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Hydroxytyrosol Inhibits MDSCs and Promotes M1 Macrophages in Mice With Orthotopic Pancreatic Tumor.

The poor immunotherapy of pancreatic cancer is mainly due to its complex immunosuppressive microenvironment. The Mediterranean diet contributes to low cancer incidence. Hydroxytyrosol (HT) derived from olive oil has multiple health-promoting effects, but its therapeutic effect on pancreatic cancer remains controversial. Here, we evaluated the inhibitory effect of HT on mouse pancreatic cancer, and the effect of HT on the immune microenvironment. We found that HT can inhibit the proliferation of Panc 02 cells through signal transducer and activator of transcription (STAT) 3/Cyclin D1 signaling

Immunotherapy in prostate cancer: new horizon of hurdles and hopes.

PURPOSE: Prostate cancer (PCa) is the most common malignancy in men and the cause for the second most common cancer-related death in the wes … ODS: We searched for relevant publications on molecular and cellular mechanisms involved in the PCa tumor microenvironment and response to IT as well as completed and ongoing IT studies and screened appropriate abstracts of international congresses. RESULTS: Tumor progression and patient outcomes depend on complex cellular and molecular interactions of the tumor with t …

Molecular cargo of small EVs from NSCLC patient BALF and plasma: unveiling their role in airway inflammation and immune regulation in a novel human 3D bronchial model.

BACKGROUND: Tumor-derived small extracellular vesicles (EVs) play a crucial role in modulating immune responses and shaping the tumor microenvironment; however, their functional impact on airway immunity in NSCLC remains largely unexplored. This study represents the first attempt to investigate the immunomodulatory and tumor-promoting effects of NSCLC-derived EVs in a human 3D bronchial airway model, which closely mimics the human lung microenvironment. METHODS: EVs were isolated from the plasma and bronchoalveolar lavage fluid (BALF) of NSCLC patients and analyzed via nanoparticle tracking a…

Metabolic and Immunological Implications of MME+CAF-Mediated Hypoxia Signaling in Pancreatic Cancer Progression: Therapeutic Insights and Translational Opportunities.

Pancreatic cancer is a devastating malignancy with a high mortality rate, poor prognosis, and limited treatment options. The tumor microenvironment (TME) plays a crucial role in tumor progression and therapy resistance. Multiple subpopulations of cancer-associated fibroblasts (CAFs) within the TME can switch between different states, exhibiting both antitumorigenic and protumorigenic functions in pancreatic cancer. It seems that targeting fibroblast-related proteins and other stromal components is an appealing approach to combat pancreatic cancer. This study employed single-cell transcriptome …

Protocol for surgical stress-promoted colorectal cancer liver metastasis in mice.

Although hepatectomy can be therapeutic, ischemia-reperfusion (I/R) caused by temporary interruption of blood flow creates an inflammatory microenvironment that facilitates tumor-cell seeding and postoperative metastasis. Here, we present a protocol for combining hepatic I/R in mice with portal vein injection of syngeneic colorectal cancer cells. We describe steps for injecting tumor cells under anesthesia, transiently occluding hepatic blood flow, and monitoring liver metastasis. This model recapitulates tumor-host interactions and enables investigation of surgical stress-promoted colorectal

Scope of nanobodies in hepatopancreatobiliary oncology.

Hepatopancreatobiliary (HPB) cancers remain among the most aggressive malignancies. Nanobodies are single-domain antibodies derived from cam … rove pharmacokinetics, enhance tumor penetration, enhance therapeutic performance, and modulate the tumor microenvironment. This article also addresses key challenges in the clinical translation and large-scale production of nanobodies for precise diagnosis and treatment applications in HPB oncology.

Innovations in peptide-based targeted therapies for breast cancer: From conjugates to precision delivery.

Breast cancer remains a leading cause of mortality among women worldwide, necessitating therapeutic innovations that combine precision targe … ity of peptides to enable precise drug delivery, disrupt oncogenic signaling pathways, modulate the tumor microenvironment, and overcome therapeutic resistance. This review presents recent advances in peptide-based targeted therapies, highlighting the ongoing need to address tumor heterogeneity and resistance.

Ret transgenic mouse model of spontaneous skin melanoma: focus on regulatory T cells.

