bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2024–05–05
thirty-one papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Targeting tumor‑associated macrophages: Critical players in tumor progression and therapeutic strategies (Review).
  2. Macrophages and tumor-associated macrophages in the senescent microenvironment: From immunosuppressive TME to targeted tumor therapy.
  3. Cross-talk between leukemic and immune cells at the tumor microenvironment in chronic lymphocytic leukemia: An update review.
  4. CD44v5 domain regulates crosstalk between TNBC cells and tumor-associated macrophages by enhancing the IL-4R/STAT3 axis.
  5. The Influence of Exercise on Cancer Risk, the Tumor Microenvironment and the Treatment of Cancer.
  6. CAR-based immunotherapy for breast cancer: peculiarities, ongoing investigations, and future strategies.
  7. Role of cancer stem cell ecosystem on breast cancer metastasis and related mouse models.
  8. Nanomaterials in modulating tumor-associated macrophages and enhancing immunotherapy.
  9. Targeting metabolism of breast cancer and its implications in T cell immunotherapy.
  10. Editorial: Tumor microenvironment and hematological malignancies: new evidences and new questions.
  11. Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy.
  12. The immunosuppressive landscape in tumor microenvironment.
  13. Abnormal changes in metabolites caused by m6A methylation modification: The leading factors that induce the formation of immunosuppressive tumor microenvironment and their promising potential for clinical application.
  14. Crosstalk between T lymphocyte and extracellular matrix in tumor microenvironment.
  15. Extracellular matrix stiffness and tumor-associated macrophage polarization: new fields affecting immune exclusion.
  16. Phytonanomedicine as a therapeutic regulator of the tumor microenvironment for inhibiting cancer metastasis.
  17. Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma: A comprehensive review.
  18. The Biological Role of Macrophage in Lung and Its Implications in Lung Cancer Immunotherapy.
  19. Effects of chronic stress on cancer development and the therapeutic prospects of adrenergic signaling regulation.
  20. Cycling back to folate metabolism in cancer.
  21. Finding your CAR: The road ahead for engineered T-cells.
  22. B cell trajectories influence cancer outcomes.
  23. Senescent CAFs mediate immunosuppression and drive breast cancer progression.
  24. Exosomal NAT10 from esophageal squamous cell carcinoma cells modulates macrophage lipid metabolism and polarization through ac4C modification of FASN.
  25. Prostaglandin E2 in the Tumor Microenvironment, a Convoluted Affair Mediated by EP Receptors 2 and 4.
  26. The hidden messengers: cancer associated fibroblasts-derived exosomal miRNAs as key regulators of cancer malignancy.
  27. Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression.
  28. Dual-crosslinking gelatin-hyaluronic acid methacrylate based biomimetic PDAC desmoplastic niche enhances tumor-associated macrophages recruitment and M2-like polarization.
  29. Promising Therapeutic Approach in Pancreatic Cancer: Metabolism-Related Genes.
  30. Myeloid-derived suppressor cells in influenza virus-induced asthma exacerbation.
  31. Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity.
  1. Int J Oncol. 2024 Jun;pii: 60. [Epub ahead of print]64(6):
    Targeting tumor‑associated macrophages: Critical players in tumor progression and therapeutic strategies (Review).
    Pengfei Su, Ou Li, Kun Ke, Zhichen Jiang, Jianzhang Wu, Yuanyu Wang, Yiping Mou, Weiwei Jin.
      Tumor‑associated macrophages (TAMs) are essential components of the tumor microenvironment (TME) and display phenotypic heterogeneity and plasticity associated with the stimulation of bioactive molecules within the TME. TAMs predominantly exhibit tumor‑promoting phenotypes involved in tumor progression, such as tumor angiogenesis, metastasis, immunosuppression and resistance to therapies. In addition, TAMs have the potential to regulate the cytotoxic elimination and phagocytosis of cancer cells and interact with other immune cells to engage in the innate and adaptive immune systems. In this context, targeting TAMs has been a popular area of research in cancer therapy, and a comprehensive understanding of the complex role of TAMs in tumor progression and exploration of macrophage‑based therapeutic approaches are essential for future therapeutics against cancers. The present review provided a comprehensive and updated overview of the function of TAMs in tumor progression, summarized recent advances in TAM‑targeting therapeutic strategies and discussed the obstacles and perspectives of TAM‑targeting therapies for cancers.
    Keywords:  targeted therapy; tumor microenvironment; tumor progression; tumor-associated macrophage
    DOI:  https://doi.org/10.3892/ijo.2024.5648
  2. Pharmacol Res. 2024 Apr 30. pii: S1043-6618(24)00142-7. [Epub ahead of print]204 107198
    Macrophages and tumor-associated macrophages in the senescent microenvironment: From immunosuppressive TME to targeted tumor therapy.
    Ming Du, Lu Sun, Jinshuai Guo, Huina Lv.
      In-depth studies of the tumor microenvironment (TME) have helped to elucidate its cancer-promoting mechanisms and inherent characteristics. Cellular senescence, which acts as a response to injury and can the release of senescence-associated secretory phenotypes (SASPs). These SASPs release various cytokines, chemokines, and growth factors, remodeling the TME. This continual development of a senescent environment could be associated with chronic inflammation and immunosuppressive TME. Additionally, SASPs could influence the phenotype and function of macrophages, leading to the recruitment of tumor-associated macrophages (TAMs). This contributes to tumor proliferation and metastasis in the senescent microenvironment, working in tandem with immune regulation, angiogenesis, and therapeutic resistance. This comprehensive review covers the evolving nature of the senescent microenvironment, macrophages, and TAMs in tumor development. We also explored the links between chronic inflammation, immunosuppressive TME, cellular senescence, and macrophages. Moreover, we compiled various tumor-specific treatment strategies centered on cellular senescence and the current challenges in cellular senescence research. This study aimed to clarify the mechanism of macrophages and the senescent microenvironment in tumor progression and advance the development of targeted tumor therapies.
