bims-flamet Biomed News
on Cytokines and immunometabolism in metastasis
Issue of 2025–01–05
23 papers selected by
Peio Azcoaga, Biodonostia HRI
  1. Targeting immune checkpoints on myeloid cells: current status and future directions.
  2. The Role of Innate Priming in Modifying Tumor-associated Macrophage Phenotype.
  3. Tumor microenvironment in oral squamous cell carcinoma.
  4. Iron metabolism and the tumor microenvironment: A new perspective on cancer intervention and therapy (Review).
  5. Targeting Cancer-Associated Fibroblasts: Eliminate or Reprogram?
  6. Effects of metabolism upon immunity: Targeting myeloid-derived suppressor cells for the treatment of breast cancer is a promising area of study.
  7. Tumor microenvironment and immunotherapy for triple-negative breast cancer.
  8. Targeting the tumor immune microenvironment: GPCRs as key regulators in triple-negative breast cancer.
  9. The heterogeneity of neutrophils in cancer and its implication for therapeutic targeting.
  10. [Tumor-associated macrophages promote pre-metastatic niche formation in ovarian cancer].
  11. Targeting glutamine metabolism crosstalk with tumor immune response.
  12. CCR5 and IL-12 co-expression in CAR T cells improves antitumor efficacy by reprogramming tumor microenvironment in solid tumors.
  13. Angiogenesis and EMT regulators in the tumor microenvironment in lung cancer and immunotherapy.
  14. Interplay and therapeutic implications of colorectal cancer stem cells, tumor microenvironment, and gut microbiota.
  15. Metabolism of cancer cells and immune cells in the initiation, progression, and metastasis of cancer.
  16. Inhalable nanovesicles loaded with a STING agonist enhance CAR-T cell activity against solid tumors in the lung.
  17. The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment.
  18. Activated hepatic stellate cell-derived small extracellular vesicles facilitate M2 macrophage polarization and hepatoma progression via miR-27a-3p.
  19. Senescent Macrophages and the Lung Cancer Microenvironment: A New Perspective on Tumor Immune Evasion.
  20. Advancements in immunotherapy for colorectal cancer treatment: a comprehensive review of strategies, challenges, and future prospective.
  21. Shedding light on the role of complement C4 activation in cancer.
  22. Multi-drug sequential release systems: Construction and application for synergistic tumor treatment.
  23. Black phosphorus nanosheets activate tumor immunity of glioblastoma by modulating the expression of the immunosuppressive molecule PD-L1.
  1. Cancer Immunol Immunother. 2025 Jan 03. 74(2): 40
    Targeting immune checkpoints on myeloid cells: current status and future directions.
    Chuhan Ma, Yang Li, Min Li, Chao Lv, Yu Tian.
      Myeloid cells accumulate extensively in most tumors and play a critical role in immunosuppression of the tumor microenvironment (TME). Like T cells, myeloid cells also express immune checkpoint molecules, which induce the immunosuppressive phenotype of these cells. In this review, we summarize the tumor-promoting function and immune checkpoint expression of four types of myeloid cells: macrophages, neutrophils, dendritic cells, and myeloid-derived suppressor cells, which are the main components of the TME. By summarizing the research status of myeloid checkpoints, we propose that blocking immune checkpoints on myeloid cells might be an effective strategy to reverse the immunosuppressive status of the TME. Moreover, combining nanotechnology, cellular therapy, and bispecific antibodies to achieve precise targeting of myeloid immune checkpoints can help to avoid the adverse effects of systemic administration, ultimately achieving a balance between efficacy and safety in cancer therapy.
    Keywords:  Immune checkpoint; Myeloid cells; Nanotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s00262-024-03856-6
  2. Front Biosci (Landmark Ed). 2024 Dec 17. 29(12): 418
    The Role of Innate Priming in Modifying Tumor-associated Macrophage Phenotype.
    Ben Topham, Barry Hock, Elisabeth Phillips, George Wiggins, Margaret Currie.
      Tumor-associated macrophages (TAMs) are innate immune cells that exert far reaching influence over the tumor microenvironment (TME). Depending on cues within the local environment, TAMs may promote tumor angiogenesis, cancer cell invasion and immunosuppression, or, alternatively, inhibit tumor progression via neoantigen presentation, tumoricidal reactive oxygen species generation and pro-inflammatory cytokine secretion. Therefore, TAMs have a pivotal role in determining tumor progression and response to therapy. TAM phenotypes are driven by cytokines and physical cues produced by tumor cells, adipocytes, fibroblasts, pericytes, immune cells, and other cells within the TME. Research has shown that TAMs can be primed by environmental stimuli, adding another layer of complexity to the environmental context that determines TAM phenotype. Innate priming is a functional consequence of metabolic and epigenetic reprogramming of innate cells by a primary stimulant, resulting in altered cellular response to future secondary stimulation. Innate priming offers a novel target for development of cancer immunotherapy and improved prognosis of disease, but also raises the risk of exacerbating existing inflammatory pathologies. This review will discuss the mechanisms underlying innate priming including metabolic and epigenetic modification, its relevance to TAMs and tumor progression, and possible clinical implications for cancer treatment.
