bims-flamet 2025-02-16 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2025–02–16
nineteen papers selected by
Peio Azcoaga, Biodonostia HRI

The Recruitment and Immune Suppression Mechanisms of Myeloid-Derived Suppressor Cells and Their Impact on Bone Metastatic Cancer.
Patient-Derived Organoid Models for NKT Cell-Based Cancer Immunotherapy.
The success of the tumor immunotherapy: neutrophils from bench to beside.
Inflammation and tumor immune escape in response to DNA damage.
Metabolic reprogramming and immunological changes in the microenvironment of esophageal cancer: future directions and prospects.
Cancer-associated fibroblast-derived extracellular vesicles: regulators and therapeutic targets in the tumor microenvironment.
Role of amino acid metabolism in tumor immune microenvironment of colorectal cancer.
Pathways and outputs orchestrated in tumor microenvironment cells by hypoxia-induced tumor-derived exosomes in pan-cancer.
NF-κB signaling and the tumor microenvironment in osteosarcoma: implications for immune evasion and therapeutic resistance.
Tumor secretome shapes the immune landscape during cancer progression.
Tumor microbiome: roles in tumor initiation, progression, and therapy.
Exploring Cancer-Associated Fibroblasts in OSCC and OPMDs: Microenvironment Insights. Scoping Review.
Immune Cell Interactions and Immune Checkpoints in the Tumor Microenvironment of Gastric Cancer.
Coactivation of innate immune suppressive cells induces acquired resistance against combined TLR agonism and PD-1 blockade.
Exosomes play a crucial role in remodeling the tumor microenvironment and in the treatment of gastric cancer.
Identification of Natural Killer Cell Enhancers Through Mimicking of the Tumor Microenvironment.
STING activation and overcoming the challenges associated with STING agonists using ADC (antibody-drug conjugate) and other delivery systems.
Neutrophil Engulfment in Cancer: Friend or Foe?
An update on cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer.

Cancer Rep (Hoboken). 2025 Feb;8(2): e70044

The Recruitment and Immune Suppression Mechanisms of Myeloid-Derived Suppressor Cells and Their Impact on Bone Metastatic Cancer.

Chengyuan Li, Yucheng Xue, Eloy Yinwang, Zhaoming Ye.

   BACKGROUND: MDSCs are immature neutrophils and monocytes with immunosuppressive potentials, involving mononuclear MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs).
RECENT FINDINGS: They are significant components of the tumor microenvironment (TME). Besides, recent studies also verified that MDSCs also facilitated the progression of bone metastasis by regulating the network of cytokines and the function of immune cells.
CONCLUSION: It is necessary to summarize the mechanisms of MDSC recruitment and immunosuppression, and their impact on bone metastasis.

Keywords:  bone metastasis; immune suppression; myeloid‐derived suppressor cells

DOI:  https://doi.org/10.1002/cnr2.70044
Cancers (Basel). 2025 Jan 26. pii: 406. [Epub ahead of print]17(3):

Patient-Derived Organoid Models for NKT Cell-Based Cancer Immunotherapy.

Pablo A Palacios, Iván Flores, Lucas Cereceda, Francisco F Otero, Marioly Müller, Priscilla Brebi, Héctor R Contreras, Leandro J Carreño.

  Invariant Natural Killer T (iNKT) cells are a unique subset of T cells that bridge innate and adaptive immunity, displaying potent anti-tumor properties through cytokine secretion, direct cytotoxicity, and recruitment of immune effector cells such as CD8+ T cells and NK cells. Despite their therapeutic potential, the immunosuppressive tumor microenvironment (TME), characterized by regulatory T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), limits iNKT cell efficacy. Patient-derived organoid (PDO) platforms provide an innovative model for dissecting these complex interactions and evaluating strategies to reinvigorate iNKT cell functionality within the TME. PDOs closely mimic the genetic, phenotypic, and structural characteristics of primary tumors, enabling the study of tumor-immune dynamics. Integrating iNKT cells into PDOs offers a robust platform for investigating CD1d-mediated interactions, Th1-biased immune responses driven by glycolipid analogs like α-GalCer, and combination therapies such as immune checkpoint inhibitors. Additionally, PDO systems can assess the effects of metabolic modulation, including reducing lactic acid accumulation or targeting glutamine pathways, on enhancing iNKT cell activity. Emerging innovations, such as organoid-on-a-chip systems, CRISPR-Cas9 gene editing, and multi-omics approaches, further expand the potential of PDO-iNKT platforms for personalized immunotherapy research. Although the application of iNKT cells in PDOs is still undeveloped, these systems hold immense promise for bridging preclinical studies and clinical translation. By addressing the challenges of the TME and optimizing therapeutic strategies, PDO-iNKT platforms offer a transformative avenue for advancing cancer immunotherapy and personalized medicine.

