bims-flamet 2024-06-02 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–06–02
thirty-two papers selected by
Peio Azcoaga, Biodonostia HRI

Erratum: New insights into the role of macrophages in cancer immunotherapy.
A novel insight into cancer therapy: Lipid metabolism in tumor-associated macrophages.
Exploring the interplay between triple-negative breast cancer stem cells and tumor microenvironment for effective therapeutic strategies.
Targeting metabolism to enhance immunotherapy within tumor microenvironment.
Targeting LxCxE cleft pocket of retinoblastoma protein in M2 macrophages inhibits ovarian cancer progression.
Targeting senescent cells to reshape the tumor microenvironment and improve anticancer efficacy.
Crosstalk between the nervous system and tumor microenvironment: Functional aspects and potential therapeutic strategies.
Erratum to: Anti-IL-8 monoclonal antibodies inhibits the autophagic activity and cancer stem cells maintenance within breast cancer tumor microenvironment.
Immunosuppressive regulatory cells in cancer immunotherapy: restrain or modulate?
CXCL10 and IL15 co-expressing chimeric antigen receptor T cells enhance anti-tumor effects in gastric cancer by increasing cytotoxic effector cell accumulation and survival.
Protocol to quantify immune cell distribution from the vasculature to the glioma microenvironment on sequential immunofluorescence multiplex images.
Revolutionizing Cancer Treatment: Harnessing the Power of Mesenchymal Stem Cells for Precise Targeted Therapy in the Tumor Microenvironment.
Thetumor microenvironment'sinpancreatic cancer:Effects onimmunotherapy successandnovel strategiestoovercomethehostile environment.
The inhibitory effect of adenosine on tumor adaptive immunity and intervention strategies.
Bioconjugated Antibody-Trojan Immune Converter Enhance Cancer Immunotherapy with Minimized Toxicity by Programmed Two-Step Immunomodulation of Myeloid Cells.
The synergistic immunotherapeutic impact of engineered CAR-T cells with PD-1 blockade in lymphomas and solid tumors: a systematic review.
Hypoxia-inducible factor in breast cancer: role and target for breast cancer treatment.
Advances in nano-immunotherapy for hematological malignancies.
Unveiling the intratumoral microbiota within cancer landscapes.
Human 3D ovarian cancer models reveal malignant cell intrinsic and extrinsic factors that influence CAR T cell activity.
Spatial interaction and functional status of CD68+SHP2+ macrophages in tumor microenvironment correlate with overall survival of NSCLC.
Enhancing immunotherapy outcomes by targeted remodeling of the tumor microenvironment via combined cGAS-STING pathway strategies.
Netrin G1 Ligand is a new stromal immunomodulator that promotes pancreatic cancer.
Intra-tumoral administration of CHST15 siRNA remodels tumor microenvironment and augments tumor-infiltrating T cells in pancreatic cancer.
Microbes in the tumor microenvironment: New additions to break the tumor immunotherapy dilemma.
Editorial: Tumor metabolic microenvironment: one man's meat is another man's poison.
Characterization of a Trispecific PD-L1 Blocking Antibody That Exhibits EGFR-Conditional 4-1BB Agonist Activity.
Branched glycopolymer prodrug-derived nanoassembly combined with a STING agonist activates an immuno-supportive status to boost anti-PD-L1 antibody therapy.
Extracellular vesicles mediated gastric cancer immune response: tumor cell death or immune escape?
Neutrophil Extracellular Traps in Breast Cancer: Roles in Metastasis and Beyond.
Cellular collusion: cracking the code of immunosuppression and chemo resistance in PDAC.
Nerve-tumor crosstalk in tumor microenvironment: From tumor initiation and progression to clinical implications.

Front Immunol. 2024 ;15 1427337

Erratum: New insights into the role of macrophages in cancer immunotherapy.

Frontiers Production Office

  [This corrects the article DOI: 10.3389/fimmu.2024.1381225.].

Keywords:  PD-L1; cancer; immunotherapy; macrophages; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1427337
Int Immunopharmacol. 2024 May 26. pii: S1567-5769(24)00839-7. [Epub ahead of print]135 112319

A novel insight into cancer therapy: Lipid metabolism in tumor-associated macrophages.

Yvxiao Ren, Mingjie Wang, Hanghang Yuan, Zhicheng Wang, Lei Yu.

  The tumor immune microenvironment (TIME) can limit the effectiveness and often leads to significant side effects of conventional cancer therapies. Consequently, there is a growing interest in identifying novel targets to enhance the efficacy of targeted cancer therapy. More research indicates that tumor-associated macrophages (TAMs), originating from peripheral blood monocytes generated from bone marrow myeloid progenitor cells, play a crucial role in the tumor microenvironment (TME) and are closely associated with resistance to traditional cancer therapies. Lipid metabolism alterations have been widely recognized as having a significant impact on tumors and their immune microenvironment. Lipids, lipid derivatives, and key substances in their metabolic pathways can influence the carcinogenesis and progression of cancer cells by modulating the phenotype, function, and activity of TAMs. Therefore, this review focuses on the reprogramming of lipid metabolism in cancer cells and their immune microenvironment, in which the TAMs are especially concentrated. Such changes impact TAMs activation and polarization, thereby affecting the tumor cell response to treatment. Furthermore, the article explores the potential of targeting the lipid metabolism of TAMs as a supplementary approach to conventional cancer therapies. It reviews and evaluates current strategies for enhancing efficacy through TAMs' lipid metabolism and proposes new lipid metabolism targets as potential synergistic options for chemo-radiotherapy and immunotherapy. These efforts aim to stimulate further research in this area.

Keywords:  Chemotherapy; Immunotherapy; Lipid metabolism; Radiotherapy; Tumor immune microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.intimp.2024.112319
J Cell Physiol. 2024 May 28.

Exploring the interplay between triple-negative breast cancer stem cells and tumor microenvironment for effective therapeutic strategies.

Zhuoling Zou, Tinglan Luo, Xinyuan Wang, Bin Wang, Qing Li.

  Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic malignancy with poor treatment outcomes. The interaction between the tumor microenvironment (TME) and breast cancer stem cells (BCSCs) plays an important role in the development of TNBC. Owing to their ability of self-renewal and multidirectional differentiation, BCSCs maintain tumor growth, drive metastatic colonization, and facilitate the development of drug resistance. TME is the main factor regulating the phenotype and metastasis of BCSCs. Immune cells, cancer-related fibroblasts (CAFs), cytokines, mesenchymal cells, endothelial cells, and extracellular matrix within the TME form a complex communication network, exert highly selective pressure on the tumor, and provide a conducive environment for the formation of BCSC niches. Tumor growth and metastasis can be controlled by targeting the TME to eliminate BCSC niches or targeting BCSCs to modify the TME. These approaches may improve the treatment outcomes and possess great application potential in clinical settings. In this review, we summarized the relationship between BCSCs and the progression and drug resistance of TNBC, especially focusing on the interaction between BCSCs and TME. In addition, we discussed therapeutic strategies that target the TME to inhibit or eliminate BCSCs, providing valuable insights into the clinical treatment of TNBC.