    Keywords:  Macrophages; chronic inflammation; immunosuppressive TME; senescent microenvironment; tumor therapy; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.phrs.2024.107198
  3. Eur J Haematol. 2024 May 02.
    Cross-talk between leukemic and immune cells at the tumor microenvironment in chronic lymphocytic leukemia: An update review.
    Saeid Taghiloo, Hossein Asgarian-Omran.
      Chronic lymphocytic leukemia (CLL) is a mature-type B cell malignancy correlated with significant changes and defects in both the innate and adaptive arms of the immune system, together with a high dependency on the tumor microenvironment. Overall, the tumor microenvironment (TME) in CLL provides a supportive niche for leukemic cells to grow and survive, and interactions between CLL cells and the TME can contribute to disease progression and treatment resistance. Therefore, the increasing knowledge of the complicated interaction between immune cells and tumor cells, which is responsible for immune evasion and cancer progression, has provided an opportunity for the development of new therapeutic approaches. In this review, we outline tumor microenvironment-driven contributions to the licensing of immune escape mechanisms in CLL patients.
    Keywords:  CLL; immune evasion; tumor microenvironment
    DOI:  https://doi.org/10.1111/ejh.14224
  4. Cancer Sci. 2024 May 03.
    CD44v5 domain regulates crosstalk between TNBC cells and tumor-associated macrophages by enhancing the IL-4R/STAT3 axis.
    Yanhua Dai, Zhongjian Ji, Hongyan Liang, Meng Jiang, Lan Wang, Xinyi Bao, Jiaren Liu, Ming Liu, Chun Yang.
      Triple-negative breast cancer (TNBC) has greater infiltration of M2-like macrophages (TAMs), which enhances cancer cell invasion and leads to a poor prognosis. TNBC progression is mediated by both tumor cells and the tumor microenvironment (TME). Here we elucidate the mechanism of the interaction between TNBC cells and TAMs. In this study, we confirmed that CD44v5 is highly expressed in TNBC, which drives TNBC cell metastasis and promotes TAM polarization by co-localizing with IL4Rα and inhibiting its internalization and degradation, thereby promoting activation of the STAT3/IL6 signaling axis. At the same time, TAMs also facilitate TNBC cell metastasis by secreting IL-4, IL-6, and other cytokines, in which the IL-4/IL-4R/STAT3/IL-6 signaling axis plays the same role for TNBC cells responding to TAMs. Moreover, we found that the above progress could be suppressed when the CD44v5 domain was blocked. We demonstrated that the CD44v5/IL-4R/STAT3/IL-6 signaling pathway plays a key role in TNBC cell metastasis, and in TNBC cells inducing TAM polarization and responding to TAMs, promoting metastasis. Collectively, we suggest that the CD44v5 domain may be a promising target for regulating the TME of TNBC as well as treating TNBC.
    Keywords:  CD44v5 domain; IL‐4R; triple‐negative breast cancer; tumor‐associated macrophages
    DOI:  https://doi.org/10.1111/cas.16200
  5. Sports Med. 2024 Apr 30.
    The Influence of Exercise on Cancer Risk, the Tumor Microenvironment and the Treatment of Cancer.
    Anqi He, Yamin Pu, Chengsen Jia, Mengling Wu, Hongchen He, Yong Xia.
      There are several modifiable factors that can be targeted to prevent and manage the occurrence and progression of cancer, and maintaining adequate exercise is a crucial one. Regular physical exercise has been shown to be a beneficial strategy in preventing cancer, potentially amplifying the effectiveness of established cancer therapies, alleviating certain cancer-related symptoms, and possibly mitigating side effects resulting from treatment. Nevertheless, the exact mechanisms by which exercise affects tumors, especially its impact on the tumor microenvironment (TME), remain uncertain. This review aims to present an overview of the beneficial effects of exercise in the context of cancer management, followed by a summary of the exercise parameters, especially exercise intensity, that need to be considered when prescribing exercise for cancer patients. Finally, we discuss the influence of exercise on the TME, including its effects on crucial immune cells (e.g., T cells, macrophages, neutrophils, natural killer cells, myeloid-derived suppressor cells, B cells), intratumor angiogenesis, and cancer metabolism. This comprehensive review provides up-to-date scientific evidence on the effects of exercise training on cancer and offers guidance to clinicians for the development of safe and feasible exercise training programs for cancer patients in clinical practice.
    DOI:  https://doi.org/10.1007/s40279-024-02031-2
  6. Front Immunol. 2024 ;15 1385571
    CAR-based immunotherapy for breast cancer: peculiarities, ongoing investigations, and future strategies.
    Zhipu Niu, Jingyuan Wu, Qiancheng Zhao, Jinyu Zhang, Pengyu Zhang, Yiming Yang.
      Surgery, chemotherapy, and endocrine therapy have improved the overall survival and postoperative recurrence rates of Luminal A, Luminal B, and HER2-positive breast cancers but treatment modalities for triple-negative breast cancer (TNBC) with poor prognosis remain limited. The effective application of the rapidly developing chimeric antigen receptor (CAR)-T cell therapy in hematological tumors provides new ideas for the treatment of breast cancer. Choosing suitable and specific targets is crucial for applying CAR-T therapy for breast cancer treatment. In this paper, we summarize CAR-T therapy's effective targets and potential targets in different subtypes based on the existing research progress, especially for TNBC. CAR-based immunotherapy has resulted in advancements in the treatment of breast cancer. CAR-macrophages, CAR-NK cells, and CAR-mesenchymal stem cells (MSCs) may be more effective and safer for treating solid tumors, such as breast cancer. However, the tumor microenvironment (TME) of breast tumors and the side effects of CAR-T therapy pose challenges to CAR-based immunotherapy. CAR-T cells and CAR-NK cells-derived exosomes are advantageous in tumor therapy. Exosomes carrying CAR for breast cancer immunotherapy are of immense research value and may provide a treatment modality with good treatment effects. In this review, we provide an overview of the development and challenges of CAR-based immunotherapy in treating different subtypes of breast cancer and discuss the progress of CAR-expressing exosomes for breast cancer treatment. We elaborate on the development of CAR-T cells in TNBC therapy and the prospects of using CAR-macrophages, CAR-NK cells, and CAR-MSCs for treating breast cancer.
