bims-flamet 2024-11-10 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–11–10
thirty-one papers selected by
Peio Azcoaga, Biodonostia HRI

Solid cancer-directed CAR T cell therapy that attacks both tumor and immunosuppressive cells via targeting PD-L1.
NF-κB signaling pathway in tumor microenvironment.
Applying metabolic control strategies to engineered T cell cancer therapies.
T cell landscape in the microenvironment of human solid tumors.
Rough neighborhood: Intricacies of cancer stem cells and infiltrating immune cell interaction in tumor microenvironment and potential in therapeutic targeting.
Ferroptosis in Cancer: A new perspective on T cells.
Tissue-Resident Macrophages in Cancer: Friend or Foe?
The complex role of immune cells in antigen presentation and regulation of T-cell responses in hepatocellular carcinoma: progress, challenges, and future directions.
Breaking the shield of solid tumors: a combined approach for enhanced efficacy of CAR-T cells.
Cancer Metabolism: Historical Landmarks, New Concepts, and Opportunities.
Exploring the Interplay between the Warburg Effect and Glucolipotoxicity in Cancer Development: A Novel Perspective on Cancer Etiology.
Hypoxia-Inducible Factor 1-Alpha (HIF-1α) and Cancer: Mechanisms of Tumor Hypoxia and Therapeutic Targeting.
BTLA and HVEM: Emerging players in the tumor microenvironment and cancer progression.
Molecular mechanisms of transmitted endoplasmic reticulum stress mediating immune escape of gastric cancer via PVR overexpression in TAMs.
Biomaterial-Mediated Metabolic Regulation of Ferroptosis for Cancer Immunotherapy.
Autophagy as a critical driver of metabolic adaptation, therapeutic resistance, and immune evasion of cancer.
Photothermally Reinforced Nanozyme Remodeling Tumor Microenvironment of Redox and Metabolic Homeostasis to Enhance Ferroptosis in Tumor Therapy.
Neuroscience in peripheral cancers: tumors hijacking nerves and neuroimmune crosstalk.
Exploring Tumor Microenvironment in Breast Cancer: Parameters that can be Assessed with Light Microscopy.
Fibrocytes in tumor microenvironment: Identification of their fraction and novel therapeutic strategy.
The cancer risk of repeat RNAs.
The multifaceted modulation of mitochondrial metabolism in tumorigenesis.
Endothelin-1 receptor blockade impairs invasion patterns in engineered 3D high-grade serous ovarian cancer tumoroids.
Receptor tyrosine kinases and steroid hormone receptors in breast cancer: Review of recent evidences.
Focusing on exosomes to overcome the existing bottlenecks of CAR-T cell therapy.
Obesity, white adipose tissue and cancer.
Triggered Cascade-Activation Nanoplatform to Alleviate Hypoxia for Effective Tumor Immunotherapy Guided by NIR-II Imaging.
ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis.
Enhancing immuno-oncology efficacy with H1-antihistamine in cancer therapy: a review of current research and findings.
Engineering and targeting potential of CAR NK cells in colorectal cancer.
Stress response regulation of mRNA translation: Implications for antioxidant enzyme expression in cancer.

Mol Ther Oncol. 2024 Dec 19. 32(4): 200891

Solid cancer-directed CAR T cell therapy that attacks both tumor and immunosuppressive cells via targeting PD-L1.

Yan Luo, Martha E Gadd, Yaqing Qie, Andrea Otamendi-Lopez, Jesus E Sanchez-Garavito, Mieu M Brooks, Maria J Ulloa Navas, Tanya Hundal, Shuhua Li, Vanessa K Jones, Yanyan Lou, Tushar Patel, Roxana Dronca, Mohamed A Kharfan-Dabaja, Haidong Dong, Alfredo Quinones-Hinojosa, Hong Qin.

  Chimeric antigen receptor (CAR) T cell therapy has encountered limited success in solid tumors. The lack of dependable antigens and the immunosuppressive tumor microenvironment (TME) are major challenges. Within the TME, tumor cells along with immunosuppressive cells employ an immune-evasion mechanism that upregulates programmed death ligand 1 (PD-L1) to deactivate effector T cells; this makes PD-L1 a reliable, universal target for solid tumors. We developed a novel PD-L1 CAR (MC9999) using our humanized anti-PD-L1 monoclonal antibody, designed to simultaneously target tumor and immunosuppressive cells. The antigen-specific antitumor effects of MC9999 CAR T cells were observed consistently across four solid tumor models: breast cancer, lung cancer, melanoma, and glioblastoma multiforme (GBM). Notably, intravenous administration of MC9999 CAR T cells eradicated intracranially established LN229 GBM tumors, suggesting penetration of the blood-brain barrier. The proof-of-concept data demonstrate the cytolytic effect of MC9999 CAR T cells against immunosuppressive cells, including microglia HMC3 cells and M2 macrophages. Furthermore, MC9999 CAR T cells elicited cytotoxicity against primary tumor-associated macrophages within GBM tumors. The concept of targeting both tumor and immunosuppressive cells with MC9999 was further validated using CAR T cells derived from cancer patients. These findings establish MC9999 as a foundation for the development of effective CAR T cell therapies against solid tumors.

Keywords:  CAR T cells; MT: Regular Issue; PD-L1; T cells; chimeric antigen receptor; immunotherapy; solid tumor; tumor microenvironment

DOI:  https://doi.org/10.1016/j.omton.2024.200891
Front Immunol. 2024 ;15 1476030

NF-κB signaling pathway in tumor microenvironment.

Yaning Cao, Yanan Yi, Chongxu Han, Bingwei Shi.

  The genesis and progression of tumors are multifaceted processes influenced by genetic mutations within the tumor cells and the dynamic interplay with their surrounding milieu, which incessantly impacts the course of cancer. The tumor microenvironment (TME) is a complex and dynamic entity that encompasses not only the tumor cells but also an array of non-cancerous cells, signaling molecules, and the extracellular matrix. This intricate network is crucial in tumor progression, metastasis, and response to treatments. The TME is populated by diverse cell types, including immune cells, fibroblasts, endothelial cells, alongside cytokines and growth factors, all of which play roles in either suppressing or fostering tumor growth. Grasping the nuances of the interactions within the TME is vital for the advancement of targeted cancer therapies. Consequently, a thorough understanding of the alterations of TME and the identification of upstream regulatory targets have emerged as a research priority. NF-κB transcription factors, central to inflammation and innate immunity, are increasingly recognized for their significant role in cancer onset and progression. This review emphasizes the crucial influence of the NF-κB signaling pathway within the TME, underscoring its roles in the development and advancement of cancer. By examining the interactions between NF-κB and various components of the TME, targeting the NF-κB pathway appears as a promising cancer treatment approach.