Keywords:  cancer stem cells; drug resistance; treatment; triple‐negative breast cancer; tumor microenvironment

DOI:  https://doi.org/10.1002/jcp.31278
Acta Pharmacol Sin. 2024 May 29.

Targeting metabolism to enhance immunotherapy within tumor microenvironment.

Xiao-Hui Liang, Xin-Yi Chen, Yue Yan, Ao-Yu Cheng, Jia-Yi Lin, Yi-Xin Jiang, Hong-Zhuan Chen, Jin-Mei Jin, Xin Luan.

  Cancer metabolic reprogramming has been considered an emerging hallmark in tumorigenesis and the antitumor immune response. Like cancer cells, immune cells within the tumor microenvironment or premetastatic niche also undergo extensive metabolic reprogramming, which profoundly impacts anti-tumor immune responses. Numerous evidence has illuminated that immunosuppressive TME and the metabolites released by tumor cells, including lactic acid, Prostaglandin E2 (PGE2), fatty acids (FAs), cholesterol, D-2-Hydroxyglutaric acid (2-HG), adenosine (ADO), and kynurenine (KYN) can contribute to CD8+ T cell dysfunction. Dynamic alterations of these metabolites between tumor cells and immune cells can similarly initiate metabolic competition in the TME, leading to nutrient deprivation and subsequent microenvironmental acidosis, which impedes immune response. This review summarizes the new landscape beyond the classical metabolic pathways in tumor cells, highlighting the pivotal role of metabolic disturbance in the immunosuppressive microenvironment, especially how nutrient deprivation in TME leads to metabolic reprogramming of CD8+ T cells. Likewise, it emphasizes the current therapeutic targets or strategies related to tumor metabolism and immune response, providing therapeutic benefits for tumor immunotherapy and drug development in the future. Cancer metabolic reprogramming has been considered an emerging hallmark in tumorigenesis and the antitumor immune response. Dynamic alterations of metabolites between tumor cells and immune cells initiate metabolic competition in the TME, leading to nutrient deprivation and subsequent microenvironmental acidosis, which impedes immune response.

Keywords:  dynamic interplay; immune response; metabolic reprogramming; targeted strategies; tumor microenvironment

DOI:  https://doi.org/10.1038/s41401-024-01304-w
bioRxiv. 2024 May 14. pii: 2024.05.10.593562. [Epub ahead of print]

Targeting LxCxE cleft pocket of retinoblastoma protein in M2 macrophages inhibits ovarian cancer progression.

Evgenii N Tcyganov, Taekyoung Kwak, Xue Yang, Adi Narayana Reddy Poli, Colin Hart, Avishek Bhuniya, Joel Cassel, Andrew Kossenkov, Noam Auslander, Lily Lu, Paridhima Sharma, Maria De Grecia Cauti Mendoza, Dmitry Zhigarev, Mark Gregory Cadungog, Stephanie Jean, Sudeshna Chatterjee-Paer, David Weiner, Laxminarasimha Donthireddy, Bryan Bristow, Rugang Zhang, Vladimir A Tyurin, Yulia Y Tyurina, Hülya Bayir, Valerian E Kagan, Joseph M Salvino, Luis J Montaner.

Ovarian cancer remains a major health threat with limited treatment options available. It is characterized by immunosuppressive tumor microenvironment (TME) maintained by tumor- associated macrophages (TAMs) hindering anti-tumor responses and immunotherapy efficacy. Here we show that targeting retinoblastoma protein (Rb) by disruption of its LxCxE cleft pocket, causes cell death in TAMs by induction of ER stress, p53 and mitochondria-related cell death pathways. A reduction of pro-tumor Rb high M2-type macrophages from TME in vivo enhanced T cell infiltration and inhibited cancer progression. We demonstrate an increased Rb expression in TAMs in women with ovarian cancer is associated with poorer prognosis. Ex vivo, we show analogous cell death induction by therapeutic Rb targeting in TAMs in post-surgery ascites from ovarian cancer patients. Overall, our data elucidates therapeutic targeting of the Rb LxCxE cleft pocket as a novel promising approach for ovarian cancer treatment through depletion of TAMs and re-shaping TME immune landscape.
Statement of significance: Currently, targeting immunosuppressive myeloid cells in ovarian cancer microenvironment is the first priority need to enable successful immunotherapy, but no effective solutions are clinically available. We show that targeting LxCxE cleft pocket of Retinoblastoma protein unexpectedly induces preferential cell death in M2 tumor-associated macrophages. Depletion of immunosuppressive M2 tumor-associated macrophages reshapes tumor microenvironment, enhances anti-tumor T cell responses, and inhibits ovarian cancer. Thus, we identify a novel paradoxical function of Retinoblastoma protein in regulating macrophage viability as well as a promising target to enhance immunotherapy efficacy in ovarian cancer.

DOI: https://doi.org/10.1101/2024.05.10.593562
Semin Cancer Biol. 2024 May 27. pii: S1044-579X(24)00036-1. [Epub ahead of print]

Targeting senescent cells to reshape the tumor microenvironment and improve anticancer efficacy.

Birong Jiang, Wei Zhang, Xuguang Zhang, Yu Sun.

  Cancer is daunting pathology with remarkable breadth and scope, spanning genetics, epigenetics, proteomics, metalobomics and cell biology. Cellular senescence represents a stress-induced and essentially irreversible cell fate associated with aging and various age-related diseases, including malignancies. Senescent cells are characterized of morphologic alterations and metabolic reprogramming, and develop a highly active secretome termed as the senescence-associated secretory phenotype (SASP). Since the first discovery, senescence has been understood as an important barrier to tumor progression, as its induction in pre-neoplastic cells limits carcinogenesis. Paradoxically, senescent cells arising in the tumor microenvironment (TME) contribute to tumor progression, including augmented therapeutic resistance. In this article, we define typical forms of senescent cells commonly observed within the TME and how senescent cells functionally remodel their surrounding niche, affect immune responses and promote cancer evolution. Furthermore, we highlight the recently emerging pipelines of senotherapies particularly senolytics, which can selectively deplete senescent cells from affected organs in vivo and impede tumor progression by restoring therapeutic responses and securing anticancer efficacies. Together, co-targeting cancer cells and their normal but senescent counterparts in the TME holds the potential to achieve increased therapeutic benefits and restrained disease relapse in future clinical oncology.

Keywords:  senescence-associated secretory phenotype; senescent cell; senolytics; senotherapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.semcancer.2024.05.002
Cancer Lett. 2024 May 24. pii: S0304-3835(24)00380-X. [Epub ahead of print]594 216986

Crosstalk between the nervous system and tumor microenvironment: Functional aspects and potential therapeutic strategies.

