Search Results (837)

Prostate cancer is formed of a heterogeneous population of cancer cells with different biological properties. They initially form a small part of the normal stromal microenvironment but are able, through cell-to-cell contact and via exosomes, small nanoparticles containing DNA, mRNA, microRNA, long non-coding RNA, enzymes, and chemokines and cytokines, to transform the normal stromal cells into tumour-associated cells to create an immunosuppressive environment as well as inhibit the antitumour immune response. Matrix metalloproteinases are able to degrade not only the basement membrane but also the extracellular matrix, allowing the exosomes to disseminate via the circulation. Exosomes are organotrophic, homing in to specific tissues such as bone. Here, they create the premetastatic niche devoid of cancer cells and cause an immunosuppressive environment, as well as induce changes in the host cells and produce myeloid-derived suppressor cells, of which some migrate to the primary tumour inhibiting the antitumour immune response further. Prostate cancer cells can disseminate even before the cancer is detected and thus escape curative therapy. If they survive the shear forces of the circulation and the antitumour immune response, they are able to implant in the premetastatic niche, transforming it into the metastatic niche. Here, they enter a latent state or dormancy period, which may last for months or years but later can “awake” to form metastasis. This review critically analyses the cellular and molecular mechanisms, which produce this process from cellular aspects to the signalling pathways responsible for this process. Multiple mechanisms are involved in a coordinated fashion to permit the survival of the cancer cells, from cellular changes in host cells and immunomodulation via chemokines and cytokines. It emphasizes the role of microRNAs and long non-coding RNAs in this process, and that patients with higher Gleason scores have a worse prognosis in terms of biochemical free survival at 10 years. Therefore, a precision medical approach may improve the biochemical free survival rate without affecting the role of the signalling pathways in normal cells. This includes the modulation of interleukin expression, elimination of exosomes, or the inhibition of important enzymes, such as MMP-2, thus mitigating the residual recurrence risk that persists with conventional therapy. Full article

Gliomas, and glioblastoma in particular, remain difficult to model because molecular heterogeneity, diffuse invasion, blood–brain and blood–tumour barrier effects, immune suppression and repeated therapeutic escape converge in the same disease. Two-dimensional cultures, glioma stem cell (GSC) systems, acute tumour slices and animal models remain indispensable for mechanistic research, pharmacology and in vivo validation. Glioma organoids are complementary research platforms, not components of routine diagnostic or treatment procedures. This review links model construction, microenvironmental validation, treatment perturbation and evidence-graded interpretation. We compare patient-derived glioma organoids, GSC-derived organoids, brain organoid–glioma co-cultures, genetically engineered brain tumour organoids, and vascular-associated, immune-cell-containing and chip-based platforms. We distinguish phenotypic resemblance from physiological fidelity, tumour-intrinsic drug sensitivity from delivery competence, and proof-of-concept activity from demonstrated clinical utility. We also examine temozolomide resistance, radiotherapy, targeted and combination therapy, antiangiogenic treatment, tumour-treating fields, immune-cell therapy, oncolytic viruses, multi-omic quality control and prospective validation. Organoids should not substitute for animal models or clinical trials. Their most defensible role is to provide a patient-derived functional layer between mechanism, regimen ranking and molecular tumour-board interpretation, with claims limited by assay reproducibility, clinically achievable exposure and outcome linkage. Full article