Keywords:  NF-κB signaling pathway; cancer metabolism; inflammation; tumor immunity; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1476030
Metab Eng. 2024 Oct 25. pii: S1096-7176(24)00137-X. [Epub ahead of print]

Applying metabolic control strategies to engineered T cell cancer therapies.

Andrea C Fox, John Blazeck.

  Chimeric antigen receptor (CAR) T cells are an engineered immunotherapy that express synthetic receptors to recognize and kill cancer cells. Despite their success in treating hematologic cancers, CAR T cells have limited efficacy against solid tumors, in part due to the altered immunometabolic profile within the tumor environment, which hinders T cell proliferation, infiltration, and anti-tumor activity. For instance, CAR T cells must compete for essential nutrients within tumors, while resisting the impacts of immunosuppressive metabolic byproducts. In this review, we will describe the altered metabolic features within solid tumors that contribute to immunosuppression of CAR T cells. We'll discuss how overexpression of key metabolic enzymes can enhance the ability of CAR T cells to resist corresponding tumoral metabolic changes or even revert the metabolic profile of a tumor to a less inhibitory state. In addition, metabolic remodeling is intrinsically linked to T cell activity, differentiation, and function, such that metabolic engineering strategies can also promote establishment of more or less efficacious CAR T cell phenotypes. Overall, we will show how applying metabolic engineering strategies holds significant promise to improve CAR T cells for the treatment of solid tumors.

Keywords:  CAR T cell therapies; Cellular engineering; Immunotherapy; Metabolic engineering; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.ymben.2024.10.009
Immunol Lett. 2024 Oct 31. pii: S0165-2478(24)00116-0. [Epub ahead of print]270 106942

T cell landscape in the microenvironment of human solid tumors.

Enrico Maggi, Enrico Munari, Nadine Landolina, Francesca Romana Mariotti, Bruno Azzarone, Lorenzo Moretta.

  T cells are the main effectors involved in anti-tumor immunity, mediating most of the adaptive response towards cancer. After priming in lymph nodes, tumor antigens-specific naïve T lymphocytes proliferate and differentiate into effector CD4+ and CD8+ T cells that migrate from periphery into tumor sites aiming to eliminate cancer cells. Then while most effector T cells die, a small fraction persists and recirculates as long-lived memory T cells which generate enhanced immune responses when re-encountering the same antigen. A number of T (and non-T) cell subsets, stably resides in non-lymphoid peripheral tissues and may provide rapid immune response independently of T cells recruited from blood, against the reemergence of cancer cells. When tumor grows, however, tumor cells have evaded immune surveillance of effector cells (NK and CTL cells) which are exhausted, thus favoring the local expansion of T (and non-T) regulatory cells. In this review, the current knowledge of features of T cells present in the tumor microenvironment (TME) of solid adult and pediatric tumors, the mechanisms upregulating immune-checkpoint molecules and transcriptional and epigenetic landscapes leading to dysfunction and exhaustion of T effector cells are reviewed. The interaction of T cells with cancer- or TME non-neoplastic cells and their secreted molecules shape the T cell profile compromising the intrinsic plasticity of T cells and, therefore, favoring immune evasion. In this phase regulatory T cells contribute to maintain a high immunosuppressive TME thus facilitating tumor cell proliferation and metastatic spread. Despite the advancements of cancer immunotherapy, many tumors are unresponsive to immune checkpoint inhibitors, or therapeutical vaccines or CAR T cell-based adoptive therapy: some novel strategies to improve these T cell-based treatments are lastly proposed.

Keywords:  Immunosuppression; Immunotherapy of tumors; Pediatric and adult Solid tumors; T effector cells; T regulatory cells; Tumor infiltrating lymphocytes

DOI:  https://doi.org/10.1016/j.imlet.2024.106942
Transl Res. 2023 Oct 27. pii: S1931-5244(23)00176-7. [Epub ahead of print]

Rough neighborhood: Intricacies of cancer stem cells and infiltrating immune cell interaction in tumor microenvironment and potential in therapeutic targeting.

Krishna Mahanti, Sankar Bhattacharyya.

  Ongoing research on cellular heterogeneity of Cancer stem cells (CSCs) and its synergistic involvement with tumor milieu reveals enormous complexity, resulting in diverse hindrance in immune therapy. CSCs has captured attention for their contribution in shaping of tumor microenvironment and as target for therapeutic intervention. Recent studies have highlighted cell-extrinsic and intrinsic mechanisms of reciprocal interaction between tumor stroma constituents and CSCs. Therapeutic targeting requires an in-depth understanding of the underlying mechanisms involved with the rate limiting factors in tumor aggressiveness and pinpoint role of CSCs. Some of the major constituents of tumor microenvironment includes resident and infiltrating immune cell, both innate and adaptive. Some of these immune cells play crucial role as adjustors of tumor immune response. Tumor-adjustor immune cell interaction confer plasticity and features enabling tumor growth and metastasis in one hand and on the other hand blunts anti-tumor immunity. Detail understanding of CSC and TME resident immune cells interaction can shape new avenues for cancer immune therapy. In this review, we have tried to summarize the development of knowledge on cellular, molecular and functional interaction between CSCs and tumor microenvironment immune cells, highlighting immune-mediated therapeutic strategies aimed at CSCs. We also discussed developing a potential CSC and TME targeted therapeutic avenue.

Keywords:  Cancer; Cancer stem cells; Innate immunity; Myeloid derived suppressor cells; T cell; Tumor immune therapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.trsl.2023.10.003
Int Immunopharmacol. 2024 Nov 01. pii: S1567-5769(24)02061-7. [Epub ahead of print]143(Pt 3): 113539

Ferroptosis in Cancer: A new perspective on T cells.

Yuping Lai, Chunxia Huang, Jiaqiang Wu, Kangping Yang, Liang Yang.

  T cells occupy a pivotal position in the immune response against cancer by recognizing and eliminating cancer cells. However, the tumor microenvironment often suppresses the function of T cells, leading to immune evasion and cancer progression. Recent research has unveiled novel connections among T cells, ferroptosis, and cancer. Ferroptosis is a type of regulated cell death that relies iron and reactive oxygen species and is distinguished by the proliferation of lipid peroxides. Emerging scientific findings underscore the potential of ferroptosis to modulate the function and survival of T cells in the tumor microenvironment. Moreover, T cells or immunotherapy can also affect cancer by modulating ferroptosis in cancer cells. This review delved into the intricate crosstalk between T cells and ferroptosis in the context of cancer, highlighting the molecular mechanisms involved. We also explored the therapeutic potential of targeting ferroptosis to enhance the anticancer immune response mediated by T cells. Understanding the interplay among T cells, ferroptosis, and cancer may provide new insights into developing innovative cancer immunotherapies.

