Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma.

Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.

The American Cancer Society National Lung Cancer Roundtable strategic plan: Advancing comprehensive biomarker testing in non-small cell lung cancer.

Comprehensive biomarker testing is a crucial requirement for the optimal treatment of advanced-stage non-small cell lung cancer (NSCLC), with emerging relevance in the adjuvant treatment setting. To advance its goal of ensuring optimal therapy for persons diagnosed with lung cancer, the American Cancer Society National Lung Cancer Roundtable (ACS NLCRT) held The Summit on Optimizing Lung Cancer Biomarkers in Practice in September 2020 to align its partners toward the goal of ensuring comprehensive biomarker testing for all eligible patients with NSCLC. The ACS NLCRT's Strategic Plan for Advancing Comprehensive Biomarker Testing in NSCLC, a product of the summit, comprises actions to promote comprehensive biomarker testing for all eligible patients. The approach is multifaceted, including policy-level advocacy and the development and dissemination of targeted educational materials, clinical decision tools, and guides to patients, physicians, and payers aimed at ameliorating barriers to testing experienced by each of these groups. PLAIN LANGUAGE SUMMARY: The ACS NLCRT works to improve care for patients with lung cancer. The ACS NLCRT supports comprehensive biomarker testing as essential to determine treatment options for all eligible patients with non-small cell lung cancer. Many factors lead to some patients not receiving optimal biomarker testing. The ACS NLCRT held a collaborative summit and developed a strategic plan to achieve and promote comprehensive biomarker testing for all patients. These plans include developing educational materials and physician tools and advocating for national policies in support of biomarker testing.

From promise to progress: the dynamic landscape of glioblastoma immunotherapy.

Glioblastoma multiforme (GBM) is the most common CNS cancer, it has dismal survival rates despite several effective mediators: intensified cytotoxic therapy, chimeric antigen receptor (CAR)-T cell therapy, viral therapy, adoptive cell therapy, immune checkpoint blockade therapy, radiation therapy and vaccine therapy. This review examines the basic concepts underlying immune targeting and examines products such as checkpoint blockade drugs, CAR-T cells, oncolytic viruses, combinatory multimodal immunotherapy and cancer vaccines. New approaches to overcoming current constraints and challenges in GBM therapy are discussed, based on recent studies into these tactics, findings from ongoing clinical trials, as well as previous trial results.

Decoding the secret of extracellular vesicles in the immune tumor microenvironment of the glioblastoma: on the border of kingdoms.

Over the last decades, extracellular vesicles (EVs) have become increasingly popular for their roles in various pathologies, including cancer and neurological and immunological disorders. EVs have been considered for a long time as a means for normal cells to get rid of molecules it no longer needs. It is now well established that EVs play their biological roles also following uptake or by the interaction of EV surface proteins with cellular receptors and membranes. In this review, we summarize the current status of EV production and secretion in glioblastoma, the most aggressive type of glioma associated with high mortality. The main purpose is to shed light on the EVs as a universal mediator of interkingdom and intrakingdom communication in the context of tumor microenvironment heterogeneity. We focus on the immunomodulatory EV functions in glioblastoma-immune cross-talk to enhance immune escape and reprogram tumor-infiltrating immune cells. We critically examine the evidence that GBM-, immune cell-, and microbiome-derived EVs impact local tumor microenvironment and host immune responses, and can enter the circulatory system to disseminate and drive premetastatic niche formation in distant organs. Taking into account the current state of the art in intratumoral microbiome studies, we discuss the emerging role of bacterial EV in glioblastoma and its response to current and future therapies including immunotherapies.

[Chinese consensus for the bispecific T cell engager in the treatment of acute lymphoblastic leukemia (2024)].

Acute lymphoblastic leukemia (ALL) is one of the most common acute leukemias, with rapid onset and progression. The standardized application of chemotherapy and transplantation have improved the prognosis of patients, while the unmet therapeutic needs still exist. Recently novel immunotherapies including Bispecific T cell Engager develop rapidly, offering more options for ALL treatment and also demanding higher requirements for clinical diagnosis and treatment management. Based on the evidence of domestic and international medical evidence and clinical experience, the expert panel updated Chinese consensus for the Bispeific T cell Engager in the treatment of B-cell acute lymphoblastic leukemia (2022) and formulated this edition of the Chinese expert consensus.

Strategies for treating the cold tumors of cholangiocarcinoma: core concepts and future directions.