Glioblastoma remains the most lethal primary malignancy of the central nervous system, and the modest gains achieved with maximal surgery, radiotherapy and temozolomide have not been matched by the immune checkpoint inhibitors and antigen-specific vaccines that reshaped the treatment of many extracranial cancers. The recurrent disappointment of these approaches has been attributed less to a single molecular lesion than to a confluence of obstacles: profound intratumoural heterogeneity, a densely immunosuppressive and myeloid-rich microenvironment, sequestration and exhaustion of conventional T cells, and the practical difficulty of delivering effectors across the blood–brain barrier. Against this background, γδ T cells have attracted interest as an unconventional effector population that recognises transformed cells through stress-associated and metabolic cues rather than peptide–major histocompatibility complex (MHC) complexes, that kills in an MHC-unrestricted manner, and that can be expanded from healthy donors for allogeneic, off-the-shelf use with little expectation of graft-versus-host disease. This narrative review examines, with a deliberately critical lens, the biological rationale and the experimental evidence for γδ T cell-based immunotherapy of glioblastoma. We summarise the developmental biology and functional subsets of human γδ T cells, the natural killer group 2 member D (NKG2D)-, DNAX accessory molecule 1 (DNAM-1)- and T-cell-receptor-dependent mechanisms through which they engage glioblastoma cells and glioma stem-like cells, and the in vitro and animal-model studies that underpin the field, taking care not to overstate efficacy that has so far been demonstrated only in preclinical or early-phase settings. We then weigh the principal opportunities—locoregional and repeated dosing, combination with chemoradiotherapy, checkpoint blockade and antibody-based redirection—against barriers that include limited persistence, uncertain intratumoural trafficking, donor and manufacturing variability, and the unsettled requirements of potency testing and trial design. We give particular weight to what becomes of γδ T cells inside a hostile tumour—the exhaustion-like dysfunction that follows chronic stimulation, the oxygen and glucose dependence of their effector programme, the interleukin-17-polarising signals generated by activated microglia and by genotoxic therapy, and the confounding effect of corticosteroids—together with the engineering and pharmacological strategies proposed to counter them. The first peer-reviewed phase 1 report of intracranially delivered, drug-resistant γδ T cells has now appeared and documents tolerability in a small, single-arm cohort without establishing survival benefit. Throughout, γδ T cells are presented as a biologically plausible but still investigational strategy whose clinical value will be determined by adequately powered trials rather than by mechanistic appeal alone. Full article

Cancer pain affects more than half of all oncology patients and represents one of the most challenging therapeutic problems in modern medicine. Despite the central role of opioids in cancer pain management—codified by the WHO analgesic ladder—the clinical response to these agents is highly variable between individuals. Pharmacogenomics promises to explain this heterogeneity by identifying functionally relevant genetic polymorphisms in genes encoding opioid receptors, metabolizing enzymes, and membrane transport proteins. However, after two decades of intensive research, clinical translation of genetic data into actionable prescribing strategies remains elusive. A narrative-critical review of the literature was conducted by searching PubMed, Scopus, and Web of Science databases from inception to March 2026, using the search terms “opioid,” “pharmacogenomics,” “pharmacogenetics,” “cancer pain,” “polymorphism,” and individual gene names (OPRM1, CYP2D6, COMT, ABCB1, SLC22A1, UGT2B7, and others). Reference lists of included articles were hand-searched for additional relevant studies. Inclusion was restricted to English-language articles reporting original data or systematic reviews on genetic polymorphisms and opioid response, with priority given to studies conducted in cancer pain populations. Clinical practice guidelines from CPIC, NCCN, ESMO, EAPC, and ASCO were consulted for current recommendations. This narrative-critical review examines the evidence on genetic polymorphisms relevant to opioid response in cancer pain, covering three functional categories: (1) pharmacodynamic genes, including opioid receptors (OPRM1, OPRD1, OPRK1) and neuromodulatory targets (COMT, KCNJ6, MC1R); (2) pharmacokinetic enzymes (CYP2D6, CYP3A4/5, UGT2B7); and (3) membrane transporters, including ABC efflux pumps (ABCB1, ABCG2, ABCC2) and SLC uptake carriers (SLC22A1, SLCO1B1, SLC6A4, SLC6A2). A dedicated section addresses the direct and indirect interference of the tumour itself—through the tumour microenvironment, neuroimmune signalling, epigenetic reprogramming, and cancer-induced organ dysfunction—on opioid pharmacogenomics. The overall evidence is poor and fragmented, a finding intrinsic to the extraordinary diversity, large number, and context-dependent biological activity of the polymorphisms identified. The tumour itself acts as a pervasive confounder that systematically distorts genotype–phenotype relationships. The path forward requires a paradigm shift from candidate-gene association studies to system pharmacogenomics and multi-omic integration. Full article