Keywords:  Cancer; Ferroptosis; Immunotherapy; T cells

DOI:  https://doi.org/10.1016/j.intimp.2024.113539
Cancer Med. 2024 Nov;13(21): e70387

Tissue-Resident Macrophages in Cancer: Friend or Foe?

Jianhua Chi, Qinglei Gao, Dan Liu.

   INTRODUCTION: Macrophages are essential in maintaining homeostasis, combating infections, and influencing the process of various diseases, including cancer. Macrophages originate from diverse lineages: Notably, tissue-resident macrophages (TRMs) differ from hematopoietic stem cells and circulating monocyte-derived macrophages based on genetics, development, and function. Therefore, understanding the recruited and TRM populations is crucial for investigating disease processes.
METHODS: By searching literature databses, we summarized recent relevant studies. Research has shown that tumor-associated macrophages (TAMs) of distinct origins accumulate in tumor microenvironment (TME), with TRM-derived TAMs closely resembling gene signatures of normal TRMs.
RESULTS: Recent studies have revealed that TRMs play a crucial role in cancer progression. However, organ-specific effects complicate TRM investigations. Nonetheless, the precise involvement of TRMs in tumors is unclear. This review explores the multifaceted roles of TRMs in cancer, presenting insights into their origins, proliferation, the latest research methodologies, their impact across various tumor sites, their potential and strategies as therapeutic targets, interactions with other cells within the TME, and the internal heterogeneity of TRMs.
CONCLUSIONS: We believe that a comprehensive understanding of the multifaceted roles of TRMs will pave the way for targeted TRM therapies in the treatment of cancer.

Keywords:  cancer immunology; tissue‐resident macrophages; tumor microenvironment; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/cam4.70387
Front Immunol. 2024 ;15 1483834

The complex role of immune cells in antigen presentation and regulation of T-cell responses in hepatocellular carcinoma: progress, challenges, and future directions.

Jianbo Ning, Yutao Wang, Zijia Tao.

  Hepatocellular carcinoma (HCC) is a prevalent form of liver cancer that poses significant challenges regarding morbidity and mortality rates. In the context of HCC, immune cells play a vital role, especially concerning the presentation of antigens. This review explores the intricate interactions among immune cells within HCC, focusing on their functions in antigen presentation and the modulation of T-cell responses. We begin by summarizing the strategies that HCC uses to escape immune recognition, emphasizing the delicate equilibrium between immune surveillance and evasion. Next, we investigate the specific functions of various types of immune cells, including dendritic cells, natural killer (NK) cells, and CD8+ T cells, in the process of antigen presentation. We also examine the impact of immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the pathways involving programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1), on antigen presentation, while taking into account the clinical significance of checkpoint inhibitors. The review further emphasizes the importance of immune-based therapies, including cancer vaccines and CAR-T cell therapy, in improving antigen presentation. In conclusion, we encapsulate the latest advancements in research, propose future avenues for exploration, and stress the importance of innovative technologies and customized treatment strategies. By thoroughly analyzing the interactions of immune cells throughout the antigen presentation process in HCC, this review provides an up-to-date perspective on the field, setting the stage for new therapeutic approaches.

Keywords:  CTLA-4; PD-1/PD-L1; dendritic cells; hepatocellular carcinoma; natural killer cells

DOI:  https://doi.org/10.3389/fimmu.2024.1483834
Cancer Immunol Immunother. 2024 Nov 02. 74(1): 3

Breaking the shield of solid tumors: a combined approach for enhanced efficacy of CAR-T cells.

Marat Khaliulin, Aygul Valiullina, Alexey Petukhov, Youyong Yuan, Sheila Spada, Emil Bulatov.

  The use of chimeric antigen receptor (CAR)-T cells has enhanced the range of available therapeutic modalities in the context of cancer treatment. CAR-T cells have demonstrated considerable efficacy in the targeted eradication of blood cancer cells, thereby stimulating substantial interest in the advancement of such therapeutic approaches. However, the efficacy of CAR-T cells against solid tumor cells has been limited due to the presence of various obstacles. Solid tumors exhibit antigenic diversity and an immunosuppressive microenvironment, which presents a challenge for immune cells attempting to penetrate the tumor. CAR-T cells also demonstrate decreased proliferative activity and cytotoxicity. Furthermore, concerns exist regarding tumor antigen loss and therapy-associated toxicity. Currently, scientists are working to enhance the structure of the CAR and improve the survival and efficiency of CAR-T cells in recognizing tumor antigens in solid tumors. Chemotherapy drugs are frequently employed in the treatment of malignant neoplasms and can also be used prior to cell therapy to enhance CAR-T cell engraftment. Recent studies have demonstrated that chemotherapy drugs can mitigate the suppressive impact of TME, eliminate the physical barrier by destroying the tumor stroma, and facilitate greater penetration of immune cells and CAR-T cells into the tumor. This, in turn, increases their survival, persistence, and cytotoxicity, as well as affects the metabolism of immune cells inside the tumor. However, the effectiveness of the combined approach against solid tumors depends on several factors, including the type of tumor, dosage, population of CAR-T cells, and individual characteristics of the body. This review examines the principal obstacles to the utilization of CAR-T cells against solid tumors, proposes solutions to these issues, and assesses the potential advantages of a combined approach to radiation exposure, which has the potential to enhance the sensitivity of the tumor to other agents.

Keywords:  CAR-T cell therapy; Chemotherapy; Chimeric antigen receptor; Radiation therapy; Solid tumor

DOI:  https://doi.org/10.1007/s00262-024-03817-z
Cold Spring Harb Perspect Med. 2024 Nov 05. pii: a041814. [Epub ahead of print]

Cancer Metabolism: Historical Landmarks, New Concepts, and Opportunities.

Navdeep S Chandel, Karen H Vousden, Ralph J DeBerardinis.

Cancer cells undergo changes in metabolism that distinguish them from non-malignant tissue. These may provide a growth advantage by promoting oncogenic signaling and redirecting intermediates to anabolic pathways that provide building blocks for new cellular components. Cancer metabolism is far from uniform, however, and recent work has shed light on its heterogenity within and between tumors. This work is also revealing how cancer metabolism adapts to the tumor microenvironment, as well as ways in which we may capitalize on metabolic changes in cancer cells to create new therapies.