    Keywords:  CAR-M; CAR-NK; CAR-T; TME; TNBC; breast cancer; exosome
    DOI:  https://doi.org/10.3389/fimmu.2024.1385571
  7. Zool Res. 2024 May 18. pii: 2095-8137(2024)03-0506-12. [Epub ahead of print]45(3): 506-517
    Role of cancer stem cell ecosystem on breast cancer metastasis and related mouse models.
    Xilei Peng, Haonan Dong, Lixing Zhang, Suling Liu.
      Breast cancer metastasis is responsible for most breast cancer-related deaths and is influenced by many factors within the tumor ecosystem, including tumor cells and microenvironment. Breast cancer stem cells (BCSCs) constitute a small population of cancer cells with unique characteristics, including their capacity for self-renewal and differentiation. Studies have shown that BCSCs not only drive tumorigenesis but also play a crucial role in promoting metastasis in breast cancer. The tumor microenvironment (TME), composed of stromal cells, immune cells, blood vessel cells, fibroblasts, and microbes in proximity to cancer cells, is increasingly recognized for its crosstalk with BCSCs and role in BCSC survival, growth, and dissemination, thereby influencing metastatic ability. Hence, a thorough understanding of BCSCs and the TME is critical for unraveling the mechanisms underlying breast cancer metastasis. In this review, we summarize current knowledge on the roles of BCSCs and the TME in breast cancer metastasis, as well as the underlying regulatory mechanisms. Furthermore, we provide an overview of relevant mouse models used to study breast cancer metastasis, as well as treatment strategies and clinical trials addressing BCSC-TME interactions during metastasis. Overall, this study provides valuable insights for the development of effective therapeutic strategies to reduce breast cancer metastasis.
    Keywords:  Breast cancer; Cancer stem cell; Ecosystem; Metastasis; Mouse model; Tumor microenvironment
    DOI:  https://doi.org/10.24272/j.issn.2095-8137.2023.411
  8. J Mater Chem B. 2024 May 02.
    Nanomaterials in modulating tumor-associated macrophages and enhancing immunotherapy.
    Chen Liang, Yihan Zhang, Siyao Wang, Wangbo Jiao, Jingyi Guo, Nan Zhang, Xiaoli Liu.
      Tumor-associated macrophages (TAMs) are predominantly present in the tumor microenvironment (TME) and play a crucial role in shaping the efficacy of tumor immunotherapy. These TAMs primarily exhibit a tumor-promoting M2-like phenotype, which is associated with the suppression of immune responses and facilitation of tumor progression. Interestingly, recent research has highlighted the potential of repolarizing TAMs from an M2 to a pro-inflammatory M1 status-a shift that has shown promise in impeding tumor growth and enhancing immune responsiveness. This concept is particularly intriguing as it offers a new dimension to cancer therapy by targeting the tumor microenvironment, which is a significant departure from traditional approaches that focus solely on tumor cells. However, the clinical application of TAM-modulating agents is often challenged by issues such as insufficient tumor accumulation and off-target effects, limiting their effectiveness and safety. In this regard, nanomaterials have emerged as a novel solution. They serve a dual role: as delivery vehicles that can enhance the accumulation of therapeutic agents in the tumor site and as TAM-modulators. This dual functionality of nanomaterials is a significant advancement as it addresses the key limitations of current TAM-modulating strategies and opens up new avenues for more efficient and targeted therapies. This review provides a comprehensive overview of the latest mechanisms and strategies involving nanomaterials in modulating macrophage polarization within the TME. It delves into the intricate interactions between nanomaterials and macrophages, elucidating how these interactions can be exploited to drive macrophage polarization towards a phenotype that is more conducive to anti-tumor immunity. Additionally, the review explores the burgeoning field of TAM-associated nanomedicines in combination with tumor immunotherapy. This combination approach is particularly promising as it leverages the strengths of both nanomedicine and immunotherapy, potentially leading to synergistic effects in combating cancer.
    DOI:  https://doi.org/10.1039/d4tb00230j
  9. Front Immunol. 2024 ;15 1381970
    Targeting metabolism of breast cancer and its implications in T cell immunotherapy.
    Jialuo Zou, Cunjun Mai, Zhiqin Lin, Jian Zhou, Guie Lai.
      Breast cancer is a prominent health issue amongst women around the world. Immunotherapies including tumor targeted antibodies, adoptive T cell therapy, vaccines, and immune checkpoint blockers have rejuvenated the clinical management of breast cancer, but the prognosis of patients remains dismal. Metabolic reprogramming and immune escape are two important mechanisms supporting the progression of breast cancer. The deprivation uptake of nutrients (such as glucose, amino acid, and lipid) by breast cancer cells has a significant impact on tumor growth and microenvironment remodeling. In recent years, in-depth researches on the mechanism of metabolic reprogramming and immune escape have been extensively conducted, and targeting metabolic reprogramming has been proposed as a new therapeutic strategy for breast cancer. This article reviews the abnormal metabolism of breast cancer cells and its impact on the anti-tumor activity of T cells, and further explores the possibility of targeting metabolism as a therapeutic strategy for breast cancer.