Lung cancer remains the leading cause of cancer-related mortality worldwide, and durable benefit from immune checkpoint inhibitors is limited by immune exclusion, microenvironmental immunosuppression, and toxicity. This narrative translational review evaluates whether endobronchial intratumoral delivery of immuno- and gene-based therapies can transform bronchoscopic access into a therapeutic platform linking local tumour intervention with systemic antitumour immunity. We synthesise evidence on endobronchial ultrasound, electromagnetic navigation bronchoscopy, and robotic-assisted bronchoscopy, together with local checkpoint blockade, cytokine and mRNA-lipid nanoparticle constructs, oncolytic virotherapy, dendritic-cell approaches, viral and non-viral gene transfer, and enzyme- or metabolite-based strategies. Current clinical evidence remains preliminary, consisting mainly of Phase I trials, small prospective cohorts, and case-based signals, with feasibility and safety observations but no completed randomised trial demonstrating efficacy against standard-of-care systemic therapy. The most plausible candidates are patients with advanced or recurrent NSCLC, bronchoscopically accessible lesions, inadequate response to systemic immunotherapy, and immune-excluded or locally immunosuppressed tumours. Biomarkers such as PD-L1, tumour mutational burden, CD8+ infiltration, tertiary lymphoid structures, radiomics, and circulating tumour DNA require validation. This review integrates delivery technology, immune mechanisms, statistical evidence appraisal, biomarker limitations, AI-guided planning, and global feasibility. Full article

Objectives: Lung adenocarcinoma (LUAD) is molecularly heterogeneous, and the prognostic relevance of fatty acid metabolism (FAM) remains incompletely defined. We aimed to develop a concise FAM-associated prognostic signature and examine its associations with the immune microenvironment and candidate therapeutic vulnerabilities. Methods: TCGA-LUAD transcriptomic and survival data were integrated with MSigDB FAM gene sets. Univariate Cox and elastic-net Cox regression were used to derive a risk score. The locked formula was evaluated in a Japanese cohort (GSE31210) and a U.S. cohort (GSE72094). Immune-infiltration algorithms as well as TIDE, GDSC2, and CPTAC data were used for exploratory immune, drug sensitivity, and protein-level analyses. Results: The six-gene signature comprised CYP4B1, ACOXL, DPEP2, HPGDS, CA4, and ALOX15. High-risk patients had shorter overall survival in the TCGA and both external cohorts (GSE31210, log-rank p = 0.0039; GSE72094, p < 0.0001). The risk score remained independently prognostic after adjustment for age, sex, and clinical stage. High-risk tumours showed lower immune and stromal signals, greater immune exclusion, and a lower TIDE-predicted ICB response proportion. GDSC2 analyses and expression comparisons identified associations with predicted drug sensitivity and lipogenic target expression. Five detectable signature proteins were less abundant in tumours in CPTAC data. Conclusions: This signature stratified patients by prognosis in two geographically distinct external cohorts and generated testable metabolic and immune hypotheses. Prospective validation, assay standardisation, and functional studies are required before clinical use. Full article

Breast cancer (BC) progression is strongly influenced by the extracellular matrix (ECM), whose remodelling regulates tumour growth, invasion, metastasis, immune modulation, and therapeutic response. Among ECM components, collagens have emerged as both structural proteins and active mediators of mechanotransduction, stromal interactions, and tumour cell behaviour. This narrative review analyses collagen families and collagen-associated proteins implicated in BC, integrating evidence on their expression patterns, biological functions, clinical significance, and translational potential. We examine fibrillar and non-fibrillar collagens, including fibril-associated collagens with interrupted triple helices (FACITs), membrane-associated collagens with interrupted triple helices (MACITs), basement membrane (BM) collagens, and multiplexins, together with their interactions with cancer-associated fibroblasts (CAFs), immune cells, and signalling pathways involved in tumour progression. Alterations in collagen composition, organization, crosslinking, and degradation regulate ECM stiffness, epithelial–mesenchymal transition (EMT), invasion, metastatic dissemination, and therapy resistance. Several collagen types and collagen-derived fragments also show promise as prognostic biomarkers and therapeutic targets, particularly in aggressive BC subtypes such as human epidermal growth factor receptor 2 (HER2)-positive and triple-negative breast cancer (TNBC). Overall, this review highlights the collagenome as a dynamic component of the breast tumour microenvironment (TME) and supports collagen-informed strategies for improved patient stratification and targeted therapies. Full article