DOI: https://doi.org/10.1101/cshperspect.a041814
Adv Pharm Bull. 2024 Oct;14(3): 705-713

Exploring the Interplay between the Warburg Effect and Glucolipotoxicity in Cancer Development: A Novel Perspective on Cancer Etiology.

Maher Monir Akl, Amr Ahmed.

  The Warburg effect, first observed by Otto Warburg in the 1920s, delineates a metabolic phenomenon in which cancer cells exhibit heightened glucose uptake and lactate production, even under normoxic conditions. This metabolic shift towards glycolysis, despite the presence of oxygen, fuels the energy demands of rapidly proliferating cancer cells. Dysregulated glucose metabolism, characterized by the overexpression of glucose transporters and the redirection of metabolic pathways towards glycolysis, lies at the crux of this metabolic reprogramming. Consequently, the accumulation of lactate as a byproduct contributes to the creation of an acidic tumor microenvironment, fostering tumor progression and metastasis. However, recent research, notably proposed by Maher Akl, introduces a novel perspective regarding the role of glycolipids in cancer metabolism. Akl's glucolipotoxicity hypothesis posits that aberrant glycolipid metabolism, specifically the intracellular buildup of glycolipids, significantly influences tumor initiation and progression. This hypothesis underscores the disruptive impact of accumulated glycolipids on cellular homeostasis, thereby activating oncogenic pathways and promoting carcinogenesis. This perspective aims to synthesize the intricate mechanisms underlying both the Warburg effect and glucolipotoxicity, elucidating their collective contributions to tumor growth and malignancy. By comprehensively understanding these metabolic aberrations, novel avenues for therapeutic intervention targeting the fundamental drivers of cancer initiation and progression emerge, holding promise for more efficacious treatment strategies in the future.

Keywords:  Cancer etiology; Glycolipid metabolism; Metabolic paradox; Oncogenic pathways; Tumor development

DOI:  https://doi.org/10.34172/apb.2024.049
Cureus. 2024 Oct;16(10): e70700

Hypoxia-Inducible Factor 1-Alpha (HIF-1α) and Cancer: Mechanisms of Tumor Hypoxia and Therapeutic Targeting.

Mohd Basheeruddin, Sana Qausain.

  Hypoxia-inducible factor 1-alpha (HIF-1α) is necessary for cells to adapt to low oxygen levels often present in the tumor microenvironment. HIF-1α triggers a transcriptional program that promotes invasion, angiogenesis, metabolic reprogramming, and cell survival when it is active in hypoxic environments. These processes together lead to the growth and spread of tumors. This review article examines the molecular mechanisms by which HIF-1α contributes to tumor progression, including its regulation by oxygen-dependent and independent pathways, interactions with oncogenic signaling networks, and impact on the tumor microenvironment. Additionally, we explore current therapeutic strategies targeting HIF-1α, such as small molecule inhibitors, RNA interference, and immunotherapy approaches. Understanding the multifaceted roles of HIF-1α in cancer biology not only elucidates the complexities of tumor hypoxia but also opens avenues for developing novel and more effective cancer therapies.

Keywords:  angiogenesis; cancer progression; hif-1α; immunotherapy; rna interference; small molecule inhibitors; therapeutic targeting

DOI:  https://doi.org/10.7759/cureus.70700
Cytokine. 2023 Oct 28. pii: S1043-4666(23)00290-9. [Epub ahead of print]172 156412

BTLA and HVEM: Emerging players in the tumor microenvironment and cancer progression.

Asma'a H Mohamed, Ruaa Ali Obeid, Ali Abdulhussain Fadhil, Ahmed Ali Amir, Zainab H Adhab, Enaam Anad Jabouri, Irfan Ahmad, Mohammad Y Alshahrani.

  Immunotherapy has emerged as a revolutionary cancer treatment, particularly with the introduction of immune checkpoint inhibitors (ICIs). ICIs target specific proteins that restrain the immune system from attacking cancer cells. Prominent examples of checkpoint proteins that ICIs block include PD-1, PD-L1, and CTLA-4. The success of PD-1/L1 and CTLA-4 blockade has prompted further research on other inhibitory mechanisms that could aid in the treatment of cancer. One such mechanism is the BTLA/HVEM checkpoint, which regulates immune responses in a similar manner to CTLA-4 and PD-1. BTLA, a member of the Ig superfamily, binds to HVEM, a member of the TNF receptor superfamily. While BTLA is essential for maintaining immunological self-tolerance and preventing autoimmune diseases, overexpression of BTLA and HVEM has been observed in various malignancies such as lung, ovarian, glioblastoma, gastric cancer, and non-Hodgkin's lymphoma. The function of the BTLA/HVEM checkpoint in various malignancies has been extensively studied, revealing its significant role in immunotherapy for cancer. This review study aims to explain the BTLA/HVEM checkpoint and its functions in different types of cancers. In conclusion, the development of new immunotherapies such as ICIs has revolutionized cancer treatment. The discovery of the BTLA/HVEM checkpoint and its role in various malignancies provides opportunities for advancing cancer treatment through immunotherapy.

Keywords:  BTLA; HEVM; Immune checkpoint Inhibitors; Inhibitory Receptor Checkpoint; Neoplasm; TNFR superfamily

DOI:  https://doi.org/10.1016/j.cyto.2023.156412
Biochim Biophys Acta Mol Basis Dis. 2024 Oct 30. pii: S0925-4439(24)00554-4. [Epub ahead of print]1871(1): 167560

Molecular mechanisms of transmitted endoplasmic reticulum stress mediating immune escape of gastric cancer via PVR overexpression in TAMs.

Xuxian Zhong, Youqin Xu, Shengnan Yang, Jiaqi Liao, Ziyang Hong, Xingyu Zhang, Ziqing Wu, Chengshu Tu, Qiang Zuo.

  Gastric cancer (GC) is the fourth leading cause of cancer death worldwide. Due to the complex tumor microenvironment (TME), the efficacy of immunotherapy in GC has not met expectations. Malignant changes in the TME induce endoplasmic reticulum stress (ERS). ERS can be transmitted between tumor cells and tumor-associated macrophages (TAMs), promoting tumor immune escape, but the specific mechanism in GC remains unclear. We established a TAM model of transmitted ERS (TERS), and iTRAQ proteomic analysis identified overexpressed proteins. The overexpression of poliovirus receptor (PVR) was screened while flow cytometry and ELISA showed that PVR mediated the immunosuppressive function of TAMs by downregulating the proliferative activity and cytotoxicity of cocultured CD8+ T lymphocytes. With EMSA and dual-luciferase reporter assays, we confirmed that erythropoietin-producing hepatocellular receptor A2 (EphA2) affected PVR expression by increasing the transcriptional activity of activator protein-1 (AP-1). MFC cells were mixed with EphA2 knockdown or control RAW264.7 cells to establish subcutaneous tumor models with or without tunicamycin treatment in vivo. The vivo experiments revealed that ERS promoted subcutaneous xenograft growth, which was reversed by EphA2 knockdown. Clinically, GC patients with high expression of PVR and EphA2 tended to have an immunosuppressive TME, which were determined by immunohistochemical and immunofluorescence analyses. In conclusion, the transcriptional activity of AP-1 is upregulated in ERS-transmitted TAMs through EphA2 to increase PVR expression, which promotes immune escape in GC. Our study provides a new perspective on the role of ERS in tumor immunity.