Lei Wang, Jingjing Ge, Huiqiong Han, Yongxu Jia, Yanru Qin.

  Recent advancements in understanding the tumor microenvironment (TME) have highlighted the critical role of the nervous system in cancer progression. This review comprehensively examines how the nervous system influences various aspects of tumorigenesis, including growth, motility, immune response, angiogenesis, and the behavior of cancer-associated fibroblasts (CAFs). We delineate the neurodevelopmental mechanisms associated with cancer, such as the secretion of neurotrophins and exosomes by cancer cells. Furthermore, we explore the emerging therapeutic strategy of targeting nerves associated with tumors. Evidence supporting this approach includes studies demonstrating direct tumor growth inhibition, enhanced efficacy of immunotherapy when combined with nervous system-modulating drugs, and the suppression of tumor blood vessel formation through nerve targeting. Finally, we discuss the current challenges in this field and emphasize the need for further exploration within cancer neuroscience.

Keywords:  Angiogenesis; Immunity; Nervous system; Therapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2024.216986
Breast Dis. 2024 ;43(1): 157

Erratum to: Anti-IL-8 monoclonal antibodies inhibits the autophagic activity and cancer stem cells maintenance within breast cancer tumor microenvironment.

Seham Abou Shousha, Eman M Osman, Suzan Baheeg, Yasmine Shahine.

DOI: https://doi.org/10.3233/BD-241111
Hum Cell. 2024 May 30.

Immunosuppressive regulatory cells in cancer immunotherapy: restrain or modulate?

Yan Wu, Dongfeng Chen, Yang Gao, Qinggang Xu, Yang Zhou, Zhong Ni, Manli Na.

  Immunosuppressive regulatory cells (IRCs) play important roles in negatively regulating immune response, and are mainly divided into myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Large numbers of preclinical and clinical studies have shown that inhibition or reduction of IRCs could effectively elevate antitumor immune responses. However, several studies also reported that excessive inhibition of IRCs function is one of the main reasons causing the side effects of cancer immunotherapy. Therefore, the reasonable regulation of IRCs is crucial for improving the safety and efficiency of cancer immunotherapy. In this review, we summarised the recent research advances in the cancer immunotherapy by regulating the proportion of IRCs, and discussed the roles of IRCs in regulating tumour immune evasion and drug resistance to immunotherapies. Furthermore, we also discussed how to balance the potential opportunities and challenges of using IRCs to improve the safety of cancer immunotherapies.

Keywords:  Immunoregulatory cells; Immunotherapy; MDSCs; Safety; Tregs

DOI:  https://doi.org/10.1007/s13577-024-01083-w
Oncoimmunology. 2024 ;13(1): 2358590

CXCL10 and IL15 co-expressing chimeric antigen receptor T cells enhance anti-tumor effects in gastric cancer by increasing cytotoxic effector cell accumulation and survival.

Siyue Nie, Yujie Song, Kun Hu, Wei Zu, Fengjiao Zhang, Lixia Chen, Qiang Ma, Zishan Zhou, Shunchang Jiao.

  Chimeric antigen receptor (CAR) T cells have demonstrated outstanding therapeutic success in hematological malignancies. Yet, their efficacy against solid tumors remains constrained due to inadequate infiltration of cytotoxic T and CAR-T cells in the tumor microenvironment (TME), a factor correlated with poor prognosis in patients with solid tumors. To overcome this limitation, we engineered CAR-T cells to secrete CXCL10 and IL15 (10 × 15 CAR-T), which sustain T cell viability and enhance their recruitment, thereby amplifying the long-term cytotoxic capacity of CAR-T cells in vitro. In a xenograft model employing NUGC4-T21 cells, mice receiving 10 × 15 CAR-T cells showed superior tumor reduction and extended survival rates compared to those treated with second-generation CAR-T cells. Histopathological evaluations indicated a pronounced increase in cytotoxic T cell accumulation in the TME post 10 × 15 CAR-T cell treatment. Therefore, the synergistic secretion of CXCL10 and IL15 in these CAR-T cells enhances T cell recruitment and adaptability within tumor tissues, improving tumor control. This approach may offer a promising strategy for advancing CAR-T therapies in the treatment of solid tumors.

Keywords:  CAR-T cells; CXCL10; Claudin18.2; infiltration; interleukin 15

DOI:  https://doi.org/10.1080/2162402X.2024.2358590
STAR Protoc. 2024 May 23. pii: S2666-1667(24)00244-2. [Epub ahead of print]5(2): 103079

Protocol to quantify immune cell distribution from the vasculature to the glioma microenvironment on sequential immunofluorescence multiplex images.

Hinda Najem, Sebastian Pacheco, Joanna Kowal, Dan Winkowski, Jared K Burks, Amy B Heimberger.

  Although myeloid-derived immune cells can be dispersed throughout the tumor microenvironment (TME), anti-tumor effector cells are confined to the perivascular space. Here, we present a protocol to quantify immune cell distribution from tumor vasculature to its glioma microenvironment on sequential immunofluorescence multiplex images. We describe steps for sequential immunofluorescence multiplex staining, image generation, and storage. We then detail the procedures for tissue, vessel, and nuclei segmentation; cell phenotyping; data extraction; and training using RStudio and Spyder.

Keywords:  Cancer; Immunology; Neuroscience

DOI:  https://doi.org/10.1016/j.xpro.2024.103079
Curr Top Med Chem. 2024 May 23.

Revolutionizing Cancer Treatment: Harnessing the Power of Mesenchymal Stem Cells for Precise Targeted Therapy in the Tumor Microenvironment.

Shahram Taeb, Davoud Rostamzadeh, Seyed Mohammad Amini, Mohamad Rahmati, Mostafa Golshekan, Mahmoud Abedinzadeh, Elham Ahmadi, Singh Neha, Masoud Najafi.

  In recent years, mesenchymal stem cells (MSCs) have emerged as promising anti-- cancer mediators with the potential to treat several cancers. MSCs have been modified to produce anti-proliferative, pro-apoptotic, and anti-angiogenic molecules that could be effective against a variety of malignancies. Additionally, customizing MSCs with cytokines that stimulate pro-tumorigenic immunity or using them as vehicles for traditional chemical molecules with anti-cancer characteristics. Even though the specific function of MSCs in tumors is still challenged, promising outcomes from preclinical investigations of MSC-based gene therapy for a variety of cancers inspire the beginning of clinical trials. In addition, the tumor microenvironment (TME) could have a substantial influence on normal tissue stem cells, which can affect the treatment outcomes. To overcome the complications of TME in cancer development, MSCs could provide some signs of hope for converting TME into unequivocal therapeutic tools. Hence, this review focuses on engineered MSCs (En-MSCs) as a promising approach to overcoming the complications of TME.