    Keywords:  cancer; epigenetic modification; innate priming; metabolic modification; tumor-associated macrophage (TAM)
    DOI:  https://doi.org/10.31083/j.fbl2912418
  3. Front Immunol. 2024 ;15 1485174
    Tumor microenvironment in oral squamous cell carcinoma.
    Chenxi Li, Xiaodan Dong, Bo Li.
      Oral squamous cell carcinoma (OSCC) is a highly aggressive and malignant tumor of oral cavity with a poor prognosis and high mortality due to the limitations of existing therapies. The significant role of tumor microenvironment (TME) in the initiation, development, and progression of OSCC has been widely recognized. Various cells in TME, including tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), T lymphocytes, tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs) and dendritic cells (DCs), form a complicated and important cellular network to modulate OSCC proliferation, invasion, migration, and angiogenesis by secreting RNAs, proteins, cytokines, and metabolites. Understanding the interactions among cells in TME provides the foundation for advanced clinical diagnosis and therapies. This review summarizes the current literature that describes the role of various cellular components and other TME factors in the progression of OSCC, hoping to provide new ideas for the novel OSCC treatment strategies targeting the complicated cellular network and factors that mediate the interactive loops among cells in TME.
    Keywords:  cellular network; interaction; oral squamous cell carcinoma; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2024.1485174
  4. Int J Mol Med. 2025 Mar;pii: 39. [Epub ahead of print]55(3):
    Iron metabolism and the tumor microenvironment: A new perspective on cancer intervention and therapy (Review).
    Xiaorui Bu, Lufang Wang.
      Iron metabolism plays a crucial role in the tumor microenvironment, influencing various aspects of cancer cell biology and tumor progression. This review discusses the regulatory mechanisms of iron metabolism within the tumor microenvironment and highlights how tumor cells and associated stromal cells manage iron uptake, accumulation and regulation. The sources of iron within tumors and the biological importance of ferroptosis in cancer were explored, focusing on its mechanisms, biological effects and, in particular, its tumor‑suppressive properties. Furthermore, the protective strategies employed by cancer cells to evade ferroptosis were examined. This review also delves into the intricate relationship between iron metabolism and immune modulation within the tumor microenvironment, detailing the impact on tumor‑associated immune cells and immune evasion. The interplay between ferroptosis and immunotherapy is discussed and potential strategies to enhance cancer immunotherapy by modulating iron metabolism are presented. Finally, the current ferroptosis‑based cancer therapeutic approaches were summarized and future directions for therapies that target iron metabolism were proposed.
    Keywords:  cancer immunotherapy; cancer therapy; ferroptosis; iron metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3892/ijmm.2024.5480
  5. Cancer Sci. 2025 Jan 02.
    Targeting Cancer-Associated Fibroblasts: Eliminate or Reprogram?
    Masaya Yamazaki, Takatsugu Ishimoto.
      Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME). Given their various roles in tumor progression and treatment resistance, CAFs are promising therapeutic targets in cancer. The elimination of tumor-promoting CAFs has been investigated in various animal models to determine whether it effectively suppresses tumor growth. Based on recent evidence, several simple strategies have been proposed to eliminate tumor-promoting CAFs and attenuate these features. In addition, attention has focused on the critical role that CAFs play in the immunosuppressive TME. Therefore, the functional reprogramming of CAFs in combination with immune checkpoint inhibitors has also been investigated as a possible therapeutic approach. However, although potential targets in CAFs have been widely characterized, the plasticity and heterogeneity of CAFs complicate the understanding of their properties and present difficulties for clinical application. Moreover, the identification of tumor-suppressive CAFs highlights the necessity for the development of therapeutic approaches that can distinguish and switch between tumor-promoting and tumor-suppressive CAFs in an appropriate manner. In this review, we introduce the origins and diversity of CAFs, their role in cancer, and current therapeutic strategies aimed at targeting CAFs, including ongoing clinical evaluations.
    Keywords:  FAP; cancer‐associated fibroblasts; immunotherapy; reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.1111/cas.16443
  6. Int Immunopharmacol. 2024 Dec 30. pii: S1567-5769(24)02414-7. [Epub ahead of print]147 113892
    Effects of metabolism upon immunity: Targeting myeloid-derived suppressor cells for the treatment of breast cancer is a promising area of study.