Keywords:  Endoplasmic reticulum stress; Gastric cancer; Immune escape; Poliovirus receptor; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.bbadis.2024.167560
Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2024 Nov-Dec;16(6):16(6): e2010

Biomaterial-Mediated Metabolic Regulation of Ferroptosis for Cancer Immunotherapy.

Yingqi Liu, Dan Tao, Menghuan Li, Zhong Luo.

  Ferroptosis is a lipid peroxidation-driven cell death route and has attracted enormous interest for cancer therapy. Distinct from other forms of regulated cell death, its process is involved with multiple metabolic pathways including lipids, bioenergetics, iron, and so on, which influence cancer cell ferroptosis sensitivity and communication with the immune cells in the tumor microenvironment. Development of novel technologies for harnessing the ferroptosis-associated metabolic regulatory network would profoundly improve our understanding of the immune responses and enhance the efficacy of ferroptosis-dependent immunotherapy. Interestingly, the recent advances in bio-derived material-based therapeutic platforms offer novel opportunities to therapeutically modulate tumor metabolism through the in situ delivery of molecular or material cues, which not only allows the tumor-specific elicitation of ferroptosis but also holds promise to maximize their immunostimulatory impact. In this review, we will first dissect the crosstalk between tumor metabolism and ferroptosis and its impact on the immune regulation in the tumor microenvironment, followed by the comprehensive analysis on the recent progress in biomaterial-based metabolic regulatory strategies for evoking ferroptosis-mediated antitumor immunity. A perspective section is also provided to discuss the challenges in metabolism-regulating biomaterials for ferroptosis-immunotherapy. We envision that this review may provide new insights for improving tumor immunotherapeutic efficacy in the clinic.

Keywords:  bio‐derived materials; ferroptosis; immunotherapy; metabolic regulation

DOI:  https://doi.org/10.1002/wnan.2010
Curr Opin Biotechnol. 2023 Oct 27. pii: S0958-1669(23)00122-2. [Epub ahead of print]84 103012

Autophagy as a critical driver of metabolic adaptation, therapeutic resistance, and immune evasion of cancer.

Keisuke Yamamoto, Dosuke Iwadate, Eri Naito, Keisuke Tateishi, Mitsuhiro Fujishiro.

Autophagy is a well-conserved intracellular degradation pathway. Besides its physiological role in normal cells, autophagy is activated in various cancer types and protects cancer cells from stresses such as nutrient deprivation, therapeutic insults, and antitumor immunity. Autophagy in cancer cells as well as normal cells in the host supports tumor metabolism, allowing for tumor growth under a nutrient-limited tumor microenvironment. Autophagy also protects cancer cells from treatments such as radiation therapy, cytotoxic chemotherapy, and targeted therapy. Though the roles of autophagy in antitumor immunity are complex and highly context-dependent, accumulating evidence now supports the role of autophagy in mediating immunotherapy resistance. Based on these preclinical findings, multiple clinical trials are currently ongoing to test the therapeutic efficacy of autophagy inhibition in cancer. Here, we review recent findings on the tumor-promoting roles of autophagy in cancer and discuss advances in therapeutic approaches that target autophagy in cancer.

DOI: https://doi.org/10.1016/j.copbio.2023.103012
ACS Nano. 2024 Nov 05.

Photothermally Reinforced Nanozyme Remodeling Tumor Microenvironment of Redox and Metabolic Homeostasis to Enhance Ferroptosis in Tumor Therapy.

Shuheng Qin, Hui-Yue Zhao, Xing-Yu Luo, Fei Wang, Jun Liu, Yin Ding, Yong Hu.

  The acidity and high GSH level in the tumor microenvironment (TME) greatly limit the antitumor activity of nanozymes. Thus, enhancing nanozymes' activity is fundamentally challenging in tumor therapy. Although the combination of photothermal therapy (PTT) and nanozymes can enhance the catalytic activity, cancer cells will overexpress heat shock proteins (HSPs) at high temperature, aggravating the heat resistance of tumor cells, which in turn compromises the outcome of chemodynamic therapy. Herein, we propose an iron-doped metal-organic framework nanozyme (IB@Fe-ZIF8@PDFA) that can be activated under the weak acidity and high level of GSH, demonstrating the activities of GSH oxidation (GSH-OXD), peroxidase (POD), and NADH oxidase (NADH-OXD). Under laser irradiation, it displays photothermal-enhanced multienzyme activities to simultaneously eliminate tumors and inhibit tumor metastasis. While consuming endogenous GSH, IB@Fe-ZIF8@PDFA promotes the decomposition of H2O2 into ·OH, enhancing ferroptosis in tumor cells. Surprisingly, IB@Fe-ZIF8@PDFA nanozyme can oxide NADH and subsequently limit the ATP supply, reducing the expression of HSPs and significantly weakening the heat resistance of tumor cells during PTT. Meanwhile, H2O2 is generated during this procedure, which can endogenously replenish the consumed H2O2. Thus, this IB@Fe-ZIF8@PDFA nanozyme constitutes a self-cascading platform to consume GSH and NADH, endogenously replenish the H2O2 and continuously generate ·OH to facilitate ferroptosis by disrupting the redox and metabolic homeostasis in tumor cells, achieving tumor elimination and tumor metastasis inhibition.

Keywords:  ferroptosis; metabolic dyshomeostasis; nanozyme; photothermal therapy; redox dyshomeostasis

DOI:  https://doi.org/10.1021/acsnano.4c13087
MedComm (2020). 2024 Nov;5(11): e784

Neuroscience in peripheral cancers: tumors hijacking nerves and neuroimmune crosstalk.

Hua-Yang Fan, Xin-Hua Liang, Ya-Ling Tang.