Keywords:  Angiogenesis.; Cancer; Cytokines; Engineered MSCs (En-MSCs); Mesenchymal stem cells (MSCs); Stem cells; Tumor microenvironment (TME)

DOI:  https://doi.org/10.2174/0115680266299112240514103048
Pathol Res Pract. 2024 May 27. pii: S0344-0338(24)00281-4. [Epub ahead of print]259 155370

Thetumor microenvironment'sinpancreatic cancer:Effects onimmunotherapy successandnovel strategiestoovercomethehostile environment.

Jan Sören Eichhorn, Jim Petrik.

  Cancer is a significant global health issue that poses a considerable burden on both patients and healthcare systems. Many different types of cancers exist that often require unique treatment approaches and therapies. A hallmark of tumor progression is the creation of an immunosuppressive environment, which poses complex challenges for current treatments. Amongst the most explored characteristics is a hypoxic environment, high interstitial pressure, and immunosuppressive cells and cytokines. Traditional cancer treatments involve radiotherapy, chemotherapy, and surgical procedures. The advent of immunotherapies was regarded as a promising approach with hopes of greatly increasing patients' survival and outcome. Although some success is seen with various immunotherapies, the vast majority of monotherapies are unsuccessful. This review examines how various aspects of the tumor microenvironment (TME) present challenges that impede the success of immunotherapies. Subsequently, we review strategies to manipulate the TME to facilitate the success of immunotherapies.

Keywords:  Immunotherapy; Pancreatic cancer; Therapeutic strategy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.prp.2024.155370
Acta Pharm Sin B. 2024 May;14(5): 1951-1964

The inhibitory effect of adenosine on tumor adaptive immunity and intervention strategies.

Longsheng Wang, Jie Zhang, Wenxin Zhang, Mingming Zheng, Hongjie Guo, Xiaohui Pan, Wen Li, Bo Yang, Ling Ding.

  Adenosine (Ado) is significantly elevated in the tumor microenvironment (TME) compared to normal tissues. It binds to adenosine receptors (AdoRs), suppressing tumor antigen presentation and immune cell activation, thereby inhibiting tumor adaptive immunity. Ado downregulates major histocompatibility complex II (MHC II) and co-stimulatory factors on dendritic cells (DCs) and macrophages, inhibiting antigen presentation. It suppresses anti-tumor cytokine secretion and T cell activation by disrupting T cell receptor (TCR) binding and signal transduction. Ado also inhibits chemokine secretion and KCa3.1 channel activity, impeding effector T cell trafficking and infiltration into the tumor site. Furthermore, Ado diminishes T cell cytotoxicity against tumor cells by promoting immune-suppressive cytokine secretion, upregulating immune checkpoint proteins, and enhancing immune-suppressive cell activity. Reducing Ado production in the TME can significantly enhance anti-tumor immune responses and improve the efficacy of other immunotherapies. Preclinical and clinical development of inhibitors targeting Ado generation or AdoRs is underway. Therefore, this article will summarize and analyze the inhibitory effects and molecular mechanisms of Ado on tumor adaptive immunity, as well as provide an overview of the latest advancements in targeting Ado pathways in anti-tumor immune responses.

Keywords:  Adenosine; Adenosine receptors; Adenosine-generating enzymes; Clinical treatment; Immune escape; Immune suppression; Targeting drugs; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.apsb.2023.12.004
Adv Healthc Mater. 2024 May 21. e2401270

Bioconjugated Antibody-Trojan Immune Converter Enhance Cancer Immunotherapy with Minimized Toxicity by Programmed Two-Step Immunomodulation of Myeloid Cells.

Soyoung Park, Seung Mo Jin, Suhyeon Kim, Ju Hee Cho, JungHyub Hong, Yong-Soo Bae, Yong Taik Lim.

  Current immune checkpoint blockade therapy (ICBT) predominantly targets T cells to harness the antitumor effects of adaptive immune system. However, the effectiveness of ICBT is reduced by immunosuppressive innate myeloid cells in tumor microenvironments (TMEs). Toll-like receptor 7/8 agonists (TLR7/8a) are often used to address this problem because they can reprogram myeloid-derived suppressor cells (MDSCs) and tumor-associated M2 macrophages, and boost dendritic cell (DC)-based T-cell generation; however, the systemic toxicity of TLR7/8a limits its clinical translation. Here, to address this limitation and utilize the effectiveness of TLR7/8a, this work suggests a programmed two-step activation strategy via Antibody-Trojan Immune Converter Conjugates (ATICC) that specifically targets myeloid cells by anti-SIRPα followed by reactivation of transiently inactivated Trojan TLR7/8a after antibody-mediated endocytosis. ATICC blocks the CD47-SIRPα ("don't eat me" signal), enhances phagocytosis, reprograms M2 macrophages and MDSCs, and increases cross-presentation by DCs, resulting in antigen-specific CD8+ T-cell generation in tumor-draining lymph nodes and TME while minimizing systemic toxicity. The local or systemic administration of ATICC improves ICBT responsiveness through reprogramming of the immunosuppressive TME, increased infiltration of antigen-specific CD8+ T cells, and antibody-dependent cellular phagocytosis. These results highlight the programmed and target immunomodulation via ATICC could enhance cancer immunotherapy with minimized systemic toxicities.

Keywords:  antibody conjugate; cancer immunotherapy; immune suppression; targeting myeloid cells; toll‐like receptor agonist

DOI:  https://doi.org/10.1002/adhm.202401270
Front Immunol. 2024 ;15 1389971

The synergistic immunotherapeutic impact of engineered CAR-T cells with PD-1 blockade in lymphomas and solid tumors: a systematic review.

Bibhu Prasad Satapathy, Pooja Sheoran, Rohit Yadav, Dewan Chettri, Dhruba Sonowal, Chinmayee Priyadarsini Dash, Prachi Dhaka, Vivek Uttam, Ritu Yadav, Manju Jain, Aklank Jain.

  Currently, therapies such as chimeric antigen receptor-T Cell (CAR-T) and immune checkpoint inhibitors like programmed cell death protein-1 (PD-1) blockers are showing promising results for numerous cancer patients. However, significant advancements are required before CAR-T therapies become readily available as off-the-shelf treatments, particularly for solid tumors and lymphomas. In this review, we have systematically analyzed the combination therapy involving engineered CAR-T cells and anti PD-1 agents. This approach aims at overcoming the limitations of current treatments and offers potential advantages such as enhanced tumor inhibition, alleviated T-cell exhaustion, heightened T-cell activation, and minimized toxicity. The integration of CAR-T therapy, which targets tumor-associated antigens, with PD-1 blockade augments T-cell function and mitigates immune suppression within the tumor microenvironment. To assess the impact of combination therapy on various tumors and lymphomas, we categorized them based on six major tumor-associated antigens: mesothelin, disialoganglioside GD-2, CD-19, CD-22, CD-133, and CD-30, which are present in different tumor types. We evaluated the efficacy, complete and partial responses, and progression-free survival in both pre-clinical and clinical models. Additionally, we discussed potential implications, including the feasibility of combination immunotherapies, emphasizing the importance of ongoing research to optimize treatment strategies and improve outcomes for cancer patients. Overall, we believe combining CAR-T therapy with PD-1 blockade holds promise for the next generation of cancer immunotherapy.

