine: A Didactic Review on Biological Rationales and Key Imaging Agents.

Juliette Fouillet, Jade Torchio, Léa Rubira, Cyril Fersing.

  The tumor microenvironment (TME) is a dynamic and complex medium that plays a central role in cancer progression, metastasis, and treatment resistance. Among the key elements of the TME, cancer-associated fibroblasts (CAFs) are particularly important for their ability to remodel the extracellular matrix, promote angiogenesis, and suppress anti-tumor immune responses. Fibroblast activation protein (FAP), predominantly expressed by CAFs, has emerged as a promising target in both cancer diagnostics and therapeutics. In nuclear medicine, targeting FAP offers new opportunities for non-invasive imaging using radiolabeled fibroblast activation protein inhibitors (FAPIs). These FAP-specific radiotracers have demonstrated excellent tumor detection properties compared to traditional radiopharmaceuticals such as [18F]FDG, especially in cancers with low metabolic activity, like liver and biliary tract tumors. The most recent FAPI derivatives not only enhance the accuracy of positron emission tomography (PET) imaging but also hold potential for theranostic applications by delivering targeted radionuclide therapies. This review examines the biological underpinnings of FAP in the TME, the design of FAPI-based imaging agents, and their evolving role in cancer diagnostics, highlighting the potential of FAP as a target for precision oncology.

Keywords:  cancer associated fibroblasts; fibroblast activation protein; molecular imaging; nuclear medicine; radiopharmaceuticals; tumor microenvironment

DOI:  https://doi.org/10.3390/biology13120967
Mol Cancer. 2025 Jan 08. 24(1): 6

Intra-tumoral sphingobacterium multivorum promotes triple-negative breast cancer progression by suppressing tumor immunosurveillance.

Zhikai Mai, Liwu Fu, Jiyan Su, Kenneth K W To, Chuansheng Yang, Chenglai Xia.

   BACKGROUND: Intratumor-resident bacteria represent an integral component of the tumor microenvironment (TME). Microbial dysbiosis, which refers to an imbalance in the bacterial composition and bacterial metabolic activities, plays an important role in regulating breast cancer development and progression. However, the impact of specific intratumor-resident bacteria on tumor progression and their underlying mechanisms remain elusive.
METHODS: 16S rDNA gene sequencing was used to analyze the cancerous and paracancerous tissues from breast cancer patients. The mouse models of bearing 4T1 cell tumors were employed to assess the influence of bacterial colonization on tumor growth. Tissue infiltration of regulatory T (Treg) cells and CD8+ T cells was evaluated through immunohistochemistry and flow cytometric analysis. Comparative metabolite profiling in mice tumors was conducted using targeted metabolomics. Differential genes of tumor cells stimulated by bacteria were analyzed by transcriptomics and validated by qPCR assay.
RESULTS: We found that Sphingobacterium displayed high abundance in cancerous tissues. Intra-tumoral colonization of Sphingobacterium multivorum (S. multivorum) promoted tumor progression in 4T1 tumor-bearing mice. Moreover, S. multivorum diminished the therapeutic efficacy of αPD-1 mAb, which was associated with the increase of regulatory T cell (Treg) infiltration, and decrese of the CD8+ T cell infiltration. Targeted metabolomics revealed a conspicuous reduction of propionylcarnitine in tumors colonized by S. multivorum Furthermore, the combination of metabolite propionylcarnitine and S. multivorum shown to suppress tumor growth compared that in S. multivorum alone in vivo. Mechanistically, S. multivorum promoted the secretion of chemokines CCL20 and CXCL8 from tumor cells. CCL20 secreted into the TME facilitated the recruitment of Treg cells and reduced CD8+ T cell infiltration, thus promoting tumor immune escape.
CONCLUSIONS: This study reveals S. multivorum suppresses immune surveillance within the TME, thereby promoting breast cancer progression.