  Cancer neuroscience is an emerging field that investigates the intricate relationship between the nervous system and cancer, gaining increasing recognition for its importance. The central nervous system governs the development of the nervous system and directly affects brain tumors, and the peripheral nervous system (PNS) shapes the tumor microenvironment (TME) of peripheral tumors. Both systems are crucial in cancer initiation and progression, with recent studies revealing a more intricate role of the PNS within the TME. Tumors not only invade nerves but also persuade them through remodeling to further promote malignancy, creating a bidirectional interaction between nerves and cancers. Notably, immune cells also contribute to this communication, forming a triangular relationship that influences protumor inflammation and the effectiveness of immunotherapy. This review delves into the intricate mechanisms connecting the PNS and tumors, focusing on how various immune cell types influence nerve‒tumor interactions, emphasizing the clinical relevance of nerve‒tumor and nerve‒immune dynamics. By deepening our understanding of the interplay between nerves, cancer, and immune cells, this review has the potential to reshape tumor biology insights, inspire innovative therapies, and improve clinical outcomes for cancer patients.

Keywords:  cancer neuroscience; cancer therapy; neuroimmune crosstalk; peripheral nervous system; tumor microenvironment; tumor‒nerve interactions

DOI:  https://doi.org/10.1002/mco2.784
Turk Patoloji Derg. 2024 Nov 07.

Exploring Tumor Microenvironment in Breast Cancer: Parameters that can be Assessed with Light Microscopy.

Seetu Palo.

DOI: https://doi.org/10.5146/tjpath.2024.13748
Cancer Sci. 2024 Nov 04.

Fibrocytes in tumor microenvironment: Identification of their fraction and novel therapeutic strategy.

Atsushi Mitsuhashi, Yasuhiko Nishioka.

  Fibrocytes were identified as bone marrow-derived myeloid cells that also have fibroblast-like phenotypes, such as ECM production and differentiation to myofibroblasts. Although fibrocytes are known to contribute to various types of tissue fibrosis, their functions in the tumor microenvironment are unclear. We focused on fibrocytes as pivotal regulators of tumor progression. Our previous studies have indicated that fibrocytes induce angiogenesis and cancer stem cell-like phenotypes by secreting various growth factors. In contrast, immune checkpoint inhibitor (ICI)-treated fibrocytes demonstrated antigen-presenting capacity and enhanced antitumor T cell proliferation. Taken together, these findings indicate that fibrocytes have multiple effects on tumor progression. However, the detailed phenotypes of fibrocytes have not been fully elucidated because the isolation of distinct fibrocyte clusters has not been achieved without culturing in ECM-coated conditions or intracellular staining of ECM. The development of single-cell analyses partially resolves these problems. Single-cell RNA sequences in CD45+ immune cells from tumor tissue identified ECM-expressing myeloid-like cells as distinct fibrocyte clusters. In addition, these findings enabled the isolation of tumor-infiltrating fibrocytes as CD45+CD34+ cells. These tumor-infiltrating fibrocytes demonstrated both antigen-presenting ability and differentiation into myofibroblast-like cancer-associated fibroblasts. Considering these functions of fibrocytes in tumor progression, molecular-targeting agents for the migration, activity, and differentiation of fibrocytes are promising therapeutic strategies. Furthermore, identification of specific cell surface markers and master regulators of fibrocytes will advance novel fibrocyte-targeting therapies. In this review, we discuss the multiple roles of tumor-infiltrating fibrocytes and novel cancer therapeutic strategies.

Keywords:  angiogenesis; cancer stem cell; cancer‐associated fibroblast; fibrocyte; immune checkpoint inhibitor

DOI:  https://doi.org/10.1111/cas.16385
Sci Signal. 2024 Nov 05. 17(861): eadu2651

The cancer risk of repeat RNAs.

Wei Wong.

Repeat RNAs reprogram tumor cells and cancer-associated fibroblasts in pancreatic cancer.

DOI: https://doi.org/10.1126/scisignal.adu2651
Mitochondrion. 2024 Nov 04. pii: S1567-7249(24)00135-1. [Epub ahead of print] 101977

The multifaceted modulation of mitochondrial metabolism in tumorigenesis.

Rajendiran Keerthiga, Yafang Xie, Desheng Pei, Ailing Fu.

  Changes in mitochondrial metabolism produce a malignant transformation from normal cells to tumor cells. Mitochondrial metabolism, comprising bioenergetic metabolism, biosynthetic process, biomolecular decomposition, and metabolic signal conversion, obviously forms a unique sign in the process of tumorigenesis. Several oncometabolites produced by mitochondrial metabolism maintain tumor phenotype, which are recognized as tumor indicators. The mitochondrial metabolism synchronizes the metabolic and genetic outcome to the potent tumor microenvironmental signals, thereby further promoting tumor initiation. Moreover, the bioenergetic and biosynthetic metabolism within tumor mitochondria orchestrates dynamic contributions toward cancer progression and invasion. In this review, we describe the contribution of mitochondrial metabolism in tumorigenesis through shaping several hallmarks such as microenvironment modulation, plasticity, mitochondrial calcium, mitochondrial dynamics, and epithelial-mesenchymal transition. The review will provide a new insight into the abnormal mitochondrial metabolism in tumorigenesis, which will be conducive to tumor prevention and therapy through targeting tumor mitochondria.

Keywords:  EMT-MET transition; OXPHOS; Oncometabolites; Plasticity; TCA cycle; Tumorigenesis

DOI:  https://doi.org/10.1016/j.mito.2024.101977
Clin Sci (Lond). 2024 Nov 06. pii: CS20240371. [Epub ahead of print]

Endothelin-1 receptor blockade impairs invasion patterns in engineered 3D high-grade serous ovarian cancer tumoroids.

Judith Pape, Umber Cheema, Piera Tocci, Rosanna Sestito, Ilenia Masi, Marilena Loizidou, Anna Bagnato, Laura Rosanò.

  High-grade serous ovarian cancer (HG-SOC), accounting for 70-80% of ovarian cancer deaths, is characterized by a widespread and rapid metastatic nature, influenced by diverse cell types, cell-cell interactions, and acellular components of the tumor microenvironment (TME). Within this tumor type, autocrine and paracrine activation of the endothelin-1 receptors (ET-1R), expressed in tumor cells and stromal components, drives metastatic progression. The lack of three-dimensional models that faithfully recapitulate the unique HG-SOC TME has been the bottleneck in performing drug screening for personalized medicine. Herein, we developed HG-SOC tumoroids by engineering a dense central artificial cancer mass (ACM) containing HG-SOC cells, nested within a compressed hydrogel recapitulating the stromal compartment comprising type I collagen, laminin, fibronectin, and stromal cells (fibroblasts and endothelial cells). ET-1-stimulated HG-SOC cells in the tumoroids showed an altered migration pattern and formed cellular aggregates, mimicking micrometastases that invaded the stroma. Compared to control cells, ET-1-stimulated tumoroids showed a higher number of invasive bodies, which were reduced by treatment with the dual ET-1 receptor (ET-1R) antagonist macitentan. In addition, ET-1 increased the size of the invading aggregates compared to control cells. This study establishes an experimental 3D multicellular model eligible for mechanical research, investigating the impact of matrix stiffness and TME interactions, which will aid drug screening to guide therapeutic decisions in HG-SOC patients.