Ret transgenic mouse model of skin malignant melanoma is characterized by the overexpression of the human ret transgene in melanin-containing cells. Transgenic mice spontaneously develop skin tumors with metastases in lymph nodes, lungs, liver, brain, and the bone marrow. Tumor lesions show typical melanoma morphology and express melanoma-associated antigens. Although transgenic mice demonstrate an accumulation of melanoma antigen-specific memory and effector T cells, their anti-tumor effects could be blocked by highly immunosuppressive leukocytes enriched in the tumor microenvironment and in …

Bone Metastasis: Molecular Mechanisms, Clinical Management, and Therapeutic Targets.

Bone metastasis (BoMet) is a common complication in various cancers. Approximately 20-30% of patients with cancer develop BoMet, which is most frequently associated with solid tumors, such as breast, prostate, and lung cancers. BoMet can lead to skeletal-related events such as fractures, bone pain, and hypercalcemia, negatively affecting the patient's quality of life and markedly shortening overall survival. The development of BoMet is a complex, multistep process driven by dynamic interactions between tumor cells and the bone microenvironment. The bone microenvironment provides a supportive n

Immunotherapy plus chemotherapy in advanced biliary tract cancers: pros and cons.

INTRODUCTION: Biliary tract cancers (BTC) are highly immunosuppressive 'cold' tumors with limited treatment options. In unresectable or advanced-stage disease, the combination of immune checkpoint inhibition with chemotherapy resulted in a modest survival benefit over chemotherapy. AREAS COVERED: In this review, current obstacles and strategies to improve the benefit of immunotherapy are highlighted. This includes challenges in optimizing patient selection, understanding the tumor microenvironment and interactions with the gut microbiome, and improving combination treatment strategies, whethe…

Beyond the marrow: insights from comprehensive next-generation sequencing of extramedullary multiple myeloma tumors.

Extramedullary multiple myeloma (EMM) is an aggressive form of multiple myeloma (MM). This study represents the most comprehensive next-generation sequencing analysis of EMM tumors (N = 14) to date, uncovering key molecular features and describing the tumor microenvironment. We observed the co-occurrence of 1q21 gain/amplification and MAPK pathway mutations in 79% of EMM samples, suggesting that these are crucial mutational events in EMM development. We also demonstrated that patients with mutated KRAS and 1q21 gain/amplification at the time of diagnosis have a significantly higher risk of EMM…

Propranolol: A "Pick and Roll" Team Player in Benign Tumors and Cancer Therapies.

Research on cancer therapies focuses on processes such as angiogenesis, cell signaling, stemness, metastasis, and drug resistance and inflammation, all of which are influenced by the cellular and molecular microenvironment of the tumor. Different strategies, such as antibodies, small chemicals, hormones, cytokines, and, recently, gene editing techniques, have been tested to reduce the malignancy and generate a harmful microenvironment for the tumor. Few therapeutic agents have shown benefits when administered alone, but a few more have demonstrated clear improvement when administered in combin

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… In addition, accumulated publications and clinical trials point to its possible role as a regulator of the tumor microenvironment (see Section 2 . “Why propranolol?”). … Furthermore, the “ starting line up ” targets in cancer therapies have been: (1) the cell cycle (proliferative signaling, cell death, and replicative immortality), (2) cellular metabolism (the Warburg effect), (3) the tumor microenvironment (immune response, inflammation and, angiogenesis), and (4) multidrug …

Printing the Pathway Forward in Bone Metastatic Cancer Research: Applications of 3D Engineered Models and Bioprinted Scaffolds to Recapitulate the Bone-Tumor Niche.

Breast cancer commonly metastasizes to bone, resulting in osteolytic lesions and poor patient quality of life. The bone extracellular matrix (ECM) plays a critical role in cancer cell metastasis by means of the physical and biochemical cues it provides to support cellular crosstalk. Current two-dimensional in-vitro models lack the spatial and biochemical complexities of the native ECM and do not fully recapitulate crosstalk that occurs between the tumor and endogenous stromal cells. Engineered models such as bone-on-a-chip, extramedullary bone, and bioreactors are presently used to model cellu

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… Applications of dECM-based bioinks hold particular promise in studying ECM components of the tumor microenvironment (TME) and tumor–ECM interplay [ 213 ]. … Novel Techniques to Study the Bone-Tumor Microenvironment, in Tumor Microenvironment: Advances in Experimental Medicine and Biology Birbrair A. Springer New York, NY, USA 2020 10.1007/978-3-030-35727-6_1 32030644 34. Belgodere J.A. King C.T. Bursavich J.B. Burow M.E. Martin E.C. Jung J.P. …

Meet me halfway: Are in vitro 3D cancer models on the way to replace in vivo models for nanomedicine development?