    Keywords:  T cell immunotherapy; amino acid; breast cancer; glucose; immune escape; lipid; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2024.1381970
  10. Front Immunol. 2024 ;15 1407981
    Editorial: Tumor microenvironment and hematological malignancies: new evidences and new questions.
    Stefania Fiorcari, Paolo Strati, Elisabetta Dondi.
      
    Keywords:  hematological malignancies; homeostasis; immune escape; niches; signaling; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1407981
  11. Cell Commun Signal. 2024 May 02. 22(1): 251
    Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy.
    Olga A Sukocheva, Margarita E Neganova, Yulia Aleksandrova, Jack T Burcher, Elena Chugunova, Ruitai Fan, Edmund Tse, Gautam Sethi, Anupam Bishayee, Junqi Liu.
      Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies.
    Keywords:  Apoptosis; Cancer drug resistance; Immunotherapy; Sphingolipids; Sphingosine kinase; Sphingosine-1-phosphate; Tumor necrosis factor-α
    DOI:  https://doi.org/10.1186/s12964-024-01626-6
  12. Immunol Res. 2024 May 01.
    The immunosuppressive landscape in tumor microenvironment.
    Wuyi Liu, Huyue Zhou, Wenjing Lai, Changpeng Hu, Rufu Xu, Peng Gu, Menglin Luo, Rong Zhang, Guobing Li.
      Recent advances in cancer immunotherapy, especially immune checkpoint inhibitors (ICIs), have revolutionized the clinical outcome of many cancer patients. Despite the fact that impressive progress has been made in recent decades, the response rate remains unsatisfactory, and many patients do not benefit from ICIs. Herein, we summarized advanced studies and the latest insights on immune inhibitory factors in the tumor microenvironment. Our in-depth discussion and updated landscape of tumor immunosuppressive microenvironment may provide new strategies for reversing tumor immune evasion, enhancing the efficacy of ICIs therapy, and ultimately achieving a better clinical outcome.
    Keywords:  Immune checkpoint inhibitors; Immune response; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12026-024-09483-8
  13. J Adv Res. 2024 Apr 25. pii: S2090-1232(24)00159-0. [Epub ahead of print]
    Abnormal changes in metabolites caused by m6A methylation modification: The leading factors that induce the formation of immunosuppressive tumor microenvironment and their promising potential for clinical application.
    Liang Zhao, Junchen Guo, Shasha Xu, Meiqi Duan, Baiming Liu, He Zhao, Yihan Wang, Haiyang Liu, Zhi Yang, Hexue Yuan, Xiaodi Jiang, Xiaofeng Jiang.
       BACKGROUND: N6-methyladenosine (m6A) RNA methylation modifications have been widely implicated in the metabolic reprogramming of various cell types within the tumor microenvironment (TME) and are essential for meeting the demands of cellular growth and maintaining tissue homeostasis, enabling cells to adapt to the specific conditions of the TME. An increasing number of research studies have focused on the role of m6A modifications in glucose, amino acid and lipid metabolism, revealing their capacity to induce aberrant changes in metabolite levels. These changes may in turn trigger oncogenic signaling pathways, leading to substantial alterations within the TME. Notably, certain metabolites, including lactate, succinate, fumarate, 2-hydroxyglutarate (2-HG), glutamate, glutamine, methionine, S-adenosylmethionine, fatty acids and cholesterol, exhibit pronounced deviations from normal levels. These deviations not only foster tumorigenesis, proliferation and angiogenesis but also give rise to an immunosuppressive TME, thereby facilitating immune evasion by the tumor.
    AIM OF REVIEW: The primary objective of this review is to comprehensively discuss the regulatory role of m6A modifications in the aforementioned metabolites and their potential impact on the development of an immunosuppressive TME through metabolic alterations.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: This review aims to elaborate on the intricate networks governed by the m6A-metabolite-TME axis and underscores its pivotal role in tumor progression. Furthermore, we delve into the potential implications of the m6A-metabolite-TME axis for the development of novel and targeted therapeutic strategies in cancer research.
    Keywords:  Cancer; Metabolites; Targeted therapy; Tumor immunosuppressive microenvironment; m(6)A
    DOI:  https://doi.org/10.1016/j.jare.2024.04.016
  14. Front Immunol. 2024 ;15 1340702
    Crosstalk between T lymphocyte and extracellular matrix in tumor microenvironment.
    Die Lv, Yujie Fei, Hongli Chen, Junfeng Wang, Wenwen Han, Bomiao Cui, Yun Feng, Ping Zhang, Jiao Chen.
      The extracellular matrix (ECM) is a complex three-dimensional structure composed of proteins, glycans, and proteoglycans, constituting a critical component of the tumor microenvironment. Complex interactions among immune cells, extracellular matrix, and tumor cells promote tumor development and metastasis, consequently influencing therapeutic efficacy. Hence, elucidating these interaction mechanisms is pivotal for precision cancer therapy. T lymphocytes are an important component of the immune system, exerting direct anti-tumor effects by attacking tumor cells or releasing lymphokines to enhance immune effects. The ECM significantly influences T cells function and infiltration within the tumor microenvironment, thereby impacting the behavior and biological characteristics of tumor cells. T cells are involved in regulating the synthesis, degradation, and remodeling of the extracellular matrix through the secretion of cytokines and enzymes. As a result, it affects the proliferation and invasive ability of tumor cells as well as the efficacy of immunotherapy. This review discusses the mechanisms underlying T lymphocyte-ECM interactions in the tumor immune microenvironment and their potential application in immunotherapy. It provides novel insights for the development of innovative tumor therapeutic strategies and drug.