Keywords:  endothelins; ovarian cancer; stroma; tumoroid

DOI:  https://doi.org/10.1042/CS20240371
Metabol Open. 2024 Dec;24 100324

Receptor tyrosine kinases and steroid hormone receptors in breast cancer: Review of recent evidences.

Awgichew Behaile Teklemariam, Zelalem Tilahun Muche, Melaku Mekonnen Agidew, Anemut Tilahun Mulu, Edgeit Abebe Zewde, Nega Dagnew Baye, Dagnew Getnet Adugna, Lemlemu Maru, Teklie Mengie Ayele.

  Breast cancer development and progression are driven by intricate networks involving receptor tyrosine kinases (RTKs) and steroid hormone receptors specifically estrogen receptor (ER) and progesterone receptor (PR). This review examined roles of each receptor under normal physiology and in breast cancer, and explored their multifaceted interactions via signaling pathways, focusing on their contributions to breast cancer progression. Since defining the mechanism by which these two-receptor mediated signaling pathways cooperate is essential for understanding breast cancer progression, we discussed the mechanisms of cross-talk between RTKs and ER and PR and their potential therapeutic implications as well. The crosstalk between RTKs and steroid hormone receptors (ER and PR) in breast cancer can influence the disease's progression and treatment outcomes. Therefore, understanding the functions of the aforementioned receptors and their interactions is crucial for developing effective therapies.

Keywords:  Breast cancer; Cross-talk; ER; PR; RTKs

DOI:  https://doi.org/10.1016/j.metop.2024.100324
Inflamm Regen. 2024 Nov 04. 44(1): 45

Focusing on exosomes to overcome the existing bottlenecks of CAR-T cell therapy.

Si-Heng Zhang, Ling-Long Peng, Yi-Fei Chen, Yan Xu, Vahid Moradi.

  Since chimeric antigen receptor T (CAR-T) cells were introduced three decades ago, the treatment using these cells has led to outstanding outcomes, and at the moment, CAR-T cell therapy is a well-established mainstay for treating CD19 + malignancies and multiple myeloma. Despite the astonishing results of CAR-T cell therapy in B-cell-derived malignancies, several bottlenecks must be overcome to promote its safety and efficacy and broaden its applicability. These bottlenecks include cumbersome production process, safety concerns of viral vectors, poor efficacy in treating solid tumors, life-threatening side effects, and dysfunctionality of infused CAR-T cells over time. Exosomes are nano-sized vesicles that are secreted by all living cells and play an essential role in cellular crosstalk by bridging between cells. In this review, we discuss how the existing bottlenecks of CAR-T cell therapy can be overcome by focusing on exosomes. First, we delve into the effect of tumor-derived exosomes on the CAR-T cell function and discuss how inhibiting their secretion can enhance the efficacy of CAR-T cell therapy. Afterward, the application of exosomes to the manufacturing of CAR-T cells in a non-viral approach is discussed. We also review the latest advancements in ex vivo activation and cultivation of CAR-T cells using exosomes, as well as the potential of engineered exosomes to in vivo induction or boost the in vivo proliferation of CAR-T cells. Finally, we discuss how CAR-engineered exosomes can be used as a versatile tool for the direct killing of tumor cells or delivering intended therapeutic payloads in a targeted manner.

Keywords:  Anti-tumor agents; CAR-T cell; Cancer immunotherapy; Exosomes; Extracellular vesicles; Targeted therapies

DOI:  https://doi.org/10.1186/s41232-024-00358-x
FEBS J. 2024 Nov 04.

Obesity, white adipose tissue and cancer.

Estel Solsona-Vilarrasa, Karen H Vousden.

  White adipose tissue (WAT) is crucial for whole-body energy homeostasis and plays an important role in metabolic and hormonal regulation. While healthy WAT undergoes controlled expansion and contraction to meet the body's requirements, dysfunctional WAT in conditions like obesity is characterized by excessive tissue expansion, alterations in lipid homeostasis, inflammation, hypoxia, and fibrosis. Obesity is strongly associated with an increased risk of numerous cancers, with obesity-induced WAT dysfunction influencing cancer development through various mechanisms involving both systemic and local interactions between adipose tissue and tumors. Unhealthy obese WAT affects circulating levels of free fatty acids and factors like leptin, adiponectin, and insulin, altering systemic lipid metabolism and inducing inflammation that supports tumor growth. Similar mechanisms are observed locally in an adipose-rich tumor microenvironment (TME), where WAT cells can also trigger extracellular matrix remodeling, thereby enhancing the TME's ability to promote tumor growth. Moreover, tumors reciprocally interact with WAT, creating a bidirectional communication that further enhances tumorigenesis. This review focuses on the complex interplay between obesity, WAT dysfunction, and primary tumor growth, highlighting potential targets for therapeutic intervention.

Keywords:  cancer; obesity; white adipose tissue

DOI:  https://doi.org/10.1111/febs.17312
ACS Nano. 2024 Nov 04.

Triggered Cascade-Activation Nanoplatform to Alleviate Hypoxia for Effective Tumor Immunotherapy Guided by NIR-II Imaging.

Yu Ji, Suchen Qu, Gaoyu Shi, Liansheng Fan, Jing Qian, Zhaorui Sun, Feng Lu, Xin Han.

  Hypoxia is one of the most typical features among various types of solid tumors, which creates an immunosuppressive tumor microenvironment (TME) and limits the efficacy of cancer treatment. Alleviating hypoxia becomes a key strategy to reshape hypoxic TME which improves cancer immunotherapy. However, it remains challenging to perform tumor precision therapy with controllable switches through hypoxia-activated gene editing and prodrugs to alleviate hypoxia. In this study, silica-coated second near-infrared window (NIR-II) emitting silver sulfide quantum dots are used as the carrier to load the Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 (CRISPR/Cas9) system to target hypoxia-inducible factor-1 (HIF-1α) and guide tumor-targeted imaging. To reduce the off-target effects in nontumor cells and better control safety risks, a TME-triggered cascade-activation nanodiagnostic and therapeutic platform (AA@Cas-H@HTS) is designed, which achieves the hypoxia activation of prodrug tirapazamine (TPZ) and spatiotemporal release of CRISPR/Cas9 ribonucleoprotein. Tumor hypoxia is greatly alleviated by the synergistic function of HIF-1α depletion by gene editing and TPZ activation. Importantly, targeting HIF-1α disrupts the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway, which effectively reshapes the immune-suppressive TME and activates T cell-mediated antitumor immunity. Taken together, we have provided a TME-triggered cascade-activation nanoplatform to alleviate hypoxia for improved cancer immunotherapy.