Keywords:  3D cancer models; immunotherapy; invariant Natural Killer T cells (iNKT); patient-derived organoid (PDO); tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/cancers17030406
Front Immunol. 2025 ;16 1524038

The success of the tumor immunotherapy: neutrophils from bench to beside.

Meng Zhu, Ru Jia, Xiaojie Zhang, Pingwei Xu.

  The present immune therapy was focused on the immune checkpoint blockade or Chimeric Antigen Receptor T-Cell Immunotherapy (CART) transfer, but how to activate the innate immune system to antitumor still lags out. Neutrophils are the most abundant circulating leukocytes in human, and heterogeneous neutrophils have been increasingly recognized as important players in tumor progression. They play double "edge-sward" by either supporting or suppressing the tumor growth, including driving angiogenesis, extracellular matrix remodeling to promote tumor growth, participating in antitumor adaptive immunity, or killing tumor cells directly to inhibit the tumor growth. The complex role of neutrophils in various tumors depends on the tumor microenvironment (TME) they are located, and emerging evidence has suggested that neutrophils may determine the success of tumor immunotherapy in the context of the immune checkpoint blockade, innate immune training, or drug-loaded extracellular microvesicles therapy, which makes them become an exciting target for tumor immunotherapy, but still with challenges. Here, we summarize the latest insights on how to activate neutrophils in antitumor immunity and discuss the advances of neutrophil-targeted immunotherapy strategies.

Keywords:  immune checkpoint; innate immunity; neutrophils; tumor cell-derived microparticles; tumor immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2025.1524038
Semin Cancer Biol. 2025 Feb 10. pii: S1044-579X(25)00015-X. [Epub ahead of print]110 36-45

Inflammation and tumor immune escape in response to DNA damage.

Naoe Taira Nihira, Rei Kudo, Tomohiko Ohta.

  Senescent and cancer cells share common inflammatory characteristics, including factors of the senescence-associated secretory phenotype (SASP) and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Inflammation in the tumor microenvironment not only provides an opportunity for immune cells to attack cancer cells, but also promotes cancer invasion and metastasis. Immune checkpoint molecule PD-L1 is transcriptionally induced by inflammation, and the immunological state of PD-L1-positive tumors influences the efficacy of Immune checkpoint inhibitors (ICIs). ICIs are effective against the PD-L1-positive "hot" tumors; however, the non-immunoactive "cold" tumors that express PD-L1 rarely respond to ICIs, suggesting that converting PD-L1-positive "cold" tumors into "hot" tumors would improve the efficacy of ICIs. To eliminate cancer via the innate immune system, a therapeutic strategy for manipulating inflammatory responses must be established. To date, the molecular mechanisms of inflammation-induced tumorigenesis are not yet fully understood. However, it is becoming clear that the regulatory mechanisms of inflammation in cancer via the cGAS-STING pathway play an important role in both cancer and sensescent cells. In this review, we focus on inflammation and immune escape triggered by DNA damage in cancer and senescent cells.

Keywords:  CGAS-STING; DNA damage response; Inflammation; NF-kB; PD-L1

DOI:  https://doi.org/10.1016/j.semcancer.2025.02.005
Front Immunol. 2025 ;16 1524801

Metabolic reprogramming and immunological changes in the microenvironment of esophageal cancer: future directions and prospects.

Zhi-Xun Guo, Jia-Li Ma, Jin-Qiu Zhang, Ling-Ling Yan, Ying Zhou, Xin-Li Mao, Shao-Wei Li, Xian-Bin Zhou.