Keywords:   Sphingobacterium multivorum ; Breast cance; Immune escape; Propionylcarnitine; Treg cell

DOI:  https://doi.org/10.1186/s12943-024-02202-9
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2024 Aug 28. pii: 1672-7347(2024)08-1316-11. [Epub ahead of print]49(8): 1316-1326

Application of tumor organoids simulating the tumor microenvironment in basic and clinical research of tumor immunotherapy.

Yizheng Li, Weihua Liao, Lunquan Sun.

  Immunotherapy has led to groundbreaking advances in anti-tumor treatment, yet significant clinical challenges remain such as the low proportion of beneficiaries and the lack of effective platforms for predicting therapeutic response. Organoid technology provides a novel solution to these issues. Organoids are three-dimensional tissue cultures derived from adult stem cells or pluripotent stem cells that closely replicate the structural and biological characteristics of native organs, demonstrating particularly strong potential in modeling the tumor microenvironment (TME). Tumor organoids can simulate TME effectively by retaining endogenous matrix components, including various immune cells, or by adding immune cells, cancer-associated fibroblasts, and other components. This provides a novel platform for predicting immunotherapy outcomes, evaluating adoptive cell therapies, and selecting personalized treatment options for patients. Summarizing strategies for constructing tumor organoids that simulate the microenvironment and understanding their advancements in immunotherapy research and clinical application can provide new insights for the development of tumor immunotherapy.

Keywords:  immunotherapy; tumor immunology; tumor microenvironment; tumor organoid

DOI:  https://doi.org/10.11817/j.issn.1672-7347.2024.240187
Genes (Basel). 2024 Dec 17. pii: 1615. [Epub ahead of print]15(12):

Mutant p53-Mediated Tumor Secretome: Bridging Tumor Cells and Stromal Cells.

Lei Qiu, Zelong Ma, Xiaoming Wu.

  The tumor secretome comprises the totality of protein factors secreted by various cell components within the tumor microenvironment, serving as the primary medium for signal transduction between tumor cells and between tumor cells and stromal cells. The deletion or mutation of the p53 gene leads to alterations in cellular secretion characteristics, contributing to the construction of the tumor microenvironment in a cell non-autonomous manner. This review discusses the critical roles of mutant p53 in regulating the tumor secretome to remodel the tumor microenvironment, drive tumor progression, and influence the plasticity of cancer-associated fibroblasts (CAFs) as well as the dynamics of tumor immunity by focusing on both secreted protein expression and secretion pathways. The aim is to provide new insights for targeted cancer therapies.

Keywords:  mutant p53; secretory pathway; tumor immunization; tumor microenvironment; tumor secretome

DOI:  https://doi.org/10.3390/genes15121615
bioRxiv. 2024 Dec 25. pii: 2024.12.24.630251. [Epub ahead of print]

Single-Cell Profiling Reveals Global Immune Responses during the Progression of Murine Epidermal Neoplasms.

Xiying Fan, Tonya M Brunetti, Kelsey Jackson, Dennis R Roop.

Immune cells determine the role of the tumor microenvironment during tumor progression, either suppressing tumor formation or promoting tumorigenesis. We analyzed the profile of immune cells in the tumor microenvironment of control mouse skins and skin tumors at the single-cell level. We identified 15 CD45 + immune cell clusters, which broadly represent the most functionally characterized immune cell types including macrophages, Langerhans cells (LC), conventional type 1 dendritic cells (cDC1), conventional type 2 dendritic cells (cDC2), migratory/mature dendritic cells (mDC), dendritic epidermal T cells (DETC), dermal γδ T cells (γδT), T cells, regulatory T cells (Tregs), natural killer cells (NK), type 2 innate lymphoid cells (ILC2), neutrophils (Neu), mast cells (Mast), and two proliferating populations (Prolif.1 and Prolif.2). Skin tumor progression reprogramed immune cells and led to a marked increase in the relative percentages of macrophages, cDC2, mDC, Tregs, and Neu. Macrophages, the largest cell cluster of immune cells in skin tumors. In addition, macrophages emerged as the predominant communication 'hub' in skin tumors, highlighting the importance of macrophages during skin tumor progression. In contrast, other immune cell clusters decreased during skin tumor progression, including DETC, γδT, ILC2, and LC. In addition, skin tumor progression dramatically upregulated Jak2/Stat3 expression and the interferon response across various immune cell clusters. Further, skin tumor progression activated T cells and NK cells indicated by elevated expression of IFN-γ and Granzyme B in skin tumors. Meanwhile, a pronounced infiltration of M2-macrophages and Tregs in skin tumors created an immunosuppressive microenvironment, consistent with the elevated expression of the Stat3 pathway in skin tumors. In summary, our study elucidates the immune cell landscape of epidermal neoplasms, offering a comprehensive understanding of the immune response during skin tumor progression and providing new insights into cancer immune evasion mechanisms.