Keywords:  cascade-activation; hypoxia-inducible factor-1; immune-suppressive tumor microenvironment; programmed cell death ligand 1; second near-infrared window imaging; tirapazamine

DOI:  https://doi.org/10.1021/acsnano.4c11334
Cancer Res. 2024 Nov 04.

ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis.

Peiyi Xie, Lei Guo, Qiang Yu, Yufei Zhao, Mincheng Yu, Hui Wang, Mengyuan Wu, Wenxin Xu, Min Xu, Xiao-Dong Zhu, Yongfeng Xu, Yong-Sheng Xiao, Cheng Huang, Jian Zhou, Jia Fan, Mien-Chie Hung, Huichuan Sun, Qing-Hai Ye, Bo Zhang, Hui Li.

Anti-PD-L1-based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. Here, we employed next-generation sequencing to analyze HCC samples from 10 patients receiving anti-PD-L1 therapy. Activation of the renin-angiotensin system was elevated in nonresponders compared with responders, and ACE2 expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti-PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune competent mice. Mass cytometry by time of flight (CyTOF) revealed that ACE2 deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages (TAMs), displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor intrinsic CCL5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1-7)/Mas receptor axis. The lower CCL5 levels led to reduced activation of the JAK-STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacological targeting of CCR5 using maraviroc enhanced the tumor suppressive effect of anti-PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0954
Curr Med Res Opin. 2024 Nov 06. 1-12

Enhancing immuno-oncology efficacy with H1-antihistamine in cancer therapy: a review of current research and findings.

Oday Hamid, Negar Hamidi.

  Cancer remains a major global cause of death, posing significant treatment challenges. The interactions between tumor cells and the tumor microenvironment (TME) are crucial in influencing tumor initiation, progression, metastasis, and treatment response. There has been significant research and clinical interest in targeting the TME as a therapeutic approach in cancer, with advancements being made through drug development. Histamine binds to HRH1 receptors on the TME, which inhibit CD8+ T cell activity, promote tumor growth, and contribute to resistance against immunotherapy. By inhibiting CD8+ T cells, the effectiveness of immunotherapies targeting these cells is reduced. By blocking the HRH1 pathway, H1-antihistamines can mitigate this suppression and enhance the response to immunotherapies that target CD8+ T cells. Therefore, understanding the role of histamine and its potential impact on T cells and the role of H1-antihistamines in improving immune-oncology (I/O) agents' efficacy ultimately could lead to more effective cancer therapies. The objective of this review is to examine the current literature to investigate the potential role of H1-antihistamines on the effectiveness of I/O drugs and their role in enhancing treatment against cancer. We conducted a comprehensive literature search, which included multiple databases including PubMed, Google Scholar, and EMBASE, as well as a search of oncology congresses. Our literature review initially identified thirty studies. Twenty-three of these were excluded for failing to meet inclusion criteria, which varied from study design to the type of antihistamines and patient populations involved. The clinical studies investigated the effect of different generations of H1-antihistamines in combination with I/O treatments on patients' outcomes. The findings from these studies indicated that patients using H1-antihistamines concomitantly with I/O agents experienced longer median overall survival (mOS), progression-free survival (mPFS), or improved survival compared to those who did not use antihistamines. Additionally, these trials differentiated between cationic and non-cationic H1-antihistamines, revealing that users of cationic antihistamines had overal better outcomes in terms of longer mOS and mPFS. The assessed trials were consistent in their comparisons of quantitative and qualitative, efficacy, and safety outcomes.

Keywords:  Cancer; H1-Antihistamine; Immuno-oncology

DOI:  https://doi.org/10.1080/03007995.2024.2427323
Chin Med J (Engl). 2024 Nov 05.

Engineering and targeting potential of CAR NK cells in colorectal cancer.

Muhammad Babar Khawar, Ali Afzal, Shuangshuang Dong, Yue Si, Haibo Sun.

ABSTRACT: Colorectal cancer (CRC), a major global health concern, necessitates innovative treatments. Chimeric antigen receptor (CAR) T cells have shown promise, yet they grapple with challenges. The spotlight pivots to the rising heroes: CAR natural killer (NK) cells, offering advantages such as higher safety profiles, cost-effectiveness, and efficacy against solid tumors. Nevertheless, the specific mechanisms underlying CAR NK cell trafficking and their interplay within the complex tumor microenvironment require further in-depth exploration. Herein, we provide insights into the design and engineering of CAR NK cells, antigen targets in CRC, and success in overcoming resistance mechanisms with an emphasis on the potential for clinical trials.

DOI: https://doi.org/10.1097/CM9.0000000000003346
Proc Natl Acad Sci U S A. 2024 Nov 12. 121(46): e2317846121

Stress response regulation of mRNA translation: Implications for antioxidant enzyme expression in cancer.

Yeon Soo Kim, Scot R Kimball, Elena Piskounova, Thomas J Begley, Nadine Hempel.

  From tumorigenesis to advanced metastatic stages, tumor cells encounter stress, ranging from limited nutrient and oxygen supply within the tumor microenvironment to extrinsic and intrinsic oxidative stress. Thus, tumor cells seize regulatory pathways to rapidly adapt to distinct physiologic conditions to promote cellular survival, including manipulation of mRNA translation. While it is now well established that metastatic tumor cells must up-regulate their antioxidant capacity to effectively spread and that regulation of antioxidant enzymes is imperative to disease progression, relatively few studies have assessed how translation and the hijacking of RNA systems contribute to antioxidant responses of tumors. Here, we review the major stress signaling pathways involved in translational regulation and discuss how these are affected by oxidative stress to promote prosurvival changes that manipulate antioxidant enzyme expression. We describe how tumors elicit these adaptive responses and detail how stress-induced translation can be regulated by kinases, RNA-binding proteins, RNA species, and RNA modification systems. We also highlight opportunities for further studies focused on the role of mRNA translation and RNA systems in the regulation of antioxidant enzyme expression, which may be of particular importance in the context of metastatic progression and therapeutic resistance.

Keywords:  Antioxidant; Cancer; RNA

DOI:  https://doi.org/10.1073/pnas.2317846121