    Keywords:  T lymphocytes; extracellular matrix; immune escape; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1340702
  15. Cancer Immunol Immunother. 2024 May 02. 73(6): 115
    Extracellular matrix stiffness and tumor-associated macrophage polarization: new fields affecting immune exclusion.
    Ke-Xun Yu, Wei-Jie Yuan, Hui-Zhen Wang, Yong-Xiang Li.
      In the malignant progression of tumors, there is deposition and cross-linking of collagen, as well as an increase in hyaluronic acid content, which can lead to an increase in extracellular matrix stiffness. Recent research evidence have shown that the extracellular matrix plays an important role in angiogenesis, cell proliferation, migration, immunosuppression, apoptosis, metabolism, and resistance to chemotherapeutic by the alterations toward both secretion and degradation. The clinical importance of tumor-associated macrophage is increasingly recognized, and macrophage polarization plays a central role in a series of tumor immune processes through internal signal cascade, thus regulating tumor progression. Immunotherapy has gradually become a reliable potential treatment strategy for conventional chemotherapy resistance and advanced cancer patients, but the presence of immune exclusion has become a major obstacle to treatment effectiveness, and the reasons for their resistance to these approaches remain uncertain. Currently, there is a lack of exact mechanism on the regulation of extracellular matrix stiffness and tumor-associated macrophage polarization on immune exclusion. An in-depth understanding of the relationship between extracellular matrix stiffness, tumor-associated macrophage polarization, and immune exclusion will help reveal new therapeutic targets and guide the development of clinical treatment methods for advanced cancer patients. This review summarized the different pathways and potential molecular mechanisms of extracellular matrix stiffness and tumor-associated macrophage polarization involved in immune exclusion and provided available strategies to address immune exclusion.
    Keywords:  Cancer-associated fibroblasts; Extracellular matrix stiffness; Immune exclusion; Tumor microenvironment; Tumor-associated macrophage
    DOI:  https://doi.org/10.1007/s00262-024-03675-9
  16. Nanomedicine (Lond). 2024 Apr 30.
    Phytonanomedicine as a therapeutic regulator of the tumor microenvironment for inhibiting cancer metastasis.
    Sonali Sahoo, Sanjeeb Kumar Sahoo.
      TWEETABLE ABSTRACT "The development of phytonanomedicine-based approach seems to be a very promising candidate for modulating protumorigenic tumor microenvironment to suppress cancer metastasis."
    Keywords:  chemotherapy; metastasis; nanomedicine; phytochemicals; tumor microenvironment
    DOI:  https://doi.org/10.2217/nnm-2024-0098
  17. World J Hepatol. 2024 Apr 27. 16(4): 537-549
    Multifaceted roles of lymphatic and blood endothelial cells in the tumor microenvironment of hepatocellular carcinoma: A comprehensive review.
    Jing-Jing Li, Jia-Xi Mao, Han-Xiang Zhong, Yuan-Yu Zhao, Fei Teng, Xin-Yi Lu, Li-Ye Zhu, Yang Gao, Hong Fu, Wen-Yuan Guo.
      The tumor microenvironment is a complex network of cells, extracellular matrix, and signaling molecules that plays a critical role in tumor progression and metastasis. Lymphatic and blood vessels are major routes for solid tumor metastasis and essential parts of tumor drainage conduits. However, recent studies have shown that lymphatic endothelial cells (LECs) and blood endothelial cells (BECs) also play multifaceted roles in the tumor microenvironment beyond their structural functions, particularly in hepatocellular carcinoma (HCC). This comprehensive review summarizes the diverse roles played by LECs and BECs in HCC, including their involvement in angiogenesis, immune modulation, lymphangiogenesis, and metastasis. By providing a detailed account of the complex interplay between LECs, BECs, and tumor cells, this review aims to shed light on future research directions regarding the immune regulatory function of LECs and potential therapeutic targets for HCC.
    Keywords:  Blood endothelial cells; Hepatocellular carcinoma; Lymphatic endothelial cells; Tumor microenvironment
    DOI:  https://doi.org/10.4254/wjh.v16.i4.537
  18. Adv Biol (Weinh). 2024 Apr 29. e2400119
    The Biological Role of Macrophage in Lung and Its Implications in Lung Cancer Immunotherapy.
    Chenyang Wang, Qing Gao, Jinghong Wu, Mingjun Lu, Jinghui Wang, Teng Ma.
      The lungs are the largest surface of the body and the most important organ in the respiratory system, which are constantly exposed to the external environment. Tissue Resident Macrophages in lung constitutes the important defense against external pathogens. Macrophages connects the innate and adaptive immune system, and also plays important roles in carcinogenesis and cancer immunotherapy. Lung cancer is the leading cause of cancer-related death worldwide, with an overall five-year survival rate of only 21%. Macrophages that infiltrate or aggregate in lung tumor microenvironment are defined as tumor-associated macrophages (TAMs). TAMs are the main components of immune cells in the lung tumor microenvironment. The differentiation and maturation process of TAMs can be roughly divided into two different types: classical activation pathway produces M1 tumor-associated macrophages, and bypass activation pathway produces M2 tumor-associated macrophages. Studies have found that TAMs are related to tumor invasion, metastasis, and treatment resistance, and show potential as a new target for tumor immunotherapy. Therefore, the biological function of macrophages in lung and the role of TAMs in the occurrence, development, and treatment of lung cancer are discussed in this paper.
    Keywords:  immunotherapy; lung cancer; macrophage; tams; tme
    DOI:  https://doi.org/10.1002/adbi.202400119
  19. Biomed Pharmacother. 2024 Apr 27. pii: S0753-3322(24)00493-1. [Epub ahead of print]175 116609
    Effects of chronic stress on cancer development and the therapeutic prospects of adrenergic signaling regulation.