TLSs are ectopic, non-encapsulated aggregates of immune cells that develop de novo in non-lymphoid tissues in response to persistent antigenic stimulation and have emerged as clinically relevant features of many solid tumours. However, conventional TLS assessment based on presence/absence, density, or simplified maturation scales does not adequately explain why TLSs are associated with favourable, neutral, or even adverse clinical outcomes across tumour types and treatment settings. In this review, we synthesise the current biological, spatial, and clinical evidence and argue that TLSs should be interpreted not as static histologic findings but as functional immune niches shaped by three interacting axes: structural maturity, spatial localisation, and the functional immune context. We discuss how mature germinal centre-positive TLSs often reflect coordinated B-cell–T-cell cooperation and sustained antigen-driven anti-tumour immunity, whereas partially organised or suppressive TLSs may display transitional or immunoregulatory properties. On this basis, we propose a pragmatic, pathology-oriented conceptual framework that groups TLSs into three simplified functional states: TLS-A, representing mature effector TLSs with germinal centre activity; TLS-B, representing organised but incompletely matured or functionally intermediate TLSs; and TLS-C, representing TLSs dominated by regulatory or suppressive immune programs. We further place these states within recurrent tumour microenvironment archetypes and outline the rationale for a “proposed functional TLS score” integrating histopathologic and molecular readouts. Rather than introducing a definitive biological taxonomy, this framework is intended as a translational model for harmonising TLS interpretation, refining biomarker development, and supporting future studies on prognosis, immunotherapy response, and standardised pathology reporting in solid tumours. Because this framework is derived from a narrative synthesis of published evidence rather than from formal validation, it should be regarded as hypothesis-generating and requires prospective, tumour-specific validation before clinical implementation. Full article

Head and neck cancer (HNC) comprises a heterogeneous group of tumours, most often of squamous cell origin, characterized by both high morbidity and mortality rates. It is the seventh most common form of cancer diagnosed in humans, accounting for approximately 4.7% of all cancers. Among HNCs, neck squamous cell carcinoma (HNSCC) is predicted to become the most common form of human cancer. Some sources include oesophagus (ESCC) in this group due to their similar histology, being described as upper aerodigestive tract cancers (UADT). Unfortunately, 60–70% of cases are diagnosed late, i.e., at clinical stages III-IV. As a result, despite modern surgical techniques and oncological treatments, the survival rate remains below 40–60% due to frequent lymph node metastases and local tumour recurrence. There is a growing concern that diet and inflammatory dietary components may influence the initiation and development of HNSCC. The inflammatory potential of diets can be quantified by the Dietary Inflammatory Index (DII). The DII was derived from an analysis of 45 dietary constituents that either increase or decrease inflammation. Several recent clinical studies have noted a significant relationship between DII score and many inflammation-associated chronic diseases, such as obesity, cardiovascular and neurodegenerative disorders, and diabetes, and the incidence of various human cancers, i.e., prostate, ovarian, breast, colorectal cancer, and HNC. However, few studies have investigated the relationship between DII and HNSCC, with most being limited to observational, case-control, and cross-sectional studies. Therefore, the aim of this narrative review is to present the substantial oncological aspects of DII, discuss the use of DII and its modification, the Energy-Adjusted Dietary Inflammatory Index (E-DII), as indicators of HNSCC risk. It also introduces key diet-induced pro- and anti-inflammatory mechanisms and the cellular molecular signalling pathways determining the carcinogenesis of HNSCC. It provides a comprehensive overview of the current literature, including key opinion-forming systematic reviews, as well as molecular, observational, cross-sectional and case-control studies, all of which are accessible via scholarly databases such as PubMed/EMBASE/Web of Science. Thus, the work serves as a compendium of up-to-date knowledge on the relationship between DII/ED-II score and HNSCC etiopathogenesis and the influence of a diet-induced persistent inflammatory microenvironment. Full article