   Background: Esophageal cancer (EC) is the seventh-most prevalent cancer worldwide and is a significant contributor to cancer-related mortality. Metabolic reprogramming in tumors frequently coincides with aberrant immune function alterations, and extensive research has demonstrated that perturbations in energy metabolism within the tumor microenvironment influence the occurrence and progression of esophageal cancer. Current treatment modalities for esophageal cancer primarily include encompass chemotherapy and a limited array of targeted therapies, which are hampered by toxicity and drug resistance issues. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway, has exhibited promising results; however, a substantial proportion of patients remain unresponsive. The optimization of these immunotherapies requires further investigation. Mounting evidence underscores the importance of modulating metabolic traits within the tumor microenvironment (TME) to augment anti-tumor immunotherapy.
Methods: We selected relevant studies on the metabolism of the esophageal cancer tumor microenvironment and immune cells based on our searches of MEDLINE and PubMed, focusing on screening experimental articles and reviews related to glucose metabolism, amino acid metabolism, and lipid metabolism, as well their interactions with tumor cells and immune cells, published within the last five years. We analyzed and discussed these studies, while also expressing our own insights and opinions.
Results: A total of 137 articles were included in the review: 21 articles focused on the tumor microenvironment of esophageal cancer, 33 delved into research related to glucose metabolism and tumor immunology, 30 introduced amino acid metabolism and immune responses, and 17 focused on the relationship between lipid metabolism in the tumor microenvironment and both tumor cells and immune cells.
Conclusion: This article delves into metabolic reprogramming and immune alterations within the TME of EC, systematically synthesizes the metabolic characteristics of the TME, dissects the interactions between tumor and immune cells, and consolidates and harnesses pertinent immunotherapy targets, with the goal of enhancing anti-tumor immunotherapy for esophageal cancer and thereby offering insights into the development of novel therapeutic strategies.

Keywords:  esophageal cancer; glycolysis; immune cells; metabolic reprogramming; targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1524801
Cancer Drug Resist. 2025 ;8 2

Cancer-associated fibroblast-derived extracellular vesicles: regulators and therapeutic targets in the tumor microenvironment.

Jindong Xie, Xinmei Lin, Xinpei Deng, Hailin Tang, Yutian Zou, Wenkuan Chen, Xiaoming Xie.

  Cancer-associated fibroblasts (CAFs) constitute a critical component of the tumor microenvironment (TME). CAFs can be reprogrammed by cancer cells, leading to the production of extracellular vesicles (EVs). These EVs serve as carriers for bioactive substances, including proteins, nucleic acids, and metabolic products, thereby facilitating tumor progression. CAF-derived EVs exert substantial influence on tumor cell proliferation, invasion, and metastasis, the immunological environment, and the processes of lymphangiogenesis and angiogenesis. Despite their potential as non-invasive biomarkers and therapeutic delivery vehicles, the clinical application of CAF-derived EVs is currently limited by challenges in purification and precise targeting. This review delineates the diverse roles of CAF-derived EVs in tumor growth, metastasis, and immune evasion within the TME.

Keywords:  Cancer-associated fibroblasts; extracellular vesicle; therapeutic targets; tumor microenvironment

DOI:  https://doi.org/10.20517/cdr.2024.152
Am J Cancer Res. 2025 ;15(1): 233-247

Role of amino acid metabolism in tumor immune microenvironment of colorectal cancer.

Minjing Zhu, Yanyan Hu, Yangjia Gu, Xuedan Lin, Xiang Jiang, Chaoju Gong, Zejun Fang.

  This review investigates the role of amino acid metabolism in the tumor microenvironment of colorectal cancer (CRC) and explores potential targeted therapeutic strategies. The paper synthesized current research on amino acid metabolism in the colorectal cancer tumor microenvironment, focusing on amino acids such as tryptophan, methionine, glutamine, and arginine. It examined their impact on tumor growth, immune evasion, and patient prognosis, as well as the metabolic reprogramming of tumor cells and complex tumor microenvironment interactions. Aberrant amino acid metabolism was a hallmark of colorectal cancer, influencing tumor proliferation, survival, and invasiveness. Key findings included: Tryptophan metabolism via the kynurenine and serotonin pathways significantly affected immune response and tumor progression in CRC. Methionine influenced T cell function and DNA methylation, playing a critical role in tumor development. Glutamine was extensively used by tumor cells for energy metabolism and supported immune cell function. Arginine metabolism impacted CD8+ T cell functionality and tumor growth. The review also discussed the dual roles of immune cells in the tumor microenvironment and the potential of targeting amino acid metabolic pathways for CRC treatment. In conclusion, amino acid metabolism significantly impacts the colorectal cancer tumor microenvironment and immunity. Understanding these metabolic pathways provides valuable insights into CRC pathogenesis and identifies potential therapeutic targets. Future research should focus on developing treatments that disrupt these metabolic processes to improve patient outcomes in CRC.