DOI: https://doi.org/10.1101/2024.12.24.630251
Int J Mol Sci. 2024 Dec 18. pii: 13569. [Epub ahead of print]25(24):

Targeting Cancer: Microenvironment and Immunotherapy Innovations.

Irena Barbara Padzińska-Pruszyńska, Bartłomiej Taciak, Łukasz Kiraga, Anna Smolarska, Małgorzata Górczak, Paulina Kucharzewska, Małgorzata Kubiak, Jacek Szeliga, Agata Matejuk, Magdalena Król.

  In 2024, the United States was projected to experience 2 million new cancer diagnoses and approximately 611,720 cancer-related deaths, reflecting a broader global trend in which cancer cases are anticipated to exceed 35 million by 2050. This increasing burden highlights ongoing challenges in cancer treatment despite significant advances that have reduced cancer mortality by 31% since 1991. Key obstacles include the disease's inherent heterogeneity and complexity, such as treatment resistance, cancer stem cells, and the multifaceted tumor microenvironment (TME). The TME-comprising various tumor and immune cells, blood vessels, and biochemical factors-plays a crucial role in tumor growth and resistance to therapies. Recent innovations in cancer treatment, particularly in the field of immuno-oncology, have leveraged insights into TME interactions. An emerging example is the FDA-approved therapy using tumor-infiltrating lymphocytes (TILs), demonstrating the potential of cell-based approaches in solid tumors. However, TIL therapy is just one of many strategies being explored. This review provides a comprehensive overview of the emerging field of immuno-oncology, focusing on how novel therapies targeting or harnessing components of the TME could enhance treatment efficacy and address persistent challenges in cancer care.

Keywords:  Tregs; cancer immunotherapy; dendritic cells; natural killer cells; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3390/ijms252413569
JCI Insight. 2025 Jan 09. pii: e178146. [Epub ahead of print]10(1):

Sustained inhibition of CSF1R signaling augments antitumor immunity through inhibiting tumor-associated macrophages.

Takahiko Sato, Daisuke Sugiyama, Jun Koseki, Yasuhiro Kojima, Satomi Hattori, Kazuki Sone, Hitomi Nishinakamura, Tomohiro Ishikawa, Yuichi Ishikawa, Takuma Kato, Hitoshi Kiyoi, Hiroyoshi Nishikawa.

  Tumor-associated macrophages (TAMs) are one of the key immunosuppressive components in the tumor microenvironment (TME) and contribute to tumor development, progression, and resistance to cancer immunotherapy. Several reagents targeting TAMs have been tested in preclinical and clinical studies, but they have had limited success. Here, we show that a unique reagent, FF-10101, exhibited a sustained inhibitory effect against colony-stimulating factor 1 receptor by forming a covalent bond and reduced immunosuppressive TAMs in the TME, which led to strong antitumor immunity. In preclinical animal models, FF-10101 treatment significantly reduced immunosuppressive TAMs and increased antitumor TAMs in the TME. In addition, tumor antigen-specific CD8+ T cells were increased; consequently, tumor growth was significantly inhibited. Moreover, combination treatment with an anti-programmed cell death 1 (anti-PD-1) antibody and FF-10101 exhibited a far stronger antitumor effect than either treatment alone. In human cancer specimens, FF-10101 treatment reduced programmed cell death 1 ligand 1 (PD-L1) expression on TAMs, as observed in animal models. Thus, FF-10101 acts as an immunomodulatory agent that can reduce immunosuppressive TAMs and augment tumor antigen-specific T cell responses, thereby generating an immunostimulatory TME. We propose that FF-10101 is a potential candidate for successful combination cancer immunotherapy with immune checkpoint inhibitors, such as PD-1/PD-L1 blockade.

