Biochimica et biophysica acta. Reviews on cancer最新文献

Immune checkpoint blockade (ICB) therapy has achieved broad applicability and durable clinical responses across cancer types. However, the overall response rate remains suboptimal because some patients do not respond or develop drug resistance. The low infiltration of CD8⁺ cytotoxic T cells (CTLs) in the tumor microenvironment due to insufficient antigen presentation is closely related to the innate resistance to ICB. The duration and spatial distribution of major histocompatibility complex class I (MHC-I) expression on the cell surface is critical for the efficient presentation of endogenous tumor antigens and subsequent recognition and clearance by CTLs. Tumor cells reduce the surface expression of MHC-I via multiple mechanisms to impair antigen presentation pathways and evade immunity and/or develop resistance to ICB therapy. As an increasing number of studies have focused on membrane MHC-I trafficking and degradation in tumor cells, which may impact the effectiveness of tumor immunotherapy. It is necessary to summarize the mechanism regulating membrane MHC-I translocation into the cytoplasm and degradation via the lysosome. We reviewed recent advances in the understanding of endosomal-lysosomal MHC-I transport and highlighted the means exploited by tumor cells to evade detection and clearance by CTLs. We also summarized new therapeutic strategies targeting these pathways to enhance classical ICB treatment and provide new avenues for optimizing cancer immunotherapy.

As a solid tumor with high glycolytic activity, hepatocellular carcinoma (HCC) produces excess lactic acid and increases extracellular acidity, thus forming a unique immunosuppressive microenvironment. L-lactate dehydrogenase (LDH) and monocarboxylate transporters (MCTs) play a very important role in glycolysis. LDH is the key enzyme for lactic acid (LA) production, and MCT is responsible for the cellular import and export of LA. The synergistic effect of the two promotes the formation of an extracellular acidic microenvironment. In the acidic microenvironment of HCC, LA can not only promote the proliferation, survival, transport and angiogenesis of tumor cells but also have a strong impact on immune cells, ultimately leading to an inhibitory immune microenvironment. This article reviews the role of LA in HCC, especially its effect on immune cells, summarizes the progress of LDH and MCT-related drugs, and highlights the potential of immunotherapy targeting lactate combined with HCC.

T cell exhaustion refers to a progressive state in which T cells become functionally impaired due to sustained antigenic stimulation, which is characterized by increased expression of immune inhibitory receptors, but weakened effector functions, reduced self-renewal capacity, altered epigenetics, transcriptional programme and metabolism. T cell exhaustion is one of the major causes leading to immune escape of cancer, creating an environment that supports tumor development and metastatic spread. In addition, T cell exhaustion plays a pivotal role to the efficacy of current immunotherapies for cancer. This review aims to provide a comprehensive view of roles of T cell exhaustion in cancer development and progression. We summerized the regulatory mechanisms that involved in T cell exhaustion, including transcription factors, epigenetic and metabolic reprogramming events, and various microenvironmental factors such as cytokines, microorganisms, and tumor autocrine substances. The paper also discussed the challenges posed by T cell exhaustion to cancer immunotherapies, including immune checkpoint blockade (ICB) therapies and chimeric antigen receptor T cell (CAR-T) therapy, highlightsing the obstacles encountered in ICB therapies and CAR-T therapies due to T cell exhaustion. Finally, the article provides an overview of current therapeutic options aimed to reversing or alleviating T cell exhaustion in ICB and CAR-T therapies. These therapeutic approaches seek to overcome T cell exhaustion and enhance the effectiveness of immunotherapies in treating tumors.

Women that present to the clinic with established breast cancer metastases have limited treatment options. Yet, the majority of preclinical studies are actually not directed at developing treatment regimens for established metastatic disease. In this review we will discuss the current state of preclinical macro-metastatic breast cancer models, including, but not limited to syngeneic GEMM, PDX and xenografts. Challenges within these models which are often overlooked include fluorophore-immunogenic neoantigens, differences in experimental vs spontaneous metastasis and tumor heterogeneity. Furthermore, due to cell plasticity in the tumor immune microenvironment (TIME) of the metastatic landscape, the treatment efficacy of newly approved immune checkpoint blockade (ICB) may differ in metastatic sites as compared to primary localized tumors.

Cancer neuroscience, a promising field dedicated to exploring interactions between cancer and the nervous system, has attracted growing attention. The gastrointestinal tracts exhibit extensive innervation, notably characterized by intrinsic innervation. The gut harbors a substantial population of glial cells, including Schwann cells wrapping axons of neurons in the peripheral nervous system and enteric glial cells intricately associated with intrinsic innervation. Glial cells play a crucial role in maintaining the physiological functions of the intestine, encompassing nutrient absorption, barrier integrity, and immune modulation. Nevertheless, it has only been in recent times that the significance of glial cells within colorectal cancer (CRC) has begun to receive considerable attention. Emerging data suggests that glial cells in the gut contribute to the progression and metastasis of CRC, by interacting with cancer cells, influencing inflammation, and modulating the tumor microenvironment. Here, we summarize the significant roles of glial cells in the development and progression of CRC and discuss the latest technologies that can be integrated into this field for in-depth exploration, as well as potential specific targeted strategies for future exploration to benefit patients.