Keywords:  Colorectal cancer; amino acid metabolism; immune evasion; therapeutic targets; tumor microenvironment

DOI:  https://doi.org/10.62347/ZSOO2247
Cell Oncol (Dordr). 2025 Feb 10.

Pathways and outputs orchestrated in tumor microenvironment cells by hypoxia-induced tumor-derived exosomes in pan-cancer.

Ozel Capik, Omer Faruk Karatas.

  Hypoxia is a critical microenvironmental condition that plays a major role in driving tumorigenesis and cancer progression. Increasing evidence has revealed novel functions of hypoxia in intercellular communication. The hypoxia induced tumor derived exosomes (hiTDExs) released in high quantities by tumor cells under hypoxia are packed with unique cargoes that are essential for cancer cells' interactions within their microenvironment. These hiTDExs facilitate not only immune evasion but also promote cancer cell growth, survival, angiogenesis, EMT, resistance to therapy, and the metastatic spread of the disease. Nevertheless, direct interventions targeting hypoxia signaling in cancer therapy face challenges related to tumor progression and resistance, limiting their clinical effectiveness. Therefore, deepening our understanding of the molecular processes through which hiTDExs remodels tumors and their microenvironment, as well as how tumor cells adjust to hypoxic conditions, remains essential. This knowledge will pave the way for novel approaches in treating hypoxic tumors. In this review, we discuss recent work revealing the hiTDExs mediated interactions between tumor and its microenvironment. We have described key hiTDExs cargos (lncRNA, circRNAs, cytokines, etc.) and their targets in the receipt cells, responsible for various biological effects. Moreover, we emphasized the importance of hiTDExs as versatile elements of cell communication in the tumor microenvironment. Finally, we highlighted the effects of hiTDExs on the molecular changes in target cells by executing molecular cargo transfer between cells and altering signaling pathways. Currently, hiTDExs show promise in the treatment of diseases. Understanding the molecular processes through which hiTDExs influence tumor behavior and their microenvironment, along with how tumor cells adapt to and survive in low-oxygen conditions, remains a central focus in cancer research, paving the way for innovative strategies in treating hypoxic tumors and enhancing immunotherapy.

Keywords:  Cancer; Exosomes; Hypoxia; Intercellular communication; Tumor microenvironment

DOI:  https://doi.org/10.1007/s13402-025-01042-z
Front Immunol. 2025 ;16 1518664

NF-κB signaling and the tumor microenvironment in osteosarcoma: implications for immune evasion and therapeutic resistance.

Shaoyan Shi, Xuehai Ou, Chao Liu, Rui Li, Qianjin Zheng, Leiming Hu.

  Osteosarcoma, a highly aggressive malignancy with a generally poor prognosis, is characterized by tumor cells' ability to evade immune responses and resist treatment. The nuclear transcription factor NF-κB signaling pathway is crucial in regulating inflammatory and immune reactions. It occupies a central position in the development of the osteosarcoma tumor microenvironment. This research aimed to explore how NF-κB influences the recruitment and polarization of tumor-associated macrophages and myeloid-derived suppressor cells, both of which contribute to immunosuppression. Furthermore, NF-κB facilitates immune surveillance evasion in osteosarcoma cells by altering the expression of immune checkpoint molecules, such as PD-L1. It also enhances tumor cell resistance to chemotherapy and radiotherapy by activating anti-apoptotic signaling pathways and exacerbating treatment-induced inflammation. Potential therapeutic approaches include using NF-κB inhibitors, possibly in combination with immune checkpoint inhibitors, to overcome tumor cell resistance mechanisms and reshape antitumor immune responses. A thorough examination of NF-κB's role in osteosarcoma development is expected to yield novel clinical treatment strategies, and significantly improve patient prognosis by targeting this key signaling pathway.