Background/Objectives: Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of advanced malignancies. However, only a subset of patients respond to treatment. Recent efforts have focused on the identification of novel biomarkers that capture the dynamic and functional state of the tumour immune microenvironment, yet their clinical translation has remained challenging. Methods: To address these limitations, we applied amplified FRET-FLIM (QF-Pro^®) technology to spatially resolve and quantitatively assess functional immune checkpoint interactions directly in cells and FFPE tissue and tumour samples. Results: Using this approach, we demonstrated that PD-1/PD-L1, CTLA-4/CD80, TIGIT/CD155, and LAG-3/MHC-II interactions can be robustly quantified in routine FFPE patient samples from multiple tumour types. Furthermore, in a proof-of-concept study in a melanoma cohort treated with immune checkpoint inhibitors (ICIs) targeting PD-1 or CTLA-4, co-analysis of all four immune checkpoints suggested patterns of concomitant engagement. Notably, patients with high PD-1/PD-L1 interaction levels tended to also exhibit elevated CTLA-4/CD80 interactions. Survival analysis further showed that high LAG-3/MHC-II interaction status was associated with a trend toward improved overall survival even when corrected for tumour stage, irrespective of the specific ICI regimen administered. Conclusions: Although prospective validation in larger independent cohorts would be critical to establish clinical relevance, these findings support the exploration of LAG-3 engagement as a potential biomarker in melanoma immunotherapy, and more broadly highlight immune checkpoint interaction profiling as a promising avenue to examine in patient stratification. Full article

Perineural invasion (PNI) is a distinct route of cancer spread associated with neuropathic pain, local recurrence, and poor survival across many solid tumours. Increasing evidence shows that PNI is not only a structural pattern of invasion but also a dynamic biological process involving neurodegeneration, nociceptor sensitisation, and marked local immunosuppression. This narrative review synthesises experimental, translational, and clinical data on the molecular, neurological, and immunological mechanisms of PNI in solid malignancies. PNI arises through complex crosstalk between tumour cells, Schwann cells, macrophages, fibroblasts, and neurotrophic pathways, leading to peripheral nerve remodelling, axonal degeneration, and abnormal regeneration. These changes promote neuropathic pain through ion-channel dysregulation, neurotrophin-driven sensitisation, and pathological neuroplasticity. At the same time, PNI creates an immunosuppressive microenvironment enriched in Tregs, M2 macrophages, and myeloid-derived suppressor cells, shaped by cholinergic, adrenergic, and neuropeptidergic signalling, which may contribute to immune exclusion and resistance to immunotherapy. We propose that PNI should be understood as a neuro-immuno-metabolic process and that recognising the PNI–pain–immunosuppression triad may support the development of targeted neuroprotective, analgesic, and immunomodulatory therapies. Full article

Multiple myeloma (MM) is a genetically and clinically heterogeneous plasma cell malignancy characterised by clonal expansion of differentiated B cells within the bone marrow (BM). Patients start with monoclonal gammopathy of undetermined significance (MGUS) and progress to an intermediate stage called smouldering multiple myeloma (SMM), characterised by several genetic alterations that represent the genomic backbone of the malignant clone. Immune checkpoint pathways play a central role in shaping an immunosuppressive BM niche, contributing to T-cell dysfunction, immune evasion, and therapeutic resistance. Key inhibitory receptors such as PD-1, CTLA-4, TIM-3, LAG-3, and CD47 are frequently dysregulated, promoting T-cell exhaustion, anergy, and senescence. Emerging evidence highlights extracellular vesicles (EVs) as critical mediators of intercellular communication in MM. MM-derived EVs carry bioactive cargo, including proteins and miRNAs, that reprogram immune and stromal cells, enhancing tumour progression and immune escape. Notably, EV-associated immune checkpoint molecules contribute to the establishment of a permissive microenvironment. This review provides an integrated overview of immune checkpoint dysregulation and EV-mediated immunomodulation in MM, emphasising their role in disease pathogenesis and progression. Furthermore, we discuss the therapeutic potential of targeting immune checkpoints and exploiting EVs as novel biomarkers and drug delivery systems, highlighting their promise for improving precision medicine approaches in MM. Full article