    Hao Zhang, Yuwei Yang, Yan Cao, Jingzhi Guan.
      Long-term chronic stress is an important factor in the poor prognosis of cancer patients. Chronic stress reduces the tissue infiltration of immune cells in the tumor microenvironment (TME) by continuously activating the adrenergic signaling, inhibits antitumor immune response and tumor cell apoptosis while also inducing epithelial-mesenchymal transition (EMT) and tumor angiogenesis, promoting tumor invasion and metastasis. This review first summarizes how adrenergic signaling activates intracellular signaling by binding different adrenergic receptor (AR) heterodimers. Then, we focused on reviewing adrenergic signaling to regulate multiple functions of immune cells, including cell differentiation, migration, and cytokine secretion. In addition, the article discusses the mechanisms by which adrenergic signaling exerts pro-tumorigenic effects by acting directly on the tumor itself. It also highlights the use of adrenergic receptor modulators in cancer therapy, with particular emphasis on their potential role in immunotherapy. Finally, the article reviews the beneficial effects of stress intervention measures on cancer treatment. We think that enhancing the body's antitumor response by adjusting adrenergic signaling can enhance the efficacy of cancer treatment.
    Keywords:  Adrenergic; Alpha-agonists; Antitumor immunity; Beta-blockers; Chronic stress; Immunotherapy
    DOI:  https://doi.org/10.1016/j.biopha.2024.116609
  20. Nat Cancer. 2024 May 02.
    Cycling back to folate metabolism in cancer.
    Younghwan Lee, Karen H Vousden, Marc Hennequart.
      Metabolic changes contribute to cancer initiation and progression through effects on cancer cells, the tumor microenvironment and whole-body metabolism. Alterations in serine metabolism and the control of one-carbon cycles have emerged as critical for the development of many tumor types. In this Review, we focus on the mitochondrial folate cycle. We discuss recent evidence that, in addition to supporting nucleotide synthesis, mitochondrial folate metabolism also contributes to metastasis through support of antioxidant defense, mitochondrial protein synthesis and the overflow of excess formate. These observations offer potential therapeutic opportunities, including the modulation of formate metabolism through dietary interventions and the use of circulating folate cycle metabolites as biomarkers for cancer detection.
    DOI:  https://doi.org/10.1038/s43018-024-00739-8
  21. Am J Pathol. 2024 Apr 30. pii: S0002-9440(24)00162-7. [Epub ahead of print]
    Finding your CAR: The road ahead for engineered T-cells.
    Po-Han Chen, Rianna Raghunandan, Jon S Morrow, Samuel G Katz.
      Adoptive cellular therapy using chimeric antigen receptors (CAR) has transformed immunotherapy by engineering T cells to target specific antigens on tumor cells. As the field continues to advance, pathology laboratories will play increasingly essential roles in the complicated multi-step process of CAR-T therapy. These include the detection of targetable tumor antigens by flow cytometry or immunohistochemistry at the time of disease diagnosis and the isolation and infusion of CAR-T cells. Additional roles include (1) detecting antigen loss or heterogeneity that renders resistance to CAR-T as well as identifying alternative targetable antigens on tumor cells, (2) monitoring the phenotype, persistence and tumor infiltration properties of CAR T-cells and the tumor microenvironment for factors that predict CAR-T success, and (3) evaluating side effects and biomarkers of CAR-T cytotoxicity such as cytokine release syndrome. In this review, we highlight existing technologies that are applicable to monitoring of CAR-T cell persistence, target antigen identification and loss. We also discuss emerging technologies that address new challenges, such as how to put a brake on CAR T-cells. While pathology laboratories have already provided companion diagnostic tests important in immunotherapy such as PD-L1, MSI, and HER2 testing, we draw attention to the exciting new translational research opportunities in adoptive cellular therapy.
    DOI:  https://doi.org/10.1016/j.ajpath.2024.04.002
  22. Science. 2024 May 03. 384(6695): 510-511
    B cell trajectories influence cancer outcomes.
    Julie Tellier, Stephen L Nutt.
      Two types of B cell in the tumor microenvironment modulate antitumor immunity.
    DOI:  https://doi.org/10.1126/science.adp1865
  23. Cancer Discov. 2024 Apr 29.
    Senescent CAFs mediate immunosuppression and drive breast cancer progression.
    Jiayu Ye, John M Baer, Douglas V Faget, Vasilios A Morikis, Qihao Ren, Anupama Melam, Ana Paula Delgado, Xianmin Luo, Satarupa Mullick Bagchi, Jad I Belle, Edward Campos, Michael Friedman, Deborah J Veis, Erik S Knudsen, Agnieszka K Witkiewicz, Scott Powers, Gregory D Longmore, David G DeNardo, Sheila A Stewart.
      The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast cancer associated fibroblasts (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in Her2+, ER+, and triple negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0426
  24. Transl Oncol. 2024 Apr 30. pii: S1936-5233(24)00061-5. [Epub ahead of print]45 101934
    Exosomal NAT10 from esophageal squamous cell carcinoma cells modulates macrophage lipid metabolism and polarization through ac4C modification of FASN.
    Chun Jin, Jian Gao, Ji Zhu, Yongqiang Ao, Bowen Shi, Xin Li.