Keywords:  NF-κB signaling; immune evasion and; malignant bone tumor; osteosarcoma; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1518664
J Exp Clin Cancer Res. 2025 Feb 10. 44(1): 47

Tumor secretome shapes the immune landscape during cancer progression.

Jianqiang Yang, Sijia Tang, Nabil F Saba, Chloe Shay, Yong Teng.

  The focus of cancer immunotherapy has traditionally been on immune cells and tumor cells themselves, often overlooking the tumor secretome. This review provides a comprehensive overview of the intricate relationship between tumor cells and the immune response in cancer progression. It highlights the pivotal role of the tumor secretome - a diverse set of molecules secreted by tumor cells - in significantly influencing immune modulation, promoting immunosuppression, and facilitating tumor survival. In addition to elucidating these complex interactions, this review discusses current clinical trials targeting the tumor secretome and highlights their potential to advance personalized medicine strategies. These trials aim to overcome the challenges of the tumor microenvironment by designing therapies tailored to the secretome profiles of individual cancer patients. In addition, advances in proteomic techniques are highlighted as essential tools for unraveling the complexity of the tumor secretome, paving the way for improved cancer treatment outcomes.

Keywords:  Biomarkers; Immunotherapy; Tumor microenvironment; Tumor secretome; Tumor-immune cell interplay

DOI:  https://doi.org/10.1186/s13046-025-03302-0
Mol Biomed. 2025 Feb 08. 6(1): 9

Tumor microbiome: roles in tumor initiation, progression, and therapy.

Shengxin Zhang, Jing Huang, Zedong Jiang, Huan Tong, Xuelei Ma, Yang Liu.

  Over the past few years, the tumor microbiome is increasingly recognized for its multifaceted involvement in cancer initiation, progression, and metastasis. With the application of 16S ribosomal ribonucleic acid (16S rRNA) sequencing, the intratumoral microbiome, also referred to as tumor-intrinsic or tumor-resident microbiome, has also been found to play a significant role in the tumor microenvironment (TME). Understanding their complex functions is critical for identifying new therapeutic avenues and improving treatment outcomes. This review first summarizes the origins and composition of these microbial communities, emphasizing their adapted diversity across a diverse range of tumor types and stages. Moreover, we outline the general mechanisms by which specific microbes induce tumor initiation, including the activation of carcinogenic pathways, deoxyribonucleic acid (DNA) damage, epigenetic modifications, and chronic inflammation. We further propose the tumor microbiome may evade immunity and promote angiogenesis to support tumor progression, while uncovering specific microbial influences on each step of the metastatic cascade, such as invasion, circulation, and seeding in secondary sites. Additionally, tumor microbiome is closely associated with drug resistance and influences therapeutic efficacy by modulating immune responses, drug metabolism, and apoptotic pathways. Furthermore, we explore innovative microbe-based therapeutic strategies, such as engineered bacteria, oncolytic virotherapy, and other modalities aimed at enhancing immunotherapeutic efficacy, paving the way for microbiome-centered cancer treatment frameworks.

Keywords:  Immune modulation; Microbe-based therapeutic strategies; Tumor initiation and progression; Tumor microbiome; Tumor microenvironment

DOI:  https://doi.org/10.1186/s43556-025-00248-9
Oral Dis. 2025 Feb 10.

Exploring Cancer-Associated Fibroblasts in OSCC and OPMDs: Microenvironment Insights. Scoping Review.

Samuele Sutera, Olga Anna Furchì, Monica Pentenero.

   INTRODUCTION: The tumor microenvironment (TME) plays a crucial role in oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). Despite progress, the mechanisms behind the TME-epithelial cell interaction remain unclear. Cancer-associated fibroblasts (CAFs), the most abundant cells in the TME, require further study.
MATERIAL AND METHODS: We conducted a scoping review, searching for clinical and vivo studies that discuss the role of CAFs in OSCC and OPMDs progression.
RESULTS: From 1152 PubMed results, 29 studies met the inclusion criteria. CAFs, identified as αSMA+ cells, interact with the TME and epithelial cells by secreting various molecules. In OSCC, CAF signals contribute to a pro-tumorigenic environment, and CAF numbers positively correlate with tumor grade, size, stage, aggressiveness, and mortality. While limited data exist on CAFs in OPMDs, they seem linked to malignant transformation risk.
DISCUSSION: CAFs are critical in OSCC pathophysiology, but the complex intercellular mechanisms are not fully understood. Currently, CAFs are not part of clinical decision-making, but emerging evidence suggests they could represent a promising new approach in managing OSCC and OPMDs.
CONCLUSION: Future research should aim to gain a deeper understanding of how CAFs contribute to OSCC progression and their role in OPMDs pathophysiology.