    Yulin Wang, Qiutong Dong, Menghan Yuan, Jingxian Hu, Peizhe Lin, Yijing Yan, Yu Wang, Yanyan Wang.
      Breast cancer (BC) ranks among the most prevalent malignancies affecting women, with advanced-stage patients facing an increased mortality risk. Myeloid-derived suppressor cells (MDSCs) contribute significantly to poor prognostic outcomes. Research has concentrated predominantly on the immunological mechanisms underlying MDSC functions, but a comprehensive investigation into the metabolic interactions between BC cells and MDSCs is lacking. In a hypoxic tumor microenvironment (TME), BC cells can enhance aerobic-glycolysis rates, upregulate expression of key lipid metabolism enzymes such as cluster of differentiation (CD) 36 and 5-lipoxygenase (5-LOX), accelerate glutamine (Gln) uptake, and elevate extracellular adenosine (eADO) levels, thereby fostering MDSC proliferation and amplifying immune suppression. Concurrently, alterations in the metabolic state of MDSCs also influence BC progression. To ensure adequate proliferative resources, MDSCs upregulate the pentose phosphate pathway and expedite glycolysis for energy supply while increasing the expression of fatty acid transport proteins (FATPs) such as CD36 and fatty acid transporter 2 (FATP2) to maintain intracellular lipid availability, thereby enhancing their adaptability within the TME. Furthermore, MDSCs undermine T-cell anti-tumor efficacy by depleting essential amino acids (AAs), such as arginine (Arg), tryptophan (Trp), and cysteine (Cys), required for T-cell function. This review elucidates how pharmacological agents such as metformin, liver X receptor (LXR) agonists, and 6-diazo-5-oxo-L-norleucine (DON) can augment anti-cancer treatment efficacy by targeting metabolic pathways in MDSCs. We systematically delineate the mechanisms governing interactions between BC cells and MDSCs from a metabolic standpoint while summarizing therapeutic strategies to modulate metabolism within MDSCs. Our review provides a framework for optimizing MDSC applications in BC immunotherapy.
    Keywords:  Breast cancer; Immunity; Metabolism; Myeloid-derived suppressor cells; Targeted therapy
    DOI:  https://doi.org/10.1016/j.intimp.2024.113892
  7. Biomark Res. 2024 Dec 31. 12(1): 166
    Tumor microenvironment and immunotherapy for triple-negative breast cancer.
    Zijie Guo, Ziyu Zhu, Xixi Lin, Shenkangle Wang, Yihong Wen, Linbo Wang, Lili Zhi, Jichun Zhou.
      Triple-negative breast cancer (TNBC) is a subtype of breast cancer known for its high aggressiveness and poor prognosis. Conventional treatment of TNBC is challenging due to its heterogeneity and lack of clear targets. Recent advancements in immunotherapy have shown promise in treating TNBC, with immune checkpoint therapy playing a significant role in comprehensive treatment plans. The tumor microenvironment (TME), comprising immune cells, stromal cells, and various cytokines, plays a crucial role in TNBC progression and response to immunotherapy. The high presence of tumor-infiltrating lymphocytes and immune checkpoint proteins in TNBC indicates the potential of immunotherapeutic strategies. However, the complexity of the TME, while offering therapeutic targets, requires further exploration of its multiple roles in immunotherapy. In this review, we discuss the interaction mechanism between TME and TNBC immunotherapy based on the characteristics and composition of TME, and elaborate on and analyze the effect of TME on immunotherapy, the potential of TME as an immune target, and the ability of TME as a biomarker. Understanding these dynamics will offer new insights for enhancing therapeutic approaches and investigating stratification and prognostic markers for TNBC patients.
    Keywords:  Biomarkers; Cancer treatment protocols; Immune checkpoint; Immunotherapy; Triple-negative breast cancer (TNBC); Tumor microenvironment (TME)
    DOI:  https://doi.org/10.1186/s40364-024-00714-6
  8. Int Immunopharmacol. 2024 Dec 30. pii: S1567-5769(24)02452-4. [Epub ahead of print]147 113930
    Targeting the tumor immune microenvironment: GPCRs as key regulators in triple-negative breast cancer.
    Chengyi Wang, Yanyan Liu, Ru Zhang, Hao Gong, Xinnong Jiang, Shuai Xia.
      Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its aggressive nature and limited therapeutic options. Recent research underscores the pivotal role of G protein-coupled receptors (GPCRs) in shaping the tumor immune microenvironment (TIME) within TNBC. This review focuses on four principal GPCRs-chemokine receptors, sphingosine-1-phosphate receptors, prostaglandin E2 receptors, and lactate receptors-that have garnered substantial attention in TNBC studies. GPCRs modulate immune cell recruitment, polarization, and function, thereby fostering an immunosuppressive milieu conducive to tumor progression and metastasis. The review examines how alterations in GPCR expression on immune cells influence the pathogenesis and advancement of TNBC. Further, it discusses emerging therapeutic strategies targeting GPCR signaling pathways to remodel the immunosuppressive TIME in TNBC. These insights into GPCR-mediated immune regulation not only deepen our comprehension of TNBC's pathophysiology but also offer promising avenues for developing novel immunotherapies aimed at enhancing clinical outcomes for TNBC patients.