Keywords:  PD-1; combination immunotherapy; engineered CAR-T cells; immunotherapy; lymphoma; solid tumor

DOI:  https://doi.org/10.3389/fimmu.2024.1389971
Front Immunol. 2024 ;15 1370800

Hypoxia-inducible factor in breast cancer: role and target for breast cancer treatment.

Shijiao Zhi, Chen Chen, Hanlin Huang, Zhengfu Zhang, Fancai Zeng, Shujun Zhang.

  Globally, breast cancer stands as the most prevalent form of cancer among women. The tumor microenvironment of breast cancer often exhibits hypoxia. Hypoxia-inducible factor 1-alpha, a transcription factor, is found to be overexpressed and activated in breast cancer, playing a pivotal role in the anoxic microenvironment by mediating a series of reactions. Hypoxia-inducible factor 1-alpha is involved in regulating downstream pathways and target genes, which are crucial in hypoxic conditions, including glycolysis, angiogenesis, and metastasis. These processes significantly contribute to breast cancer progression by managing cancer-related activities linked to tumor invasion, metastasis, immune evasion, and drug resistance, resulting in poor prognosis for patients. Consequently, there is a significant interest in Hypoxia-inducible factor 1-alpha as a potential target for cancer therapy. Presently, research on drugs targeting Hypoxia-inducible factor 1-alpha is predominantly in the preclinical phase, highlighting the need for an in-depth understanding of HIF-1α and its regulatory pathway. It is anticipated that the future will see the introduction of effective HIF-1α inhibitors into clinical trials, offering new hope for breast cancer patients. Therefore, this review focuses on the structure and function of HIF-1α, its role in advancing breast cancer, and strategies to combat HIF-1α-dependent drug resistance, underlining its therapeutic potential.

Keywords:  angiogenesis; apoptosis and autophagy; breast cancer; drug resistance; hypoxia-inducible factor; invasion and metastasis

DOI:  https://doi.org/10.3389/fimmu.2024.1370800
Exp Hematol Oncol. 2024 May 25. 13(1): 57

Advances in nano-immunotherapy for hematological malignancies.

Jian Xu, Wenqi Liu, Fengjuan Fan, Bo Zhang, Chunyan Sun, Yu Hu.

  Hematological malignancies (HMs) encompass a diverse group of blood neoplasms with significant morbidity and mortality. Immunotherapy has emerged as a validated and crucial treatment modality for patients with HMs. Despite notable advancements having been made in understanding and implementing immunotherapy for HMs over the past decade, several challenges persist. These challenges include immune-related adverse effects, the precise biodistribution and elimination of therapeutic antigens in vivo, immune tolerance of tumors, and immune evasion by tumor cells within the tumor microenvironment (TME). Nanotechnology, with its capacity to manipulate material properties at the nanometer scale, has the potential to tackle these obstacles and revolutionize treatment outcomes by improving various aspects such as drug targeting and stability. The convergence of nanotechnology and immunotherapy has given rise to nano-immunotherapy, a specialized branch of anti-tumor therapy. Nanotechnology has found applications in chimeric antigen receptor T cell (CAR-T) therapy, cancer vaccines, immune checkpoint inhibitors, and other immunotherapeutic strategies for HMs. In this review, we delineate recent developments and discuss current challenges in the field of nano-immunotherapy for HMs, offering novel insights into the potential of nanotechnology-based therapeutic approaches for these diseases.

Keywords:  Cancer vaccine; Chimeric antigen receptor T cell therapy; Hematological malignancies; Immune checkpoint inhibitors; Nano-immunotherapy; Nanoparticle; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40164-024-00525-3
iScience. 2024 Jun 21. 27(6): 109893

Unveiling the intratumoral microbiota within cancer landscapes.

Shusheng Che, Zhiyong Yan, Yugong Feng, Hai Zhao.

  Recent advances in cancer research have unveiled a significant yet previously underappreciated aspect of oncology: the presence and role of intratumoral microbiota. These microbial residents, encompassing bacteria, fungi, and viruses within tumor tissues, have been found to exert considerable influence on tumor development, progression, and the efficacy of therapeutic interventions. This review aims to synthesize these groundbreaking discoveries, providing an integrated overview of the identification, characterization, and functional roles of intratumoral microbiota in cancer biology. We focus on elucidating the complex interactions between these microorganisms and the tumor microenvironment, highlighting their potential as novel biomarkers and therapeutic targets. The purpose of this review is to offer a comprehensive understanding of the microbial dimension in cancer, paving the way for innovative approaches in cancer diagnosis and treatment.

Keywords:  Cancer; Microbiology; Microbiome; Microenvironment

DOI:  https://doi.org/10.1016/j.isci.2024.109893
Cancer Res. 2024 May 31.

Human 3D ovarian cancer models reveal malignant cell intrinsic and extrinsic factors that influence CAR T cell activity.

Joash D Joy, Beatrice Malacrida, Florian Laforets, Panoraia Kotantaki, Eleni Maniati, Ranjit Manchanda, Alessandro Annibaldi, Sarah Hopkins, Ianire Garrobo-Calleja, Julien Gautrot, Frances R Balkwill.

In vitro preclinical testing of chimeric antigen receptor (CAR) T cells is mostly carried out in monolayer cell cultures. However, alternative strategies are needed to take into account the complexity and the effects of the tumor microenvironment (TME). Here, we describe the modulation of CAR T cell activity by malignant cells and fibroblasts in human 3D in vitro cell models of increasing complexity. In models combining mucin-1 (MUC1) and TnMUC1 CAR T cells with human high-grade serous ovarian cancer (HGSOC) cell spheroids, malignant cell-intrinsic resistance to CAR T cell killing was due to defective death receptor signaling involving TNFα. Adding primary human fibroblasts to spheroids unexpectedly increased the ability of CAR T cells to kill resistant malignant cells as CCL2 produced by fibroblasts activated CCR2/4+ CAR T cells. However, culturing malignant cells and fibroblasts in collagen gels engendered production of a dense extracellular matrix that impeded CAR T cell activity in a TGFβ-dependent manner. A vascularized microfluidic device was developed that allowed CAR T cells to flow through the vessels and penetrate the gels in a more physiological way, killing malignant cells in a TNFα-dependent manner. Complex 3D human cell models may provide an efficient way of screening multiple cytotoxic human immune cell constructs while also enabling evaluation of mechanisms of resistance involving cell-cell and cell-matrix interactions, thus accelerating preclinical research on cytotoxic immune cell therapies in solid tumors.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-3007
Front Immunol. 2024 ;15 1396719

Spatial interaction and functional status of CD68+SHP2+ macrophages in tumor microenvironment correlate with overall survival of NSCLC.