Keywords:  cancer associated fibroblasts; carcinogenesis; malignant transformation; oral potentially malignant disorder; oral squamous cell carcinoma; tumor microenvironment

DOI:  https://doi.org/10.1111/odi.15275
Int J Mol Sci. 2025 Jan 29. pii: 1156. [Epub ahead of print]26(3):

Immune Cell Interactions and Immune Checkpoints in the Tumor Microenvironment of Gastric Cancer.

Andreea-Raluca Cozac-Szőke, Dan Alexandru Cozac, Anca Negovan, Andreea Cătălina Tinca, Alexandra Vilaia, Iuliu-Gabriel Cocuz, Adrian Horațiu Sabău, Raluca Niculescu, Diana Maria Chiorean, Alexandru Nicușor Tomuț, Ovidiu Simion Cotoi.

  Gastric cancer (GC) ranks as the fifth most prevalent malignant neoplasm globally, with an increased death rate despite recent advancements in research and therapeutic options. Different molecular subtypes of GC have distinct interactions with the immune system, impacting the tumor microenvironment (TME), prognosis, and reaction to immunotherapy. Tumor-infiltrating lymphocytes (TILs) in the TME are crucial for preventing tumor growth and metastasis, as evidenced by research showing that patients with GC who have a significant density of TILs have better survival rates. But cancer cells have evolved a variety of mechanisms to evade immune surveillance, both sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) and Programmed Death-Ligand 1 (PD-L1) playing a pivotal role in the development of an immunosuppressive TME. They prevent T cell activation and proliferation resulting in a decrease in the immune system's capacity to recognize and eliminate malignant cells. These immune checkpoint molecules function via different but complementary mechanisms, the expression of Siglec-15 being mutually exclusive with PD-L1 and, therefore, providing a different therapeutic approach. The review explores how TILs affect tumor growth and patient outcomes in GC, with particular emphasis on their interactions within the TME and potential targeting of the PD-L1 and Siglec-15 pathways for immunotherapy.

Keywords:  PD-L1; Siglec-15; TAMs; TILs; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms26031156
Sci Transl Med. 2025 Feb 12. 17(785): eadk3160

Coactivation of innate immune suppressive cells induces acquired resistance against combined TLR agonism and PD-1 blockade.

Hitomi Nishinakamura, Sayoko Shinya, Takuma Irie, Shugo Sakihama, Takeo Naito, Keisuke Watanabe, Daisuke Sugiyama, Motohiro Tamiya, Tatsuya Yoshida, Tetsunari Hase, Takao Yoshida, Kennosuke Karube, Shohei Koyama, Hiroyoshi Nishikawa.

Immune checkpoint blockade therapy has been successfully applied in clinical settings as a standard therapy for many cancer types, but its clinical efficacy is restricted to patients with immunologically hot tumors. Various strategies to modify the tumor microenvironment (TME), such as Toll-like receptor (TLR) agonists that can stimulate innate immunity, have been explored but have not been successful. Here, we show a mechanism of acquired resistance to combination treatment consisting of an agonist for multiple TLRs, OK-432 (Picibanil), and programmed cell death protein 1 (PD-1) blockade. Adding the TLR agonist failed to convert the TME from immunogenically cold to hot and did not augment antitumor immunity, particularly CD8+ T cell responses, in multiple animal models. The failure was attributed to the coactivation of innate suppressive cells, such as polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) expressing CXCR2, through high CXCL1 production by macrophages in the TME upon OK-432 treatment. A triple combination treatment with OK-432, PD-1 blockade, and a CXCR2 neutralizing antibody overcame the resistance induced by PMN-MDSCs, resulting in a stronger antitumor effect than that of any dual combinations or single treatments. The accumulation of PMN-MDSCs was similarly observed in the pleural effusions of patients with lung cancer after OK-432 administration. We propose that successful combination cancer immunotherapy intended to stimulate innate antitumor immunity requires modulation of unwanted activation of innate immune suppressive cells, including PMN-MDSCs.