    Keywords:  GPCR; Immune microenvironment; Triple-negative breast cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2024.113930
  9. Nat Immunol. 2025 Jan;26(1): 17-28
    The heterogeneity of neutrophils in cancer and its implication for therapeutic targeting.
    Evgeniy Eruslanov, Yulia Nefedova, Dmitry I Gabrilovich.
      Neutrophils have a pivotal role in safeguarding the host against pathogens and facilitating tissue remodeling. They possess a large array of tools essential for executing these functions. Neutrophils have a critical role in cancer, where they are largely associated with negative clinical outcome and resistance to therapy. However, the specific role of neutrophils in cancer is complex and controversial, owing to their high functional diversity and acute sensitivity to the microenvironment. In this Perspective, we discuss the accumulated evidence that suggests that the functional diversity of neutrophils can be ascribed to two principal functional states, each with distinct characteristics: classically activated neutrophils and pathologically activated immunosuppressive myeloid-derived suppressor cells. We discuss how the antimicrobial factors in neutrophils can contribute to tumor progression and the fundamental mechanisms that govern the pathologically activated myeloid-derived suppressor cells. These functional states play divergent roles in cancer and thus require separate consideration in therapeutic targeting.
    DOI:  https://doi.org/10.1038/s41590-024-02029-y
  10. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2024 Dec;40(12): 1138-1145
    [Tumor-associated macrophages promote pre-metastatic niche formation in ovarian cancer].
    Lu Wei, Jinhua Wang.
      Patients with ovarian cancer (OC) are often diagnosed at an advanced stage and have a poor prognosis because of extensive tumour metastasis. Tumour metastasis usually occurs in stages, which means that before the invasion of tumour cells, a pre-metastatic niche (PMN) has been formed to support the subsequent colonisation and growth of tumour cells. Tumour-associated macrophages (TAMs) are highly heterogeneous in terms of origin, phenotype and function. As one of the most abundant components in the tumour microenvironment (TME), TAMs can contribute to PMN formation by promoting organotropism, mediating immunosuppression, metabolic reprogramming, facilitating angiogenesis, and inducing cancer cell stemness. Therefore, TAMs play an important role in OC metastasis.
  11. Biochim Biophys Acta Rev Cancer. 2024 Dec 31. pii: S0304-419X(24)00188-4. [Epub ahead of print] 189257
    Targeting glutamine metabolism crosstalk with tumor immune response.
    Chenshuang Dong, Yan Zhao, Yecheng Han, Ming Li, Guiling Wang.
      Glutamine, akin to glucose, is a fundamental nutrient for human physiology. Tumor progression is often accompanied by elevated glutamine consumption, resulting in a disrupted nutritional balance and metabolic reprogramming within the tumor microenvironment. Furthermore, immune cells, which depend on glutamine for metabolic support, may experience functional impairments and dysregulation. Although the role of glutamine in tumors has been extensively studied, the specific impact of glutamine competition on immune responses, as well as the precise cellular alterations within immune cells, remains incompletely understood. In this review, we summarize the consequences of glutamine deprivation induced by tumor-driven glutamine uptake on immune cells, assessing the underlying mechanisms from the perspective of various components of the immune microenvironment. Additionally, we discuss the potential synergistic effects of glutamine supplementation and immunotherapy, offering insights into future research directions. This review provides compelling evidence for the integration of glutamine metabolism and immunotherapy as a promising strategy in cancer therapy.
    Keywords:  Glutamine deprivation; Glutamine therapy; Immune cells; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189257
  12. Cancer Immunol Immunother. 2025 Jan 03. 74(2): 55
    CCR5 and IL-12 co-expression in CAR T cells improves antitumor efficacy by reprogramming tumor microenvironment in solid tumors.
    Yonggui Tian, Liubo Zhang, Yu Ping, Zhen Zhang, Chang Yao, Chunyi Shen, Feng Li, Chunli Wen, Yi Zhang.