Cholangiocarcinoma (CCA) is a rare type of digestive tract cancer originating from the epithelial cells of the liver and biliary tract. Current treatment modalities for CCA, such as chemotherapy and radiation therapy, have demonstrated limited efficacy in enhancing survival rates. Despite the revolutionary potential of immunotherapy in cancer management, its application in CCA remains restricted due to the minimal infiltration of immune cells in these tumors, rendering them cold and unresponsive to immune checkpoint inhibitors (ICIs). Cancer cells within cold tumors deploy various mechanisms for evading immune attack, thus impeding clinical management. Recently, combination immunotherapy has become increasingly essential to comprehend the mechanisms underlying cold tumors to enhance a deficient antitumor immune response. Therefore, a thorough understanding of the knowledge on the combination immunotherapy of cold CCA is imperative to leverage the benefits of immunotherapy in treating patients. Moreover, gut microbiota plays an essential role in the immunotherapeutic responses in CCA. In this review, we summarize the current concepts of immunotherapy in CCA and clarify the intricate dynamics within the tumor immune microenvironment (TIME) of CCA. We also delve into the evasion mechanisms employed by CCA tumors against the anti-tumor immune responses. The context of combination immunotherapies in igniting cold tumors of CCA and the critical function of gut microbiota in prompting immune responses have also been annotated. Furthermore, we have proposed future directions in the realm of CCA immunotherapy, aiming to improve the clinical prognosis of CCA patients.

IFNγ-Induced Bcl3, PD-L1 and IL-8 Signaling in Ovarian Cancer: Mechanisms and Clinical Significance.

IFNγ, a pleiotropic cytokine produced not only by activated lymphocytes but also in response to cancer immunotherapies, has both antitumor and tumor-promoting functions. In ovarian cancer (OC) cells, the tumor-promoting functions of IFNγ are mediated by IFNγ-induced expression of Bcl3, PD-L1 and IL-8/CXCL8, which have long been known to have critical cellular functions as a proto-oncogene, an immune checkpoint ligand and a chemoattractant, respectively. However, overwhelming evidence has demonstrated that these three genes have tumor-promoting roles far beyond their originally identified functions. These tumor-promoting mechanisms include increased cancer cell proliferation, invasion, angiogenesis, metastasis, resistance to chemotherapy and immune escape. Recent studies have shown that IFNγ-induced Bcl3, PD-L1 and IL-8 expression is regulated by the same JAK1/STAT1 signaling pathway: IFNγ induces the expression of Bcl3, which then promotes the expression of PD-L1 and IL-8 in OC cells, resulting in their increased proliferation and migration. In this review, we summarize the recent findings on how IFNγ affects the tumor microenvironment and promotes tumor progression, with a special focus on ovarian cancer and on Bcl3, PD-L1 and IL-8/CXCL8 signaling. We also discuss promising novel combinatorial strategies in clinical trials targeting Bcl3, PD-L1 and IL-8 to increase the effectiveness of cancer immunotherapies.

Cardiovascular toxicities of immune therapies for cancer - a scientific statement of the Heart Failure Association (HFA) of the ESC and the ESC Council of Cardio-Oncology.

The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell-based immune therapies including chimeric antigen receptor T lymphocyte (CAR-T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune-related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune-related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI-related myocarditis with cardiogenic shock to more common complications including less severe ICI-related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non-inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR-T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus.

Photo-activated microtubule targeting drugs: Advancing therapies for colorectal cancer.

Over the years immunotherapy has demonstrably improved the field of cancer treatment. However, achieving long-term survival for colorectal cancer (CRC) patients remains a significant unmet need. Combination immunotherapies incorporating targeted drugs like MEK or multi-kinase inhibitors have offered some palliative benefit. Nevertheless, substantial gaps remain in the current therapeutic armamentarium for CRC. In recent years, there has been a surge of interest in exploring novel treatment strategies, including the application of light-activated drugs in conjunction with optical devices. This approach holds promise for achieving localized and targeted delivery of cytotoxic agents, such as microtubule-targeting drugs, directly to cancerous cells within the colon.

Natural killer cells and engagers: Powerful weapons against cancer.

Natural killer (NK) cells are innate immune effectors whose functions rely on receptors binding cytokines, recognizing self-molecules, or detecting danger signals expressed by virus-infected or tumor cells. The potent cytotoxic potential makes NK cells promising candidates for cancer immunotherapy. To enhance their activity strategies include cytokine administration, blocking of immune checkpoints, and designing of antibody-based NK cell engagers (NKCEs). NKCEs represent a cutting-edge approach to cancer therapy: they strengthen the NK-to-target cell interactions and optimize tumor killing, possibly overcoming the immunosuppressive tumor microenvironment. NK cells belong to the innate lymphoid cells (ILCs) and are categorized into different subsets also including cells with a memory-like phenotype: this complexity needs to be explored in the context of cancer immunotherapy, particularly when designing NKCEs. Two strategies to enhance NK cell activity in cancer patients can be adopted: activating patients' own NK cells versus the adoptive transfer of ex vivo activated NK cells. Furthermore, the capability of NKCEs to activate γδ T cells could have a significant synergistic effect in immunotherapy.