Xu Liu, Zengfu Zhang, Jupeng Yuan, Jinming Yu, Dawei Chen.

   Background: Tumor-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumor microenvironment (TME) that can regulate tumor proliferation and support resistance to therapy, constituting promising targets for the development of novel anticancer agents. Our previous results suggest that SHP2 plays a crucial role in reprogramming the phenotype of TAMs. Thus, we hypothesized that SHP2+ TAM may predict the treatment efficacy of non-small cell lung cancer NSCLC patients as a biomarker.
Methods: We analyzed cancer tissue samples from 79 NSCLC patients using multiplex fluorescence (mIF) staining to visualize various SHP-2+ TAM subpopulations (CD68+SHP2+, CD68+CD86+, CD68 + 206+, CD68+ CD86+SHP2+, CD68+ CD206+SHP2+) and T cells (CD8+ Granzyme B +) of immune cells. The immune cells proportions were quantified in the tumor regions (Tumor) and stromal regions (Stroma), as well as in the overall tumor microenvironment (Tumor and Stroma, TME). The analysis endpoint was overall survival (OS), correlating them with levels of cell infiltration or effective density. Cox regression was used to evaluate the associations between immune cell subsets infiltration and OS. Correlations between different immune cell subsets were examined by Spearman's tests.
Results: In NSCLC, the distribution of different macrophage subsets within the TME, tumor regions, and stroma regions exhibited inconsistency. The proportions of CD68+ SHP2+ TAMs (P < 0.05) were higher in tumor than in stroma. And the high infiltration of CD68+SHP2+ TAMs in tumor areas correlated with poor OS (P < 0.05). We found that the expression level of SHP2 was higher in M2-like macrophages than in M1-like macrophages. The CD68+SHP2+ subset proportion was positively correlated with the CD68+CD206+ subset within TME (P < 0.0001), tumor (P < 0.0001) and stroma (P < 0.0001).
Conclusions: The high infiltration of CD68+SHP2+ TAMs predict poor OS in NSCLC. Targeting SHP2 is a potentially effective strategy to inhibit M2-phenotype polarization. And it provides a new thought for SHP2 targeted cancer immunotherapy.

Keywords:  NSCLC; SHP2; os; spatial interaction; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.3389/fimmu.2024.1396719
Front Immunol. 2024 ;15 1399926

Enhancing immunotherapy outcomes by targeted remodeling of the tumor microenvironment via combined cGAS-STING pathway strategies.

Mingqing Huang, Zhuocen Cha, Rui Liu, Mengping Lin, Naif Abdul Gafoor, Tong Kong, Fei Ge, Wenlin Chen.

  Immune checkpoint inhibitors (ICIs) represent a groundbreaking advance in the treatment of malignancies such as melanoma and non-small cell lung cancer, showcasing substantial therapeutic benefits. Nonetheless, the efficacy of ICIs is limited to a small subset of patients, primarily benefiting those with "hot" tumors characterized by significant immune infiltration. The challenge of converting "cold" tumors, which exhibit minimal immune activity, into "hot" tumors to enhance their responsiveness to ICIs is a critical and complex area of current research. Central to this endeavor is the activation of the cGAS-STING pathway, a pivotal nexus between innate and adaptive immunity. This pathway's activation promotes the production of type I interferon (IFN) and the recruitment of CD8+ T cells, thereby transforming the tumor microenvironment (TME) from "cold" to "hot". This review comprehensively explores the cGAS-STING pathway's role in reconditioning the TME, detailing the underlying mechanisms of innate and adaptive immunity and highlighting the contributions of various immune cells to tumor immunity. Furthermore, we delve into the latest clinical research on STING agonists and their potential in combination therapies, targeting this pathway. The discussion concludes with an examination of the challenges facing the advancement of promising STING agonists in clinical trials and the pressing issues within the cGAS-STING signaling pathway research.

Keywords:  cGAS-STING; hot tumor; immune checkpoint inhibitor (ICI); tumor immunology; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1399926
bioRxiv. 2024 May 18. pii: 2024.05.15.594354. [Epub ahead of print]

Netrin G1 Ligand is a new stromal immunomodulator that promotes pancreatic cancer.

Débora B Vendramini-Costa, Ralph Francescone, Janusz Franco-Barraza, Tiffany Luong, Myree Graves, Ariana Musa de Aquino, Nina Steele, Jaye C Gardiner, Sérgio Alexandre Alcantara Dos Santos, Charline Ogier, Emily Malloy, Leila Borghaei, Esteban Martinez, Dmitry I Zhigarev, Yinfei Tan, Hayan Lee, Yan Zhou, Kathy Q Cai, Andres J Klein-Szanto, Huamin Wang, Mark Andrake, Roland L Dunbrack, Kerry Campbell, Edna Cukierman.

Understanding pancreatic cancer biology is fundamental for identifying new targets and for developing more effective therapies. In particular, the contribution of the stromal microenvironment to pancreatic cancer tumorigenesis requires further exploration. Here, we report the stromal roles of the synaptic protein Netrin G1 Ligand (NGL-1) in pancreatic cancer, uncovering its pro-tumor functions in cancer-associated fibroblasts and in immune cells. We observed that the stromal expression of NGL-1 inversely correlated with patients' overall survival. Moreover, germline knockout (KO) mice for NGL-1 presented decreased tumor burden, with a microenvironment that is less supportive of tumor growth. Of note, tumors from NGL-1 KO mice produced less immunosuppressive cytokines and displayed an increased percentage of CD8 + T cells than those from control mice, while preserving the physical structure of the tumor microenvironment. These effects were shown to be mediated by NGL-1 in both immune cells and in the local stroma, in a TGF-β-dependent manner. While myeloid cells lacking NGL-1 decreased the production of immunosuppressive cytokines, NGL-1 KO T cells showed increased proliferation rates and overall polyfunctionality compared to control T cells. CAFs lacking NGL-1 were less immunosuppressive than controls, with overall decreased production of pro-tumor cytokines and compromised ability to inhibit CD8 + T cells activation. Mechanistically, these CAFs downregulated components of the TGF-β pathway, AP-1 and NFAT transcription factor families, resulting in a less tumor-supportive phenotype. Finally, targeting NGL-1 genetically or using a functionally antagonistic small peptide phenocopied the effects of chemotherapy, while modulating the immunosuppressive tumor microenvironment (TME), rather than eliminating it. We propose NGL-1 as a new local stroma and immunomodulatory molecule, with pro-tumor roles in pancreatic cancer.
Statement of Significance: Here we uncovered the pro-tumor roles of the synaptic protein NGL-1 in the tumor microenvironment of pancreatic cancer, defining a new target that simultaneously modulates tumor cell, fibroblast, and immune cell functions. This study reports a new pathway where NGL-1 controls TGF-β, AP-1 transcription factor members and NFAT1, modulating the immunosuppressive microenvironment in pancreatic cancer. Our findings highlight NGL-1 as a new stromal immunomodulator in pancreatic cancer.