      Chimeric antigen receptor (CAR) T cell therapy for solid tumors faces significant challenges, including inadequate infiltration, limited proliferation, diminished effector function of CAR T cells, and an immunosuppressive tumor microenvironment (TME). In this study, we utilized The Cancer Genome Atlas database to identify key chemokines (CCL4, CCL5, and CCR5) associated with T cell infiltration across various solid tumor types. The CCL4/CCL5-CCR5 axis emerged as significantly correlated with the presence of T cells within tumors, and enhancing the expression of CCR5 in CAR T cells bolstered their migratory capacity. Furthermore, single-cell immunoprofiling of tumor tissues revealed that macrophages within the TME primarily interact with CD8+ T cells, impeding their tumor response. However, CAR T cells engineered to secrete Interleukin (IL)-12 can counteract macrophage-mediated immunosuppression and augment T cell functionality. To address these obstacles, we employed esophageal carcinoma as a model to develop mesothelin-targeted CAR T cells co-expressing CCR5 and IL-12 (CARTmeso-5-12), subsequently assessing their antitumor capabilities in vitro and in vivo. The CARTmeso-5-12 cells demonstrated enhanced tumor infiltration due to overexpression of CCR5, and IL-12 secretion further amplified CAR T cell efficacy by attenuating the suppressive influence of tumor-infiltrating macrophages, thus improving tumor eradication.
    Keywords:  CAR T cells; CCR5; IL-12; Tumor Mircoenvironment
    DOI:  https://doi.org/10.1007/s00262-024-03909-w
  13. Front Immunol. 2024 ;15 1509195
    Angiogenesis and EMT regulators in the tumor microenvironment in lung cancer and immunotherapy.
    Taotao Yan, Jiahai Shi.
      Lung cancer remains the primary cause of cancer-related mortality, with factors such as postoperative tumor recurrence, metastasis, and therapeutic drug resistance exacerbating patient outcomes. Immunotherapy has emerged as a transformative approach, challenging conventional treatment paradigms for lung cancer. Consequently, advancing research in lung cancer immunotherapy is imperative. Recent studies indicate that numerous regulators within the tumor microenvironment (TME) drive tumor angiogenesis and epithelial-mesenchymal transition (EMT); these processes are interdependent, reciprocal, and collectively contribute to tumor progression. Tumor angiogenesis not only supplies adequate oxygen and nutrients for cellular proliferation but also establishes pathways facilitating tumor metastasis and creating hypoxic regions that foster drug resistance. Concurrently, EMT enhances metastatic potential and reinforces drug-resistance genes within tumor cells, creating a reciprocal relationship with angiogenesis. This interplay ultimately results in tumor invasion, metastasis, and therapeutic resistance. This paper reviews key regulators of angiogenesis and EMT, examining their impact on lung cancer immunotherapy and progression, and investigates whether newly identified regulators could influence lung cancer treatment, thus offering valuable insights for developing future therapeutic strategies.
    Keywords:  EMT; TME; angiogenesis; immunotherapy; lung cancer
    DOI:  https://doi.org/10.3389/fimmu.2024.1509195
  14. World J Stem Cells. 2024 Dec 26. 16(12): 1110-1114
    Interplay and therapeutic implications of colorectal cancer stem cells, tumor microenvironment, and gut microbiota.
    Hui Zhang, Bo-Tao Xu, Di-Ping Luo, Tie-Fei He.
      This article discusses the interplay between colorectal cancer (CRC) stem cells, tumor microenvironment (TME), and gut microbiota, emphasizing their dynamic roles in cancer progression and treatment resistance. It highlights the adaptability of CRC stem cells, the bidirectional influence of TME, and the multifaceted impact of gut microbiota on CRC. The manuscript proposes innovative therapeutic strategies focusing on these interactions, advocating for a shift towards personalized and ecosystem-targeted treatments in CRC. The conclusion underscores the importance of continued research in these areas for developing effective, personalized therapies.
    Keywords:  Cancer ecosystem; Colorectal cancer; Gut microbiota; Personalized medicine; Research advancements; Stem cells; Therapeutic strategies; Treatment resistance; Tumor microenvironment
    DOI:  https://doi.org/10.4252/wjsc.v16.i12.1110
  15. Theranostics. 2025 ;15(1): 155-188
    Metabolism of cancer cells and immune cells in the initiation, progression, and metastasis of cancer.
    Mingxia Jiang, Huapan Fang, Huayu Tian.
      The metabolism of cancer and immune cells plays a crucial role in the initiation, progression, and metastasis of cancer. Cancer cells often undergo metabolic reprogramming to sustain their rapid growth and proliferation, along with meeting their energy demands and biosynthetic needs. Nevertheless, immune cells execute their immune response functions through the specific metabolic pathways, either to recognize, attack, and eliminate cancer cells or to promote the growth or metastasis of cancer cells. The alteration of cancer niches will impact the metabolism of both cancer and immune cells, modulating the survival and proliferation of cancer cells, and the activation and efficacy of immune cells. This review systematically describes the key characteristics of cancer cell metabolism and elucidates how such metabolic traits influence the metabolic behavior of immune cells. Moreover, this article also highlights the crucial role of immune cell metabolism in anti-tumor immune responses, particularly in priming T cell activation and function. By comprehensively exploring the metabolic crosstalk between cancer and immune cells in cancer niche, the aim is to discover novel strategies of cancer immunotherapy and provide effective guidance for clinical research in cancer treatment. In addition, the review also discusses current challenges such as the inadequacy of relevant diagnostic technologies and the issue of multidrug resistance, and proposes potential solutions including bolstering foundational cancer research, fostering technological innovation, and implementing precision medicine approaches. In-depth research into the metabolic effects of cancer niches can improve cancer treatment outcomes, prolong patients' survival period and enhance their quality of life.