DOI: https://doi.org/10.1126/scitranslmed.adk3160
Cell Commun Signal. 2025 Feb 13. 23(1): 82

Exosomes play a crucial role in remodeling the tumor microenvironment and in the treatment of gastric cancer.

Lingyun Tang, Wenjie Zhang, Teng Qi, Zhengting Jiang, Dong Tang.

  Gastric cancer (GC) is a common and frequent malignant cancer of the digestive system with a poor prognosis. In addition to common therapies such as surgical resection and chemotherapy, novel biological interventions are quite valuable for research. Exosomes are extracellular vesicles (EVs) that originate from various cell types and contain proteins, RNA, DNA, and other components that transmit biological signals and mediate intercellular communication. Numerous studies have shown that exosomes shape the tumor microenvironment (TME) by affecting hypoxia, inflammation, immunity, metabolism, and interstitial changes in the tumor, playing a crucial role in the development and metastasis of GC. This article reviews the important role of exosomes in the TME of GC and explores their potential clinical applications in GC treatment.

Keywords:  Diagnosis; Exosome; Gastric cancer; Treatment; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12964-024-02009-7
Chemistry. 2025 Feb 11. e202404006

Identification of Natural Killer Cell Enhancers Through Mimicking of the Tumor Microenvironment.

Aylin Binici, Elisabeth Hennes, Sandra Koska, Jens Alexander Niemann, Alisa Reich, Christiane Pfaff, Sonja Sievers, Astrid Stefanie Kahnt, Dominique Thomas, Slava Ziegler, Carsten Watzl, Herbert Waldmann.

  The tumor microenvironment (TME) is a pro-cancerous niche harboring immunosuppressive factors that are secreted by cancer cells and the surrounding cancer-supportive tissue, such as kynurenine, prostaglandin E2 and transforming growth factor β (TGFβ). These factors dampen the activity of cytotoxic lymphocytes like natural killer (NK) cells, allowing evasion of immune cell-mediated killing. To identify small molecules that counteract the immunosuppressive effect of the TME and restore NK cell-mediated cytotoxicity, we developed a phenotypic co-culture assay of cancer cells and primary lymphocytes suitable for medium-throughput screening. We discovered small molecules that restore NK cell-mediated cytotoxicity through diverse mechanisms. The potent TGFβ type I receptor (TGFβR-1) inhibitor, RepSox, stood out as superior to other TGFβR-1 inhibitors due to its ability to abolish the effects of both inhibitory factors used in our setup. This mode of action goes beyond TGFβR-1 inhibition and is related to the simultaneous abrogation of cyclooxygenase 1 (COX1) activity.

Keywords:  Biological activity; Immunology; Natural killer cells; Screening; small molecules

DOI:  https://doi.org/10.1002/chem.202404006
Cell Signal. 2025 Feb 06. pii: S0898-6568(25)00060-9. [Epub ahead of print]128 111647

STING activation and overcoming the challenges associated with STING agonists using ADC (antibody-drug conjugate) and other delivery systems.

Hitesh Vasiyani, Bhumika Wadhwa.

  In current immunotherapy cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway considered as most focused area after CAR-T cell. Exploitation of host immunity against cancer using STING agonists generates the most interest as a therapeutic target. Classically cGAS activation through cytoplasmic DNA generates 2'3'cGAMP that is naturally identified STING agonist. Activation of STING leads to activation of type-1 interferon response and pro-inflammatory cytokines through TBK/IRF-3, TBK/NF-κB pathways. Pro-inflammatory cytokines attract immune cells to the tumor microenvironment and type-1 interferon exposes tumor antigens to T cells and NK cells, which leads to the activation of cellular immunity against tumor cells and eliminates tumor cells. Initially bacterial-derived c-di-AMP and c-di-GMP were identified as CDNs (Cyclic-dinucleotide) STING agonists. Moreover, chemically modified CDNs and completely synthetic STING agonists have been developed. Even though the breakthrough preclinical development none of the STING agonists were approved the by FDA for cancer therapy. All identified natural CDNs have poor pharmacokinetic properties due to high hydrophilicity and negative charge. Moreover, phosphodiester bonds in CDNs are most vulnerable to enzymatic degradation. Synthetic STING agonists have an off-target effect that generates autoimmunity and cytokine storm. STING agonist needs to improve for pharmacokinetics, efficacy, and safety. In this scenario delivery systems can overcome the challenges associated with STING agonists. Here, we highlight the ways of STING agonisms as direct and indirect, and further, we also discuss the existing STING agonists associated challenges and ongoing efforts for delivery of STING agonists in the tumor microenvironment (TME) via different non-targeted carriers like Nanoparticle, Hydrogel, Micelle, Liposome. We also discussed the most advanced targeted deliveries of ADC (Antibody-drug conjugate) and aptamers-based delivery.