The complex role of macrophages in pancreatic cancer tumor microenvironment: a review on cancer progression and potential therapeutic targets.

Pancreatic cancer (PC) is one of the deadliest cancers worldwide with low survival rates and poor outcomes. The treatment landscape for PC is fraught with obstacles, including drug resistance, lack of effective targeted therapies and the immunosuppressive tumor microenvironment (TME). The resistance of PC to existing immunotherapies highlights the need for innovative approaches, with the TME emerging as a promising therapeutic target. The recent advancements in understanding the role of macrophages, this context highlight their significant impact on tumor development and progression. There are two important types of macrophages: M1 and M2, which play critical roles in the TME. Therapeutics strategies including, depletion of tumor-associated macrophages (TAMs), reprogramming TAMs to promote anti-tumor activity, and targeting macrophage recruitment can lead to promising outcomes. Targeting macrophage-related pathways may offer novel strategies for modulating immune responses, inhibiting angiogenesis, and overcoming resistance to chemotherapy in PC treatment.

Advances in exosomes utilization for clinical applications in cancer.

Exosomes are regarded as having transformative potential for clinical applications. Exosome-based liquid biopsies offer a noninvasive method for early cancer detection and real-time disease monitoring. Clinical trials are underway to validate the efficacy of exosomal biomarkers for enhancing diagnostic accuracy and predicting treatment responses. Additionally, engineered exosomes are being developed as targeted drug delivery systems that can navigate the bloodstream to deliver therapeutic agents to tumor sites, thus enhancing treatment efficacy while minimizing systemic toxicity. Exosomes also exhibit immunomodulatory properties, which are being harnessed to boost antitumor immune responses. In this review, we detail the latest advances in clinical trials and research studies, underscoring the potential of exosomes to revolutionize cancer care.

From MASLD to HCC: What's in the middle?

Metabolic dysfunction associated steatotic liver disease (MASLD) is a progressive pathological condition characterized by the accumulation of triglycerides within hepatocytes that causes histological changes, which, in the long run, might compromise liver functional capacities. MASLD predisposes to metabolic dysfunction-associated steatohepatitis (MASH), in which the persistence of inflammatory reactions perpetuates tissue injury and induces alterations of the extracellular matrix, leading to liver fibrosis and cirrhosis. Furthermore, these processes are also fertile ground for the development of hepatocellular carcinoma (HCC). In this latter respect, growing evidence suggests that chronic inflammation not only acts as the primary stimulus for hepatocellular malignant transformation, cell proliferation and cancer cell progression but also reshapes the immune landscape, inducing immune system exhaustion and favoring the loss of cancer immune surveillance. Therefore, a thorough understanding of the cellular and molecular mechanisms orchestrating hepatic inflammatory responses may open the way for fine-tuning therapeutic interventions that could, from one side, counteract MASLD progression and, on the other one, effectively treat HCCs.

Immunotherapies: A Treasure Trove of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that falls under the umbrella of dementia and is characterized by the presence of enormously neurotoxic amyloid- beta (Aß) plaques and neurofibrillary tangles (NFTs) of tau protein inside the brain. AD remains an intractable global health challenge with limited therapeutic options. Early diagnosis, enabled by biomarkers and neuroimaging, is pivotal for optimizing treatment outcomes. Immunotherapeutic strategies, including monoclonal antibodies, active vaccination, and passive immunization, have been developed to target hallmark AD pathology, such as amyloid-beta aggregation. Here we summarized the emerging role of immunotherapies in the early stages of AD, shedding light on recent breakthroughs and clinical progress. Challenges, including treatment response variability and safety concerns, are discussed alongside evolving approaches, such as personalized immunotherapy and combinatorial treatments. This concise review underscores the promise of immunotherapies as a transformative approach to AD intervention, offering hope for a brighter future in the quest to combat this devastating neurodegenerative disease.

Myeloid-derived suppressor cells: Implication in myeloid malignancies and immunotherapy.

Myeloid malignancies stem from a modified hematopoietic stem cell and predominantly include acute myeloid leukemia, myelodysplastic neoplasms, myeloproliferative malignancies, and chronic myelomonocytic leukemia. Myeloid-derived suppressor cells (MDSCs) exhibit immunoregulatory properties by governing the innate and adaptive immune systems, creating a permissive and supportive environment for neoplasm growth. This review examines the key characteristics of MDSCs in myeloid malignancies, highlighting that an increased MDSC count corresponds to heightened immunosuppressive capabilities, fostering an immune-tolerant neoplasm microenvironment. Also, this review analyzes and describes the potential of combined cancer therapies, focusing on targeting MDSC generation, expansion, and their inherent immunosuppressive activities to enhance the efficacy of current cancer immunotherapies. A comprehensive understanding of the implications of myeloid malignancies may enhance the exploration of immunotherapeutic strategies for their potential application.