    Keywords:  Anti-tumor immune responses; Cancer immunotherapy; Cancer niches; Metabolic reprogramming; Metabolism of cancer and immune cells
    DOI:  https://doi.org/10.7150/thno.103376
  16. Nat Commun. 2025 Jan 02. 16(1): 262
    Inhalable nanovesicles loaded with a STING agonist enhance CAR-T cell activity against solid tumors in the lung.
    Tianchuan Zhu, Yuchen Xiao, Zhenxing Chen, Hanxi Ding, Shoudeng Chen, Guanmin Jiang, Xi Huang.
      Suppression of chimeric antigen receptor-modified T (CAR-T) cells by the immunosuppressive tumor microenvironment remains a major barrier to their efficacy against solid tumors. To address this, we develop an anti-PD-L1-expressing nanovesicle loaded with the STING agonist cGAMP (aPD-L1 NVs@cGAMP) to remodel the tumor microenvironment and thereby enhance CAR-T cell activity. Following pulmonary delivery, the nanovesicles rapidly accumulate in the lung and selectively deliver STING agonists to PD-L1-overexpressing cells via the PD-1/PD-L1 interaction. This targeted delivery effectively avoids the systemic inflammation and poor cellular uptake that plague free STING agonists. Internalized STING agonists trigger STING signaling and induce interferon responses, which diminish immunosuppressive cell populations such as myeloid-derived suppressor cells in the tumor microenvironment and promote CAR-T cell infiltration. Importantly, the anti-PD-L1 single chain variable fragment on the nanovesicle surface blocks PD-L1 upregulation induced by STING agonists and prevents CAR-T cell exhaustion. In both orthotopic lung cancer and lung metastasis model, combined therapy with CAR-T cells and aPD-L1 NVs@cGAMP potently inhibits tumor growth and prevents recurrence. Therefore, aPD-L1 NVs@cGAMP is expected to serve as an effective CAR-T cell enhancer to improve the efficacy of CAR-T cells against solid tumors.
    DOI:  https://doi.org/10.1038/s41467-024-55751-4
  17. Nat Commun. 2025 Jan 02. 16(1): 333
    The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment.
    Tian Lan, Fengwei Gao, Yunshi Cai, Yinghao Lv, Jiang Zhu, Hu Liu, Sinan Xie, Haifeng Wan, Haorong He, Kunlin Xie, Chang Liu, Hong Wu.
      Metabolic reprogramming fuels cancer cell metastasis and remodels the immunosuppressive tumor microenvironment (TME). We report here that circPETH, a circular RNA (circRNA) transported via extracellular vesicles (EVs) from tumor-associated macrophages (TAMs) to hepatocellular carcinoma (HCC) cells, facilitates glycolysis and metastasis in recipient HCC cells. Mechanistically, circPETH-147aa, encoded by circPETH in an m6A-driven manner, promotes PKM2-catalyzed ALDOA-S36 phosphorylation via the MEG pocket. Furthermore, circPETH-147aa impairs anti-HCC immunity by increasing HuR-dependent SLC43A2 mRNA stability and driving methionine and leucine deficiency in cytotoxic CD8+ T cells. Importantly, through virtual and experimental screening, we find that a small molecule, Norathyriol, is an effective inhibitor that targets the MEG pocket on the circPETH-147aa surface. Norathyriol reverses circPETH-147aa-facilitated acquisition of metabolic and metastatic phenotypes by HCC cells, increases anti-PD1 efficacy, and enhances cytotoxic CD8+ T-cell function. Here we show that Norathyriol is a promising anti-HCC agent that contributes to attenuating the resistance of advanced HCC to immune checkpoint blocker (ICB) therapies.
    DOI:  https://doi.org/10.1038/s41467-024-55577-0
  18. Front Immunol. 2024 ;15 1489679
    Activated hepatic stellate cell-derived small extracellular vesicles facilitate M2 macrophage polarization and hepatoma progression via miR-27a-3p.
    Yufeng Sun, Xiaoqian He, Jiayi Han, Wenxuan Yin, Haichen Wang, Jing Li, Weiqi Liu, Xingwang Kuai, Jiaying Lv, Juling Ji.