Keywords:  Immunology; Macrophages

DOI:  https://doi.org/10.1172/jci.insight.178146
Mol Nutr Food Res. 2025 Jan 05. e202400750

Tumor Microenvironment Targeted by Polysaccharides in Cancer Prevention: Expanding Roles of Gut Microbiota and Metabolites.

Shuai Han, Yi Luo, Zuomin Hu, Xinhua Li, Yaping Zhou, Feijun Luo.

  Since the development of immune checkpoint inhibitors (ICIs), immunotherapy has been widely used as a novel cancer treatment. However, the efficacy of tumor immunotherapy is largely dependent on the tumor microenvironment (TME). The high degree of heterogeneity within TME remains a major obstacle to acquire satisfactory therapeutic. Emerging studies suggest that gut microbiota is becoming an important regulator of TME. Polysaccharides as tumor immunotherapeutic agents or immune adjuvants not only exhibit antitumor activity by targeting gut microbiota, but also expand their role in the tumor immunotherapy by remodeling TME. To date, the mechanism by which polysaccharides targeting TME for tumor prevention via gut microbiota has not been deeply investigated. In this review, recent advances in the regulation of TME by polysaccharides through gut microbiota were systematically outlined, and the challenges and possible solutions in the clinical application of TME-targeted polysaccharides were discussed. Exploring the relationship between polysaccharides and TME from the perspective of gut microbiota may provide new ideas for the application of polysaccharides in tumor immunotherapy. This is a new area with major challenges that deserve further exploration.

Keywords:  gut microbiota; immunotherapy; mechanism of action; polysaccharides; tumor microenvironment

DOI:  https://doi.org/10.1002/mnfr.202400750
Pharmaceutics. 2024 Dec 03. pii: 1549. [Epub ahead of print]16(12):

Innovative Nanomedicine Delivery: Targeting Tumor Microenvironment to Defeat Drug Resistance.

Wenjun Meng, Li Huang, Jiamin Guo, Qing Xin, Jiyan Liu, Yuzhu Hu.

  Nanodrug delivery systems have revolutionized tumor therapy like never before. By overcoming the complexity of the tumor microenvironment (TME) and bypassing drug resistance mechanisms, nanotechnology has shown great potential to improve drug efficacy and reduce toxic side effects. This review examines the impact of the TME on drug resistance and recent advances in nanomedicine delivery systems to overcome this challenge. Characteristics of the TME such as hypoxia, acidity, and high interstitial pressure significantly reduce the effectiveness of chemotherapy and radiotherapy, leading to increased drug resistance in tumor cells. Then, this review summarizes innovative nanocarrier designs for these microenvironmental features, including hypoxia-sensitive nanoparticles, pH-responsive carriers, and multifunctional nanosystems that enable targeted drug release and improved drug penetration and accumulation in tumors. By combining nanotechnology with therapeutic strategies, this review offers a novel perspective by focusing on the innovative design of nanocarriers that interact with the TME, a dimension often overlooked in similar reviews. We highlight the dual role of these nanocarriers in therapeutic delivery and TME modulation, emphasize their potential to overcome drug resistance, and look at future research directions.