      N-acetyltransferase 10 (NAT10) is acknowledged as a tumor promoter in various cancers due to its role as a regulator of acetylation modification. Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment (TME). However, the intercellular communication between esophageal squamous cell carcinoma (ESCC) cells and TAMs involving NAT10 remains poorly understood. This study aimed to elucidate the regulatory mechanism of NAT10 in modulating macrophage lipid metabolism and polarization. Experimental evidence was derived from in vitro and in vivo analyses. We explored the association between upregulated NAT10 in ESCC tissues, macrophage polarization, and the therapeutic efficacy of PD-1. Furthermore, we investigated the impact of methyltransferase 3 (METTL3)-induced m6A modification on the increased expression of NAT10 in ESCC cells. Additionally, we examined the role of exosomal NAT10 in stabilizing the expression of fatty acid synthase (FASN) and promoting macrophage M2 polarization through mediating the ac4C modification of FASN. Results indicated that NAT10, packaged by exosomes derived from ESCC cells, promotes macrophage M2 polarization by facilitating lipid metabolism. In vivo animal studies demonstrated that targeting NAT10 could enhance the therapeutic effect of PD-1 on ESCC by mediating macrophage reprogramming. Our findings offer novel insights into improving ESCC treatment through NAT10 targeting.
    Keywords:  ESCC; FASN; Macrophage M2 polarization; NAT10; m6A modification
    DOI:  https://doi.org/10.1016/j.tranon.2024.101934
  25. Pharmacol Rev. 2024 May 02. 76(3): 388-413
    Prostaglandin E2 in the Tumor Microenvironment, a Convoluted Affair Mediated by EP Receptors 2 and 4.
    Ana Santiso, Akos Heinemann, Julia Kargl.
      The involvement of the prostaglandin E2 (PGE2) system in cancer progression has long been recognized. PGE2 functions as an autocrine and paracrine signaling molecule with pleiotropic effects in the human body. High levels of intratumoral PGE2 and overexpression of the key metabolic enzymes of PGE2 have been observed and suggested to contribute to tumor progression. This has been claimed for different types of solid tumors, including, but not limited to, lung, breast, and colon cancer. PGE2 has direct effects on tumor cells and angiogenesis that are known to promote tumor development. However, one of the main mechanisms behind PGE2 driving cancerogenesis is currently thought to be anchored in suppressed antitumor immunity, thus providing possible therapeutic targets to be used in cancer immunotherapies. EP2 and EP4, two receptors for PGE2, are emerging as being the most relevant for this purpose. This review aims to summarize the known roles of PGE2 in the immune system and its functions within the tumor microenvironment. SIGNIFICANCE STATEMENT: Prostaglandin E2 (PGE2) has long been known to be a signaling molecule in cancer. Its presence in tumors has been repeatedly associated with disease progression. Elucidation of its effects on immunological components of the tumor microenvironment has highlighted the potential of PGE2 receptor antagonists in cancer treatment, particularly in combination with immune checkpoint inhibitor therapeutics. Adjuvant treatment could increase the response rates and the efficacy of immune-based therapies.
    DOI:  https://doi.org/10.1124/pharmrev.123.000901
  26. Front Cell Dev Biol. 2024 ;12 1378302
    The hidden messengers: cancer associated fibroblasts-derived exosomal miRNAs as key regulators of cancer malignancy.
    Zixuan Gou, Jiannan Li, Jianming Liu, Na Yang.
      Cancer-associated fibroblasts (CAFs), a class of stromal cells in the tumor microenvironment (TME), play a key role in controlling cancer cell invasion and metastasis, immune evasion, angiogenesis, and resistance to chemotherapy. CAFs mediate their activities by secreting soluble chemicals, releasing exosomes, and altering the extracellular matrix (ECM). Exosomes contain various biomolecules, such as nucleic acids, lipids, and proteins. microRNA (miRNA), a 22-26 nucleotide non-coding RNA, can regulate the cellular transcription processes. Studies have shown that miRNA-loaded exosomes secreted by CAFs engage in various regulatory communication networks with other TME constituents. This study focused on the roles of CAF-derived exosomal miRNAs in generating cancer malignant characteristics, including immune modulation, tumor growth, migration and invasion, epithelial-mesenchymal transition (EMT), and treatment resistance. This study thoroughly examines miRNA's dual regulatory roles in promoting and suppressing cancer. Thus, changes in the CAF-derived exosomal miRNAs can be used as biomarkers for the diagnosis and prognosis of patients, and their specificity can be used to develop newer therapies. This review also discusses the pressing problems that require immediate attention, aiming to inspire researchers to explore more novel avenues in this field.
    Keywords:  cancer malignant characteristics; cancer-associated fibroblasts-derived exosomal miRNA; diagnosis; dual regulatory functions; prognosis; therapy
    DOI:  https://doi.org/10.3389/fcell.2024.1378302
  27. Cancer Discov. 2024 Apr 17. OF1-OF22
    Senescent CAFs Mediate Immunosuppression and Drive Breast Cancer Progression.
    Jiayu Ye, John M Baer, Douglas V Faget, Vasilios A Morikis, Qihao Ren, Anupama Melam, Ana Paula Delgado, Xianmin Luo, Satarupa Mullick Bagchi, Jad I Belle, Edward Campos, Michael Friedman, Deborah J Veis, Erik S Knudsen, Agnieszka K Witkiewicz, Scott Powers, Gregory D Longmore, David G DeNardo, Sheila A Stewart.
      The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development.
    SIGNIFICANCE: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0426
  28. Int J Biol Macromol. 2024 Apr 26. pii: S0141-8130(24)02631-X. [Epub ahead of print] 131826
    Dual-crosslinking gelatin-hyaluronic acid methacrylate based biomimetic PDAC desmoplastic niche enhances tumor-associated macrophages recruitment and M2-like polarization.
    Di Wu, Tiancheng Gong, Zhongxiang Sun, Xihao Yao, Dongzhi Wang, Qiyang Chen, Qingsong Guo, Xiaohong Li, Yibing Guo, Yuhua Lu.