DOI: https://doi.org/10.1101/2024.05.15.594354
Mol Ther Oncol. 2024 Jun 20. 32(2): 200812

Intra-tumoral administration of CHST15 siRNA remodels tumor microenvironment and augments tumor-infiltrating T cells in pancreatic cancer.

Juanjuan Ye, Futoshi Suizu, Keiko Yamakawa, Yuri Mukai, Hiroyuki Yoneyama, Jiro Kondo, Motohiko Kato, Akira Nishiyama, Naohisa Yahagi, Kyuichi Kadota.

  The dense stroma is one cause of poor efficacy of T cell-mediated immunotherapy in pancreatic ductal adenocarcinoma (PDAC). Carbohydrate sulfotransferase 15 (CHST15) is a proteoglycan-synthetic enzyme responsible for remodeling tumor stroma. Intra-tumoral injection of CHST15 small interfering RNA (siRNA) has been shown to increase the tumor-infiltrating T cells (TILs) in patients with unresectable PDAC. However, the mechanism underlying the enhanced accumulation of TILs is not fully explored. Here, we demonstrate that intra-tumoral injection of CHST15 siRNA locally and remotely diminishes myeloid-derived suppressor cells (MDSCs) and enhances TILs in mice. CHST15 was expressed by tumor cells and MDSCs in both tumor and tumor-draining lymph nodes (TDLNs), and CHST15 siRNA repressed stromal density, neutrophil extracellular traps, and Ly6C/G+ MDSCs in vivo. Remarkably, tumor growth inhibition was only observed in the immunocompetent KPC model, which is associated with enhanced TILs. In vitro, CHST15 siRNA significantly downregulated the levels of CHST15 and indoleamine 2,3-dioxygenase mRNA in CD33+ MDSCs derived from human peripheral blood mononuclear cells. These results suggest a dual role for intra-tumorally injected CHST15 siRNA on modulating the tumor immune microenvironment for T cell entry and remotely diminishing CHST15+ MDSCs, decreasing T cell suppression and expanding T cells in the TDLN, ultimately leading to an enhanced accumulation of TILs.

Keywords:  CHST15; MDSCs; MT: Regular Issue; PDAC; T cell; TDLN; carbohydrate sulfotransferase 15; myeloid-derived suppressor cells; oligonucleotide; pancreatic ductal adenocarcinoma; tumor-draining lymph node

DOI:  https://doi.org/10.1016/j.omton.2024.200812
Microbiol Res. 2024 May 24. pii: S0944-5013(24)00178-2. [Epub ahead of print]285 127777

Microbes in the tumor microenvironment: New additions to break the tumor immunotherapy dilemma.

Lujia Zhou, Shiying Fan, Wenjie Zhang, Daorong Wang, Dong Tang.

  Immunotherapies currently used in clinical practice are unsatisfactory in terms of therapeutic response and toxic side effects, and therefore new immunotherapies need to be explored. Intratumoral microbiota (ITM) exists in the tumor environment (TME) and reacts with its components. On the one hand, ITM promotes antigen delivery to tumor cells or provides cross-antigens to promote immune cells to attack tumors. On the other hand, ITM affects the activity of immune cells and stromal cells. We also summarize the dialog pathways by which ITM crosstalks with components within the TME, particularly the interferon pathway. This interaction between ITM and TME provides new ideas for tumor immunotherapy. By analyzing the bidirectional role of ITM in TME and combining it with its experimental and clinical status, we summarized the adjuvant role of ITM in immunotherapy. We explored the potential applications of using ITM as tumor immunotherapy, such as a healthy diet, fecal transplantation, targeted ITM, antibiotics, and probiotics, to provide a new perspective on the use of ITM in tumor immunotherapy.

Keywords:  Immunotherapy; Intratumoral microbiota; Tumor; Tumor environment

DOI:  https://doi.org/10.1016/j.micres.2024.127777
Front Immunol. 2024 ;15 1422624

Editorial: Tumor metabolic microenvironment: one man's meat is another man's poison.

Jing Xu, Haitao Wang, Xiao Liang.



Keywords:  immune responses; immunotherapy; metabolic pathways; metabolic reprogramming; prognostic models; tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fimmu.2024.1422624
Antibodies (Basel). 2024 Apr 24. pii: 34. [Epub ahead of print]13(2):

Characterization of a Trispecific PD-L1 Blocking Antibody That Exhibits EGFR-Conditional 4-1BB Agonist Activity.

Laura Rubio-Pérez, Susana Frago, Marta Compte, Rocío Navarro, Seandean L Harwood, Rodrigo Lázaro-Gorines, Marina Gómez-Rosel, Oana Hangiu, Noelia Silva-Pilipich, Lucía Vanrell, Cristian Smerdou, Luis Álvarez-Vallina.

  Immune checkpoint blockade has changed the treatment paradigm for advanced solid tumors, but the overall response rates are still limited. The combination of checkpoint blockade with anti-4-1BB antibodies to stimulate tumor-infiltrating T cells has shown anti-tumor activity in human trials. However, the further clinical development of these antibodies has been hampered by significant off-tumor toxicities. Here, we generated an anti-4-1BB/EGFR/PD-L1 trispecific antibody consisting of a triple-targeting tandem trimerbody (TT) fused to an engineered silent Fc region. This antibody (IgTT-4E1-S) was designed to combine the blockade of the PD-L1/PD-1 axis with conditional 4-1BB costimulation specifically confined to the tumor microenvironment (TME). The antibody demonstrated simultaneous binding to purified EGFR, PD-L1, and 4-1BB in solution, effective blockade of the PD-L1/PD1 interaction, and potent 4-1BB-mediated costimulation, but only in the presence of EGFR-expressing cells. These results demonstrate the feasibility of IgTT-4E1-S specifically blocking the PD-L1/PD-1 axis and inducing EGFR-conditional 4-1BB agonist activity.

Keywords:  4-1BB costimulation; cancer immunotherapy; epithelial growth factor receptor; immune checkpoint blockade; trispecific antibody

DOI:  https://doi.org/10.3390/antib13020034
Acta Pharm Sin B. 2024 May;14(5): 2194-2209

Branched glycopolymer prodrug-derived nanoassembly combined with a STING agonist activates an immuno-supportive status to boost anti-PD-L1 antibody therapy.

Zhilin Li, Qianfeng Zhang, Zhiqian Li, Long Ren, Dayi Pan, Qiyong Gong, Zhongwei Gu, Hao Cai, Kui Luo.