      The progression of hepatoma is heavily influenced by the microenvironment. Tumor-associated macrophages (TAMs) are considered to play a critical role in the tumor microenvironment (TME) and increase the aggressiveness of hepatoma. The activation of hepatic stellate cells (HSCs) is involved in hepatoma progression, and accumulating evidence demonstrates a change in microRNA (miRNA) expression during HSC activation. Therefore, the potential roles of HSCs-related miRNAs in macrophage differentiation and hepatoma progression deserve to be explored. The present study aimed to investigate the effects of miRNAs carried by small extracellular vesicles (sEVs) released by activated HSCs on hepatoma progression. The results indicated that miR-27a-3p was significantly upregulated in cells and corresponding sEVs during the activation of primary rat HSCs and human HSC line-LX2 cells. Furthermore, miR-27a-3p contributed to the proliferation and migration of hepatoma cells and promoted M2 polarization of macrophage. HSC-sEVs overexpressing miR-27a-3p can directly facilitate tumor progression and modulate macrophage polarization, indirectly contributing to hepatoma progression. Finally, Sprouty2 (SPRY2) was verified to be the target gene of miR-27a-3p. In conclusion, activated HSC-derived sEVs with high levels of miR-27a-3p might induce M2 macrophage polarization and promote hepatoma progression, providing new insights into the mechanism of hepatoma progression.
    Keywords:  extracellular vesicles; hepatic stellate cell; hepatoma; miRNA-27a-3p; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2024.1489679
  19. Aging Dis. 2024 Dec 31.
    Senescent Macrophages and the Lung Cancer Microenvironment: A New Perspective on Tumor Immune Evasion.
    Lexin Qin, Tingting Liang, Xinyu Zhu, Wentao Hu, Bo Li, Meidan Wei, Jiaxin Zhang, Jianxiang Li, Jin Wang.
      Lung cancer treatment is evolving, and the role of senescent macrophages in tumor immune evasion has become a key focus. This study explores how senescent macrophages interact with lung cancer cells, contributing to tumor progression and immune dysfunction. As aging impairs macrophage functions, including phagocytosis and metabolic signaling, it promotes chronic inflammation and cancer development. p16INK4a-positive macrophages are common in aged mice, and their clearance slows tumor growth, suggesting these cells support tumor proliferation and immune evasion. Targeting the senescence-associated secretory phenotype (SASP) and reprogramming senescent macrophages offers potential therapeutic benefits, including reversing immune aging and boosting anti-tumor immunity. However, translating these findings into clinical practice requires further molecular understanding and rigorous clinical trials.
    DOI:  https://doi.org/10.14336/AD.2024.1404
  20. Int J Colorectal Dis. 2024 Dec 28. 40(1): 1
    Advancements in immunotherapy for colorectal cancer treatment: a comprehensive review of strategies, challenges, and future prospective.
    Vaishak Kaviyarasan, Alakesh Das, Dikshita Deka, Biki Saha, Antara Banerjee, Neeta Raj Sharma, Asim K Duttaroy, Surajit Pathak.
       PURPOSE: Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Metastatic colorectal cancer (mCRC) continues to present significant challenges, particularly in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors. This narrative review aims to provide recent developments in immunotherapy for CRC treatment, focusing on its efficacy and challenges.
    METHODS: This review discussed the various immunotherapeutic strategies for CRC treatment, including immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1, combination therapies involving ICIs with other modalities, chimeric antigen receptor T-cell (CAR-T) cell therapy, and cancer vaccines. The role of the tumor microenvironment and immune evasion mechanisms was also explored to understand their impact on the effectiveness of these therapies.
    RESULTS: This review provides a comprehensive update of recent advancements in immunotherapy for CRC, highlighting the potential of various immunotherapeutic approaches, including immune checkpoint inhibitors, combination therapies, CAR-T therapy, and vaccination strategies. The results of checkpoint inhibitors, particularly in patients with MSI-H/dMMR tumors, which have significant improvements in survival rates have been observed. Furthermore, this review also addresses the challenges faced in treating pMMR/MSS CRC, which remains resistant to immunotherapy.
    CONCLUSION: Immunotherapy plays a significant role in the treatment of CRC, particularly in patients with MSI-H/dMMR tumors. However, many challenges remain, especially in treating pMMR/MSS CRC. This review discussed the need for further research into combination therapies, biomarker development, CAR-T cell therapy, and a deeper understanding of immune evasion mechanisms for CRC treatment.
    Keywords:  Colorectal cancer; Diagnosis; Immune checkpoint inhibitors; Immune system; Immunotherapy; Therapeutics
    DOI:  https://doi.org/10.1007/s00384-024-04790-w
  21. Hum Immunol. 2024 Dec 27. pii: S0198-8859(24)00489-0. [Epub ahead of print]86(1): 111226
    Shedding light on the role of complement C4 activation in cancer.