Mixed-lineage kinase 3 (MLK3) is a serine/threonine kinase of the MAPK Kinase kinase (MAP3K) family that plays critical roles in various biological processes, including cancer. Upon activation, MLK3 differentially activates downstream MAPKs, such as JNK, p38, and ERK. In addition, it regulates various non-canonical signaling pathways, such as β-catenin, AMPK, Pin1, and PAK1, to regulate cell proliferation, apoptosis, invasion, and metastasis. Recent studies have also uncovered other potentially diverse roles of MLK3 in malignancy, which include metabolic reprogramming, cancer-associated inflammation, and evasion of cancer-related immune surveillance. The role of MLK3 in cancer is complex and cancer-specific, and an understanding of its function at the molecular level aligned specifically with the cancer hallmarks will have profound therapeutic implications for diagnosing and treating MLK3-dependent cancers. This review summarizes the current knowledge about the effect of MLK3 on the hallmarks of cancer, providing insights into its potential as a promising anticancer drug target.

As a free radical and endogenous effector molecule, mammalian endogenous nitric oxide (NO) is mainly derived from nitric oxide synthase (NOS) via L-arginine. NO participates in normal physiological reactions and provides immune responses to prevent the invasion of foreign bacteria. However, NO also has complex and contradictory biological effects. Abnormal NO signaling is involved in the progression of many diseases, such as cancer. In the past decades, cancer research has been closely linked with NOS/ NO, and many tumors with poor prognosis are associated with high expression of NOS. In this review, we give a overview of the biological effects of NOS/ NO. Then we focus on the oncogenic role of iNOS/ NO in HPV, HBV, EBV and H. pylori related tumors. In fact, there is growing evidence that iNOS could be used as a potential therapeutic target in cancer therapy. We emphasize that the pro-tumor effect of NOS/ NO is greater than the anti-tumor effect.

Tumor microenvironment is formed by various cellular and non-cellular components which interact with one another and form a complex network of interactions. Some of these cellular components also attain a secretory phenotype and release growth factors, cytokines, chemokines etc. in the surroundings which are capable of inducing even greater number of signalling networks. All these interactions play a decisive role in determining the course of tumorigenesis. The treatment strategies against cancer also exert their impact on the local microenvironment. Such interactions and anticancer therapies have been found to induce more deleterious outcomes like immunosuppression and chemoresistance in the process of tumor progression. Hence, understanding the tumor microenvironment is crucial for dealing with cancer and chemoresistance. This review is an attempt to develop some understanding about the tumor microenvironment and different factors which modulate it, thereby contributing to tumorigenesis. Along with summarising the major components of tumor microenvironment and various interactions taking place between them, it also throws some light on how the existing and potential therapies exert their impact on these dynamics.

Angiosarcoma is a rare endothelial-derived malignancy that is extremely diverse in anatomy, aetiology, molecular and immune characteristics. While novel therapeutic approaches incorporating targeted agents and immunotherapy have yielded significant improvements in patient outcomes across several cancers, their impact on angiosarcoma remains modest. Contributed by its heterogeneous nature, there is currently a lack of novel drug targets in this disease entity and no reliable biomarkers that predict response to conventional treatment. This review aims to examine the molecular and immune landscape of angiosarcoma in association with its aetiology, anatomical sites, prognosis and therapeutic options. We summarise current efforts to characterise angiosarcoma subtypes based on molecular and immune profiling. Finally, we highlight promising technologies such as single-cell spatial “omics” that may further our understanding of angiosarcoma and propose strategies that can be similarly applied for the study of other rare cancers.

Chimeric antigen receptor (CAR) T cell therapy presents significant results, especially for the treatment of hematologic malignancies. However, there are limitations and challenges to be overcome to achieve similar success for the treatment of solid tumors. These challenges involve selection of the target, infiltration into the tumor microenvironment and maintenance of functionality. The tumor vasculature is a major barrier for leukocytes to enter the tumor parenchyma. Due to the exposure of the vasculature to angiogenic growth factors during tumor progression, the endothelial cells become anergic to inflammatory cytokines, resulting in reduced leukocyte adhesion molecule expression. As such adhesion molecules are a prerequisite for leukocyte extravasation, endothelial cell anergy allows tumors to escape from endogenous immunity, as well as from cellular immunotherapies such as CAR T cells. Hence, overcoming endothelial cell anergy, e.g. through the administration of angiogenesis inhibitors, is believed to restore anti-tumor immunity. Concomitantly, both endogenous immune cells as well as cellular therapeutics such as CAR T cells can permeate into the tumor parenchyma. Here, we discuss how prior or concomitant treatment with an antiangiogenic drug can improve CAR T cell therapy, to become an attractive strategy for the treatment of solid tumors.