  Despite the great potential of anti-PD-L1 antibodies for immunotherapy, their low response rate due to an immunosuppressive tumor microenvironment has hampered their application. To address this issue, we constructed a cell membrane-coated nanosystem (mB4S) to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor effect. In this system, Epirubicin (EPI) as an immunogenic cell death (ICD) inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes (STING) agonist was encapsulated into mB4S. After internalization of mB4S, EPI was acidic-responsively released to induce ICD, which was characterized by an increased level of calreticulin (CRT) exposure and enhanced ATP secretion. Meanwhile, diABZI effectively activated the STING pathway. Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells (DCs) and CD8+ T cells, promoting cytokines secretion, up-regulating M1-like tumor-associated macrophages (TAMs) and down-regulating immunosuppressive myeloid-derived suppressor cells (MDSCs). Therefore, this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+ T cells infiltration, creating an immuno-supportive microenvironment, thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.

Keywords:  Epirubicin; Glycopolymer; Immuno-supportive microenvironment; Immunogenic cell death; Immunotherapy; Nanoassembly; Polymer prodrug; STING pathway

DOI:  https://doi.org/10.1016/j.apsb.2024.02.006
Cell Death Dis. 2024 May 30. 15(5): 377

Extracellular vesicles mediated gastric cancer immune response: tumor cell death or immune escape?

Shuo Yang, Shibo Wei, Fang Wei.

Gastric cancer (GC) is a major global health issue, being the fifth most prevalent cancer and the third highest contributor to cancer-related deaths. Although treatment strategies for GC have diversified, the prognosis for advanced GC remains poor. Hence, there is a critical need to explore new directions for GC treatment to enhance diagnosis, treatment, and patient prognosis. Extracellular vesicles (EVs) have emerged as key players in tumor development and progression. Different sources of EVs carry different molecules, resulting in distinct biological functions. For instance, tumor-derived EVs can promote tumor cell proliferation, alter the tumor microenvironment and immune response, while EVs derived from immune cells carry molecules that regulate immune function and possess tumor-killing capabilities. Numerous studies have demonstrated the crucial role of EVs in the development, immune escape, and immune microenvironment remodeling in GC. In this review, we discuss the role of GC-derived EVs in immune microenvironment remodeling and EVs derived from immune cells in GC development. Furthermore, we provide an overview of the potential uses of EVs in immunotherapy for GC.

DOI: https://doi.org/10.1038/s41419-024-06758-8
J Cancer. 2024 ;15(11): 3272-3283

Neutrophil Extracellular Traps in Breast Cancer: Roles in Metastasis and Beyond.

Xi Xu, Xinyu Wang, Zhuomeng Zheng, Yuxuan Guo, Guangchun He, Yian Wang, Shujun Fu, Chanjuan Zheng, Xiyun Deng.

  Despite advances in the treatment of breast cancer, the disease continues to exhibit high global morbidity and mortality. The importance of neutrophils in cancer development has been increasingly recognized. Neutrophil extracellular traps (NETs) are web-like structures released into the extracellular space by activated neutrophils, serving as a potential antimicrobial mechanism for capturing and eliminating microorganisms. The roles played by NETs in cancer development have been a subject of intense research in the last decade. In breast cancer, current evidence suggests that NETs are involved in various stages of cancer development, particularly during metastasis. In this review, we try to provide an updated overview of the roles played by NETs in breast cancer metastasis. These include: 1) facilitating systemic dissemination of cancer cells; 2) promoting cancer-associated inflammation; 3) facilitating cancer-associated thrombosis; 4) facilitating pre-metastatic niche formation; and 5) awakening dormant cancer cells. The translational implications of NETs in breast cancer treatment are also discussed. Understanding the relationship between NETs and breast cancer metastasis is expected to provide important insights for developing new therapeutic strategies for breast cancer patients.

Keywords:  Breast cancer; Neutrophil extracellular trap (NET); Therapeutic target; Tumor immunity; Tumor microenvironment

DOI:  https://doi.org/10.7150/jca.94669
Front Immunol. 2024 ;15 1341079

Cellular collusion: cracking the code of immunosuppression and chemo resistance in PDAC.

Chiara Musiu, Francesca Lupo, Antonio Agostini, Gabriella Lionetto, Michele Bevere, Salvatore Paiella, Carmine Carbone, Vincenzo Corbo, Stefano Ugel, Francesco De Sanctis.

  Despite the efforts, pancreatic ductal adenocarcinoma (PDAC) is still highly lethal. Therapeutic challenges reside in late diagnosis and establishment of peculiar tumor microenvironment (TME) supporting tumor outgrowth. This stromal landscape is highly heterogeneous between patients and even in the same patient. The organization of functional sub-TME with different cellular compositions provides evolutive advantages and sustains therapeutic resistance. Tumor progressively establishes a TME that can suit its own needs, including proliferation, stemness and invasion. Cancer-associated fibroblasts and immune cells, the main non-neoplastic cellular TME components, follow soluble factors-mediated neoplastic instructions and synergize to promote chemoresistance and immune surveillance destruction. Unveiling heterotypic stromal-neoplastic interactions is thus pivotal to breaking this synergism and promoting the reprogramming of the TME toward an anti-tumor milieu, improving thus the efficacy of conventional and immune-based therapies. We underscore recent advances in the characterization of immune and fibroblast stromal components supporting or dampening pancreatic cancer progression, as well as novel multi-omic technologies improving the current knowledge of PDAC biology. Finally, we put into context how the clinic will translate the acquired knowledge to design new-generation clinical trials with the final aim of improving the outcome of PDAC patients.

Keywords:  MDSC (myeloid-derived suppressor cells); PDAC - pancreatic ductal adenocarcinoma; TILs (tumor infiltrating lymphocytes); TME (tumor microenvironment); cancer associated fibroblast (CAF); immunosuppression; immunotherapy

DOI:  https://doi.org/10.3389/fimmu.2024.1341079
Biochim Biophys Acta Rev Cancer. 2024 May 23. pii: S0304-419X(24)00052-0. [Epub ahead of print]1879(4): 189121

Nerve-tumor crosstalk in tumor microenvironment: From tumor initiation and progression to clinical implications.

Zheng Zhang, Zhen Gang Lv, Miao Lu, Haifeng Li, Jiahua Zhou.

  The autonomic nerve system (ANS) innervates organs and tissues throughout the body and maintains functional balance among various systems. Further investigations have shown that excessive activation of ANS not only causes disruption of homeostasis, but also may promote tumor formation. In addition, the dynamic interaction between nerve and tumor cells in the tumor microenvironment also regulate tumor progression. On the one hand, nerves are passively invaded by tumor cells, that is, perineural invasion (PNI). On the other hand, compared with normal tissues, tumor tissues are subject to more abundant innervation, and nerves can influence tumor progression through regulating tumor proliferation, metastasis and drug resistance. A large number of studies have shown that nerve-tumor crosstalk, including PNI and innervation, is closely related to the prognosis of patients, and contributes to the formation of cancer pain, which significantly deteriorates the quality of life for patients. These findings suggest that nerve-tumor crosstalk represents a potential target for anti-tumor therapies and the management of cancer pain in the future. In this review, we systematically describe the mechanism by which nerve-tumor crosstalk regulates tumorigenesis and progression.

Keywords:  Crosstalk; Nerve; Tumor; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2024.189121