    Darin Cheung, Mohammad Ali Hassan, Tri Huynh, Xiaodong Feng, Hongbin Wang.
      Complement C4 is a key component in the activation of classical and lectin complement pathways, which are observed in both animal tumor models and cancer patients. While its role in autoimmune disorders has been extensively studied, the functions of complement C4 and its activation in cancer have received inadequate consideration. Recent studies have detected C4 activation in animal tumor models and cancer patients, with its fragment C4d found in cancer tissues and lymph nodes. Elevated C4d levels could be a useful biomarker for detecting various cancers. This review aims to summarize recent developments on the role of complement C4 activation in promoting an immunosuppressive tumor microenvironment, thereby supporting tumor progression and metastasis; C4d as a biomarker; and its potential as a target for cancer immunotherapy. We also conduct a critical evaluation of methods used to measure complement C4 and its activation products, highlighting possible pitfalls and areas for improvement in existing research.
    Keywords:  Biomarker; C4d; Cancer immunotherapy; Complement C4
    DOI:  https://doi.org/10.1016/j.humimm.2024.111226
  22. Int J Pharm. 2024 Dec 31. pii: S0378-5173(24)01390-5. [Epub ahead of print] 125156
    Multi-drug sequential release systems: Construction and application for synergistic tumor treatment.
    Boyuan Yang, Huijuan Liang, Jiahao Xu, Yanchi Liu, Sha Ma, Yuqiu Li, Chengxiao Wang.
      In tumor treatment, the sequence and timing of drug action have a large influence on therapeutic efficacy. Multi-drug sequential release systems (MDSRS) enable the sequential and/or on-demand release of multiple drugs following the single administration of a therapeutic agent. Several researchers have explored MDSRS, providing fresh strategies for synergistic cancer therapy. This review article first introduces the main characteristics of MDSRS. It then elaborates on the design principles of MDSRS. Subsequently, it summarizes the various structures of carriers used for constructing MDSRS, including core-shell structure, Layer-by-layer structure, Janus structure and hydrogel. Next, through specific examples, the article emphasizes the application of MDSRS in cancer treatment, focusing on their role in remodeling the tumor microenvironment (TME) and enhancing therapeutic effects through multiple mechanisms. Finally, the article discusses the current limitations and challenges of these systems and proposes potential future solutions. Overall, this review underscores the importance of the sequence and timing of drug therapy in cancer treatment, providing valuable theoretical and technical guidance for pharmaceutical research.
    Keywords:  Multi-drug; Nanotechnology; Sequential release; Synergistic treatment; Tumor
    DOI:  https://doi.org/10.1016/j.ijpharm.2024.125156
  23. Biomaterials. 2024 Dec 27. pii: S0142-9612(24)00598-2. [Epub ahead of print]317 123062
    Black phosphorus nanosheets activate tumor immunity of glioblastoma by modulating the expression of the immunosuppressive molecule PD-L1.
    Yue Xiong, Chao He, Junyang Qi, Meimei Xiong, Shuna Liu, Jingxin Zhao, Yuzhen Li, Gan Liu, Wenbin Deng.
      The tumor microenvironment in glioblastoma (GBM) is characterized by a pronounced immunosuppressive state, which significantly hampers tumor treatment and contributes to treatment resistance. While our previous research established that black phosphorus nanosheets (BPNS) inhibited glioblastoma cell migration and invasion, the impact of BPNS on the anti-tumor-associated immune mechanism remains unexplored. This study firstly investigated whether BPNS could modulate the tumor microenvironment through immunotherapy and elucidated the underlying mechanisms. We used a subcutaneous mouse model of GBM, which evaded immune surveillance to evaluate BPNS effects on immune cells within the tumor microenvironment. Our results demonstrated that BPNS significantly enhanced the tumor-suppressive microenvironment, reactivating immune cells' cytotoxicity against tumor cells. Moreover, further analysis revealed that BPNS counteracted the immunosuppressive state by reducing the expression of the immunosuppressive molecule PD-L1 in tumor cells, leading to an anti-tumor effect. Mechanistically, BPNS reduced PD-L1 expression through two main pathways: by inducing autophagy via binding to the HSP90 protein, leading to PD-L1 degradation through the autophagy pathway, and by inhibiting the PI3K-AKT signaling pathway, which reduced PD-L1 mRNA levels. This study expands the understanding of BPNS biological activity and suggests new strategies for utilizing BPNS as an adjuvant in immunotherapy.
    Keywords:  Autophagy; Black phosphorus nanosheets; Glioblastoma; HSP90; Immune reactivation; PD-L1; PI3K-AKT signaling pathway
    DOI:  https://doi.org/10.1016/j.biomaterials.2024.123062
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