Keywords:  drug resistance; nanomedicine delivery; tumor microenvironment

DOI:  https://doi.org/10.3390/pharmaceutics16121549
Front Immunol. 2024 ;15 1512981

SQLE-mediated squalene metabolism promotes tumor immune evasion in pancreatic cancer.

Junchen Pan, Haixi Liang, Lin Zhou, Wenhua Lu, Bitao Huo, Rui Liu, Peng Huang.

   Background: Squalene epoxidase (SQLE) is a key enzyme in cholesterol biosynthesis and has been shown to negatively affect tumor immunity and is associated with poor outcomes of immunotherapy in various cancers. While most research in this area has focused on the impact of cholesterol on immune functions, the influence of SQLE-mediated squalene metabolism within the tumor immune microenvironment (TIME) remains unexplored.
Methods: We established an immune-competent mouse model (C57BL/6) bearing mouse pancreatic cancer xenografts (KPC cells) with or without stable SQLE-knockdown (SQLE-KD) to evaluate the impact of SQLE-mediated metabolism on pancreatic cancer growth and immune functions. The effect of squalene on tumor growth and immune cells was tested by direct administration of squalene to C57BL/6 mice bearing KPC tumors. Flow cytometry analysis and immunohistochemical (IHC) staining of immune cells from the tumor tissues were performed to evaluate changes in immune function. We also employed RNA-sequencing to analyze the gene expression profiles in pancreatic cancer cells (PANC-1) treated with or without squalene. RT-PCR and Western blot analyses were used to investigate the relevant molecular mechanisms.
Results: We show that SQLE is significantly overexpressed in pancreatic cancer, and abrogation of SQLE results in a significant increase in squalene accumulation within tumor cells. The elevated squalene inhibits CXCL1 transcription through its impact on the NF-κB pathway via p65, and thus reduces the recruitment of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) into the tumor microenvironment. Silencing of SQLE also leads to an increased proportion of CD8+ T cells in the tumor tissues and suppresses tumor growth in vivo. Importantly, direct administration of squalene, the metabolic substrate of SQLE, to immune-competent mice bearing KPC pancreatic cancer tumors causes a substantial decrease in CD206+ TAMs and MDSCs, thus releasing immune suppression and inhibiting tumor growth.
Conclusion: Our study shows that squalene is an important immune-modulating metabolite that inhibits the infiltration of immune-suppressive cells in TIME, and that SQLE exerts its tumor immune evasion effect by metabolic removal of squalene. Thus, SQLE-mediated squalene metabolic pathway could be a potential target to enhance antitumor immunity in pancreatic cancer.

Keywords:  MDSCs; NF-κB; SQLE; TAMs; pancreatic cancer; squalene

DOI:  https://doi.org/10.3389/fimmu.2024.1512981
Int J Mol Sci. 2024 Dec 21. pii: 13689. [Epub ahead of print]25(24):

Therapeutic Significance of NLRP3 Inflammasome in Cancer: Friend or Foe?

Aliea M Jalali, Kenyon J Mitchell, Christian Pompoco, Sudeep Poludasu, Sabrina Tran, Kota V Ramana.

  Besides various infectious and inflammatory complications, recent studies also indicated the significance of NLRP3 inflammasome in cancer progression and therapy. NLRP3-mediated immune response and pyroptosis could be helpful or harmful in the progression of cancer, and also depend on the nature of the tumor microenvironment. The activation of NLRP3 inflammasome could increase immune surveillance and the efficacy of immunotherapy. It can also lead to the removal of tumor cells by the recruitment of phagocytic macrophages, T-lymphocytes, and other immune cells to the tumor site. On the other hand, NLRP3 activation can also be harmful, as chronic inflammation driven by NLRP3 supports tumor progression by creating an environment that facilitates cancer cell proliferation, migration, invasion, and metastasis. The release of pro-inflammatory cytokines such as IL-1β and IL-18 can promote tumor growth and angiogenesis, while sustained inflammation may lead to immune suppression, hindering effective anti-tumor responses. In this review article, we discuss the role of NLRP3 inflammasome-mediated inflammatory response in the pathophysiology of various cancer types; understanding this role is essential for the development of innovative therapeutic strategies for cancer growth and spread.