      The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by deposition of desmoplastic matrix (including collagen and hyaluronic acid). And the interactions between tumor-associated macrophages (TAMs) and tumor cells play a crucial role in progression of PDAC. Hence, the appropriate model of tumor cell-macrophage interaction within the unique PDAC TME is of significantly important. To this end, a 3D tumor niche based on dual-crosslinking gelatin methacrylate and hyaluronic acid methacrylate hydrogels was constructed to simulate the desmoplastic tumor matrix with matching compressive modulus and composition. The bionic 3D tumor niche creates an immunosuppressive microenvironment characterized by the downregulation of M1 markers and upregulation of M2 markers in TAMs. Mechanistically, RNA-seq analysis revealed that the PI3K-AKT signaling pathway might modulate the phenotypic balance and recruitment of macrophages through regulating SELE and VCAM-1. Furthermore, GO and GSEA revealed the biological process of leukocyte migration and the activation of cytokine-associated signaling were involved. Finally, the 3D tumor-macrophage niches with three different ratios were fabricated which displayed increased M2-like polarization and stemness. The utilization of the 3D tumor niche has the potential to provide a more accurate investigation of the interplay between PDAC tumor cells and macrophages within an in vivo setting.
    Keywords:  Dual-crosslinking gelatin-hyaluronic acid methacrylate; Macrophage m2-like polarization; Pancreatic ductal adenocarcinoma
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.131826
  29. Front Biosci (Landmark Ed). 2024 Apr 02. 29(4): 137
    Promising Therapeutic Approach in Pancreatic Cancer: Metabolism-Related Genes.
    Soohyun Choe, Woori Kwak, Ehyun Kim, Sohyeon Shin, Miyoung Shin, Hyun Jung Koh, Hyunho Yoon.
      Most pancreatic cancers are pancreatic ductal adenocarcinomas. This is an extremely lethal disease with poor prognosis and almost no treatment choices. Considering the profound role of the pancreas in the human body, malfunction of this organ can significantly affect quality of life. Although multiple metabolic pathways are altered in cancer cells, certain metabolic gene signatures may be critical for immunotherapy. The reprogrammed metabolism of glucose, amino acids, and lipids can nourish the tumor microenvironment (TME). Previous studies have also shown that reprogrammed metabolism influences immune responses. Tumor-infiltrating immune cells in the TME can adapt their metabolism to blunt the immune system, leading to immunosuppression and tumor progression. The identification of metabolism-related genes (MRGs) associated with immune reactions in pancreatic cancer may lead to improved treatments. This review highlights the characteristics of MRGs in pancreatic cancer and suggests that enhanced anti-cancer therapies could be used to overcome resistance to immunotherapy.
    Keywords:  immunotherapy; metabolism; metabolites; pancreatic cancer
    DOI:  https://doi.org/10.31083/j.fbl2904137
  30. Front Immunol. 2024 ;15 1342497
    Myeloid-derived suppressor cells in influenza virus-induced asthma exacerbation.
    Chiel van Geffen, Tim Lange, Saeed Kolahian.
      Myeloid-derived suppressor cells (MDSCs) are a phenotypically heterogenous group of cells that potently suppress the immune response. A growing body of evidence supports the important role of MDSCs in a variety of lung diseases, such as asthma. However, the role of MDSCs in asthma exacerbation has so far not been investigated. Here, we studied the role of MDSCs in a murine model of influenza virus-induced asthma exacerbation. BALB/c mice were exposed to house dust mite (HDM) three times a week for a total of five weeks to induce a chronic asthmatic phenotype, which was exacerbated by additional exposure to the A/Hamburg/5/2009 hemagglutinin 1 neuraminidase 1 (H1N1) influenza virus. Induction of lung inflammatory features, production of T helper (Th) 1- and Th2- associated inflammatory cytokines in the lavage fluid and an increased airway hyper-responsiveness were observed, establishing the asthma exacerbation model. The number and activity of pulmonary M-MDSCs increased in exacerbated asthmatic mice compared to non-exacerbated asthmatic mice. Furthermore, depletion of MDSCs aggravated airway hyper-responsiveness in exacerbated asthmatic mice. These findings further denote the role of MDSCs in asthma and provide some of the first evidence supporting a potential important role of MDSCs in asthma exacerbation.
    Keywords:  asthma; asthma exacerbation; inflammation; influenza virus; myeloid-derived suppressor cells
    DOI:  https://doi.org/10.3389/fimmu.2024.1342497
  31. Cell Rep Med. 2024 Apr 22. pii: S2666-3791(24)00199-X. [Epub ahead of print] 101530
    Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity.
    Yue Hu, Abhijit Sarkar, Kevin Song, Sara Michael, Magnus Hook, Ruoning Wang, Andras Heczey, Xiaotong Song.
      Chimeric antigen receptor (CAR) T cell therapy is hindered in solid tumor treatment due to the immunosuppressive tumor microenvironment and suboptimal T cell persistence. Current strategies do not address nutrient competition in the microenvironment. Hence, we present a metabolic refueling approach using inosine as an alternative fuel. CAR T cells were engineered to express membrane-bound CD26 and cytoplasmic adenosine deaminase 1 (ADA1), converting adenosine to inosine. Autocrine secretion of ADA1 upon CD3/CD26 stimulation activates CAR T cells, improving migration and resistance to transforming growth factor β1 suppression. Fusion of ADA1 with anti-CD3 scFv further boosts inosine production and minimizes tumor cell feeding. In mouse models of hepatocellular carcinoma and non-small cell lung cancer, metabolically refueled CAR T cells exhibit superior tumor reduction compared to unmodified CAR T cells. Overall, our study highlights the potential of selective inosine refueling to enhance CAR T therapy efficacy against solid tumors.
    Keywords:  ADA; ADA1 autocrine secretion; CAR T cell; CD26; T cell engager; adenosine; anti-CD3 scFv; inosine; metabolic reprogramming; solid tumor
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101530
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