The crosstalk between immune cells and tumor pyroptosis: advancing cancer immunotherapy strategies.

Pyroptosis is a cell death process characterized by cell swelling until membrane rupture and release of intracellular contents. As an effective tumor treatment strategy, inducing tumor cell pyroptosis has received widespread attention. In this process, the immune components within the tumor microenvironment play a key regulatory role. By regulating and altering the functions of immune cells such as cytotoxic T lymphocytes, natural killer cells, tumor-associated macrophages, and neutrophils, tumor cell pyroptosis can be induced. This article provides a comprehensive review of the molecular mechanisms of cell pyroptosis, the impact of the tumor immune microenvironment on tumor cell pyroptosis, and its mechanisms. It aims to gain an in-depth understanding of the communication between the tumor immune microenvironment and tumor cells, and to provide theoretical support for the development of new tumor immunotherapies.

Immune-related adverse events of antibody-based biological medicines in cancer therapy.

Recombinant antibodies (Abs) are an integral modality for the treatment of multiple tumour malignancies. Since the Food and Drug Administration (FDA) approval of rituximab as the first monoclonal antibody (mAb) for cancer treatment, several mAbs and antibody (Ab)-based therapies have been approved for the treatment of solid tumour malignancies and other cancers. These Abs function by either blocking oncogenic pathways or angiogenesis, modulating immune response, or by delivering a conjugated drug. The use of Ab-based therapy in cancer patients who could benefit from the treatment, however, is still limited by associated toxicity profiles which may stem from biological features and processes related to target binding, alongside biochemical and/or biophysical characteristics of the therapeutic Ab. A significant immune-related adverse event (irAE) associated with Ab-based therapies is cytokine release syndrome (CRS), characterized by the development of fever, rash and even marked, life-threatening hypotension, and acute inflammation with secondary to systemic uncontrolled increase in a range of pro-inflammatory cytokines. Here, we review irAEs associated with specific classes of approved, Ab-based novel cancer immunotherapeutics, namely immune checkpoint (IC)-targeting Abs, bispecific Abs (BsAbs) and Ab-drug-conjugates (ADCs), highlighting the significance of harmonization in preclinical assay development for safety assessment of Ab-based biotherapeutics as an approach to support and refine clinical translation.

Ubiquitination and deubiquitination in cancer: from mechanisms to novel therapeutic approaches.

Ubiquitination, a pivotal posttranslational modification of proteins, plays a fundamental role in regulating protein stability. The dysregulation of ubiquitinating and deubiquitinating enzymes is a common feature in various cancers, underscoring the imperative to investigate ubiquitin ligases and deubiquitinases (DUBs) for insights into oncogenic processes and the development of therapeutic interventions. In this review, we discuss the contributions of the ubiquitin-proteasome system (UPS) in all hallmarks of cancer and progress in drug discovery. We delve into the multiple functions of the UPS in oncology, including its regulation of multiple cancer-associated pathways, its role in metabolic reprogramming, its engagement with tumor immune responses, its function in phenotypic plasticity and polymorphic microbiomes, and other essential cellular functions. Furthermore, we provide a comprehensive overview of novel anticancer strategies that leverage the UPS, including the development and application of proteolysis targeting chimeras (PROTACs) and molecular glues.

Multiple myeloma: signaling pathways and targeted therapy.

Multiple myeloma (MM) is the second most common hematological malignancy of plasma cells, characterized by osteolytic bone lesions, anemia, hypercalcemia, renal failure, and the accumulation of malignant plasma cells. The pathogenesis of MM involves the interaction between MM cells and the bone marrow microenvironment through soluble cytokines and cell adhesion molecules, which activate various signaling pathways such as PI3K/AKT/mTOR, RAS/MAPK, JAK/STAT, Wnt/ß-catenin, and NF-κB pathways. Aberrant activation of these pathways contributes to the proliferation, survival, migration, and drug resistance of myeloma cells, making them attractive targets for therapeutic intervention. Currently, approved drugs targeting these signaling pathways in MM are limited, with many inhibitors and inducers still in preclinical or clinical research stages. Therapeutic options for MM include non-targeted drugs like alkylating agents, corticosteroids, immunomodulatory drugs, proteasome inhibitors, and histone deacetylase inhibitors. Additionally, targeted drugs such as monoclonal antibodies, chimeric antigen receptor T cells, bispecific T-cell engagers, and bispecific antibodies are being used in MM treatment. Despite significant advancements in MM treatment, the disease remains incurable, emphasizing the need for the development of novel or combined targeted therapies based on emerging theoretical knowledge, technologies, and platforms. In this review, we highlight the key role of signaling pathways in the malignant progression and treatment of MM, exploring advances in targeted therapy and potential treatments to offer further insights for improving MM management and outcomes.