The complexity and diversity of the biochemical processes that occur during tumorigenesis and metastasis are frequently over-simplified in the traditional in vitro cell cultures. Two-dimensional cultures limit researchers' experimental observations and frequently give rise to misleading and contradictory results. Therefore, in order to overcome the limitations of in vitro studies and bridge the translational gap to in vivo applications, 3D models of cancer were developed in the last decades. The three dimensions of the tumor, including its cellular and extracellular microenvironment, are recre

Sequential-Delivery Gel Microspheres Integrating HAase-Mediated ECM Remodeling and GA-Active Targeting for Deep Tumor Penetration in TACE-Treated HCC.

OBJECTIVE: Transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) is limited by inadequate intratumoral drug penetration. We developed a sequential-delivery composite gel microsphere system integrating hyaluronidase (HAase)-mediated microenvironment remodeling, glycyrrhetinic acid (GA)-mediated active targeting, and pH-responsive drug release as a potential strategy to address this barrier. METHODS: Bufalin (BUF)-loaded GA-PEG-HYD-PLGA nanoparticles and HAase were co-encapsulated within carboxymethyl chitosan/sodium alginate gel microspheres containing BaSO4 for ra

Oncolytic Virus VV-GMCSF-Lact and Human GM-CSF Against GL261 Glioma in Immunocompetent Mice.

Background/Objectives: Oncolytic viruses are an immunotherapeutic approach that can modulate the tumor microenvironment (TME), transforming immunologically 'cold' tumors into 'hot' ones. Insertion of genes encoding immunomodulatory proteins can further enhance antitumor immune responses. In this study, we compared the antitumor and immunomodulatory effects of the double recombinant vaccinia virus VV-GMCSF-Lact, which carries the human GM-CSF gene, with those of recombinant human GM-CSF (rhGM-CSF) in an immunocompetent murine GL261 glioma model. Methods: The study was conducted using a subcutan…

Lung cancer vaccines to enhance immune checkpoint inhibitor therapy: evidence and future perspectives.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of lung cancer over the past decade, markedly improving antitumor responses, overall survival, and quality of life. However, durable clinical benefit is achieved in only a subset of patients, and resistance to ICIs remains a major clinical challenge. Mechanistically, resistance arises from multiple, often overlapping processes, including inadequate tumor antigen presentation, dysfunctional T-cell priming and expansion, and the presence of physical and immunosuppressive barriers within the tumor microenvironment that l…

Unmodified γδ T cells exhibit potent antitumor activity in hepatocellular carcinoma and are enhanced by PD-L1 blockade.

OBJECTIVE: Hepatocellular carcinoma (HCC) exhibits a profoundly immunosuppressive microenvironment that limits the efficacy of current immun … V3 expression correlated with improved overall survival and reflected γδ T-cell presence within the tumor microenvironment. Unmodified γδ T cells exerted potent, dose-dependent cytotoxicity against HCC cells and suppressed tumor growth in vivo, particularly in PD-L1-negative models. In PD-L1-positive HCC-LM3 tumors, γδ T cell efficacy was reduced following systemic admi …

A New Paradigm of Bispecific Antibodies in Clinical Management of Gastrointestinal Cancers.

Gastrointestinal (GI) cancers represent a significant global health burden, characterized by high incidence, poor prognosis, and limited res … The discussion extends to innovative strategies involving BsAbs in modulating the immunosuppressive tumor microenvironment and overcoming resistance mechanisms. Furthermore, we explore promising combination therapies involving BsAbs with chemotherapy and immune checkpoint inhibitors (ICIs). The role of artificial intelligence in target prediction and structure optimizat …

Self-passivated bilayer black phosphorus QDs based multifunctional nanoparticles for tumor immune reprogramming.

It is important yet challenging to enhance immunotherapy responses using biosafe agents due to the immunosuppressive tumor microenvironment. To address this challenge, BD3PP was constructed by encapsulating black phosphorus quantum dots (BPQDs), a synthesized thioredoxin reductase inhibitor 3c, and Dir (the fluorescent dye) into PLGA nanoparticles, followed by conjugation with a PDL1 antagonist for synergistic multimodal therapy and imaging. The mechanism and efficiency of BD3PP were investigated through density functional theory (DFT) calculations, molecular docking, and in vitro and in vivo …