Keywords:  IL-1b; NLRP3; cancer; caspase-1; inflammasome; innate immunity

DOI:  https://doi.org/10.3390/ijms252413689
Cancers (Basel). 2024 Dec 21. pii: 4260. [Epub ahead of print]16(24):

Targeting Perineural Invasion in Pancreatic Cancer.

Ingrid Garajová, Elisa Giovannetti.

  Pancreatic cancer is an aggressive tumor with dismal prognosis. Neural invasion is one of the pathological hallmarks of pancreatic cancer. Peripheral nerves can modulate the phenotype and behavior of the malignant cells, as well as of different components of the tumor microenvironment, and thus affect tumor growth and metastasis. From a clinical point of view, neural invasion is translated into intractable pain and represents a predictor of tumor recurrence and poor prognosis. Several molecules are implicated in neural invasion and pain onset in PDAC, including neutrophins (e.g., NGF), chemokines, adhesion factors, axon-guidance molecules, different proteins, and neurotransmitters. In this review, we discuss the role of nerves within the pancreatic cancer microenvironment, highlighting how infiltrating nerve fibers promote tumor progression and metastasis, while tumor cells, in turn, drive nerve outgrowth in a reciprocal interaction that fuels tumor advancement. We outline key molecules involved in neural invasion in pancreatic cancer and, finally, explore potential therapeutic strategies to target neural invasion, aiming to both inhibit cancer progression and alleviate cancer-associated pain.

Keywords:  cancer pain; neural invasion; pancreatic ductal adenocarcinoma; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers16244260
Adv Sci (Weinh). 2025 Jan 09. e2404734

Metabolic-Immune Suppression Mediated by the SIRT1-CX3CL1 Axis Induces Functional Enhancement of Regulatory T Cells in Colorectal Carcinoma.

Ruiyang Zi, Xiang Zhao, Limei Liu, Yijie Wang, Rui Zhang, Zhiheng Bian, Haoran Jiang, Taorui Liu, Yixin Sun, Han Peng, Xuesong Wang, Fanghao Lu, Chao Zhang, Fan Zhang, Qing Qin, Houjie Liang, Jianjun Li, Zhihao Wei, Yan Dong.

  Metabolic reprogramming of tumor cells dynamically reshapes the distribution of nutrients and signals in the tumor microenvironment (TME), affecting intercellular interactions and resulting in metabolic immune suppression. Increased glucose uptake and metabolism are characteristic of many tumors. Meanwhile, the progression of colorectal carcinoma (CRC) relies on lipid metabolism. Therefore, investigating the role of glucolipid metabolic reprogramming on tumor immunity contributes to identifying new targets for immune suppression intervention in CRC. Our previous work demonstrated that SIRT1 is the hub gene involved in glucolipid metabolic conversion in CRC. Here, it is found that upregulated SIRT1 in CRC cells increases Treg functionality by promoting the secretion of CX3CL1. The CX3CL1-CX3CR1 signaling activated transcription factors SATB1 and BTG2, promoting the differentiation of TCF7+ Treg cells into functionally enhanced TNFRSF9+ Treg cells. Multiplex immunofluorescence (mIHC) analysis of a CRC tissue microarray confirmed the promoting effect of CX3CL1 on Treg infiltration. Additionally, the therapeutic efficacy of CX3CR1 inhibitor monotherapy and combination therapy is validated with the PD-1 antibody in the humanized subcutaneous CRC mouse model. This study elucidates a potential mechanism that metabolic reprogramming of cancer cells collaborates with subsequent immunosuppression to promote CRC progression.

Keywords:  CX3CL1; Colorectal carcinoma; Immunosuppression; Regulatory T cell; SIRT1

DOI:  https://doi.org/10.1002/advs.202404734