Keywords:  ADC: Antibody drug conjugate; Cancer immunotherpy; STING activation in cancer; STING agonists delivery

DOI:  https://doi.org/10.1016/j.cellsig.2025.111647
Cancers (Basel). 2025 Jan 24. pii: 384. [Epub ahead of print]17(3):

Neutrophil Engulfment in Cancer: Friend or Foe?

Tong Lu, Wei Li.

  Neutrophils, the most abundant circulating white blood cells, are essential for the initial immune response to infection and injury. Emerging research reveals a dualistic function of neutrophils in cancer, where they can promote or inhibit tumor progression. This dichotomy is influenced by the tumor microenvironment, with neutrophils capable of remodeling the extracellular matrix, promoting angiogenesis, or alternatively inducing cancer cell death and enhancing immune responses. An intriguing yet poorly understood aspect of neutrophil-cancer interactions is the phenomenon of neutrophil engulfment by cancer cells, which has been observed across various cancers. This process, potentially mediated by LC3-associated phagocytosis (LAP), raises questions about whether it serves as a mechanism for immune evasion or contributes to tumor cell death through pathways like ferroptosis. This review examines current knowledge on neutrophil development, their roles in cancer, and the mechanisms of LAP in neutrophil engulfment by tumor cells. We discuss how manipulating LAP impacts cancer progression and may represent a therapeutic strategy. We also explore neutrophils' potential as delivery vehicles for cancer therapeutic agents. Understanding the complex functions of tumor-associated neutrophils (TANs) and the molecular mechanisms underlying LAP in cancer may open new avenues for effective therapeutic interventions and mitigate potential risks.

Keywords:  LC3-associated phagocytosis; emperipolesis; neutrophil engulfment; neutrophil-based drug delivery; phagocytosis; tumor microenvironment; tumor-associated neutrophils

DOI:  https://doi.org/10.3390/cancers17030384
Future Oncol. 2025 Feb 12. 1-21

An update on cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer.

Asma Jan, Shazia Sofi, Nusrat Jan, Manzoor Ahmad Mir.

  Triple-negative breast cancer (TNBC) presents a formidable global health challenge, marked by its aggressive behavior and significant treatment resistance. This subtype, devoid of estrogen, progesterone, and HER2 receptors, largely relies on breast cancer stem cells (BCSCs) for its progression, metastasis, and recurrence. BCSCs, characterized by their self-renewal capacity and resistance to conventional therapies, exploit key surface markers and critical signaling pathways like Wnt, Hedgehog, Notch, TGF-β, PI3K/AKT/mTOR and Hippo-YAP/TAZ to thrive. Their adaptability is underscored by mechanisms including drug efflux and enhanced DNA repair, contributing to poor prognosis and high recurrence rates. The tumor microenvironment (TME) further facilitates BCSC survival through complex interactions with stromal and immune cells. Emerging therapeutic strategies targeting BCSCs - ranging from immunotherapy and nanoparticle-based drug delivery systems to gene-editing technologies - aim to disrupt these resistant cells. Additionally, innovative approaches focusing on exosome-mediated signaling and metabolic reprogramming show promise in overcoming chemoresistance. By elucidating the distinct characteristics of BCSCs and their role in TNBC, researchers are paving the way for novel treatments that may effectively eradicate these resilient cells, mitigate metastasis, and ultimately improve patient outcomes. This review highlights the urgent need for targeted strategies that address the unique biology of BCSCs in the pursuit of more effective therapeutic interventions for TNBC.

Keywords:  Triple negative breast cancer; breast cancer stem cells; chemoresistance; exosomes; metastasis; signaling pathways

DOI:  https://doi.org/10.1080/14796694.2025.2461443