Inflammation is a hallmark of cancer and contributes to tumour initiation, progression, and therapeutic resistance. Among inflammatory mediators, interleukin-1β (IL-1β) and interleukin-6 (IL-6) are central cytokines linking innate immune responses with oncogenic signalling networks. This narrative review summarizes current experimental and clinical evidence regarding the role of IL-1β and IL-6 in carcinogenesis, with particular emphasis on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). We discuss the molecular pathways associated with these cytokines, their interactions within the tumour microenvironment, and their contribution to tumour proliferation, angiogenesis, immune modulation, metastatic dissemination, and resistance to anticancer therapies. Particular attention is given to GEP-NENs, in which chronic inflammation and cytokine dysregulation may influence tumour behaviour, systemic inflammatory activity, and clinical outcomes. Accumulating evidence suggests that IL-6 may represent a promising exploratory biomarker associated with tumour burden, histological grade, disease progression, and systemic inflammation, whereas IL-1β appears to be more closely linked to local inflammatory signalling, microenvironmental remodelling, and potential susceptibility mechanisms. However, current evidence in GEP-NENs remains limited by small study cohorts, heterogeneous patient populations, variable analytical methodologies, and the lack of prospective validation. Further translational and clinical investigations are warranted to determine whether cytokine-based biomarkers and therapeutic modulation of inflammatory pathways may expand current diagnostic, prognostic, and therapeutic approaches in GEP-NENs. Full article

Tumour development and progression involve complex cell-cell interactions and dynamic co-evolution between cancer cells, immune cells and stromal cells in the tumour microenvironment and this may influence therapeutic resistance. A large proportion of this network relies on direct physical interactions between cells, particularly T-cell mediated interactions. Cell-cell communication inference has now become routine in downstream scRNAseq analysis but this mostly fails to capture physical cell-cell interactions due to tissue dissociation. Doublets occur naturally in scRNA-seq and are usually excluded from analysis. However, they may represent directly interacting cells that remain undissociated during library preparation. In the present study, we uncover the physical interaction landscape of the ovarian tumour microenvironment using the scRNAseq datasets from 13 treatment-naive ovarian cancer patients. Focusing on T-cell-Macrophage (T-Mac) interaction doublet, we reveal the modulatory effect of macrophages on T cells and the potential influence of this interaction on therapeutic response. Our findings show that T-Macs from resistant patients are functionally polarized to the M2 phenotype and engage T cells to induce T-cell exhaustion. Whereas, T-Macs from sensitive patients are predominantly of the M1 polarized phenotype, physically engaging T cells that lack exhaustion signatures. We also demonstrate that T cells and macrophages in T-Mac doublet are interacting primarily for the purpose of antigen presentation, with the enrichment of several ligand-receptor pairs involved in TCR-MHC interactions and immune synapse formations. We partly validated some of these findings from a spatial transcriptomics dataset of ovarian cancer patients from a separate cohort. Full article

Mismatch repair–deficient (dMMR) or microsatellite instability-high (MSI-H) colorectal cancers exhibit high mutational burden and abundant neoantigen formation, generating a highly immunogenic tumour microenvironment characterised by dense lymphocytic infiltration and strong sensitivity to immune checkpoint inhibition. In metastatic colorectal cancer, PD-1 blockade produces durable responses almost exclusively in dMMR tumours, establishing mismatch repair status as a predictive biomarker for immunotherapy responsiveness. Recent studies extending immune checkpoint inhibitors (ICIs) into the neoadjuvant setting for localised dMMR colorectal cancer have produced major pathological response rates exceeding 90%, with pathological complete response (pCR) rates frequently surpassing 60%, challenging traditional oncologic staging frameworks, particularly with respect to lymph node assessment. Baseline clinical nodal staging in dMMR tumours is complicated by immune-mediated lymphadenopathy. Reactive lymphoid hyperplasia driven by tumour antigen exposure frequently produces enlarged lymph nodes that mimic metastatic disease on cross-sectional imaging. Following neoadjuvant immunotherapy, treatment-related immune activation may further increase nodal size or metabolic activity, while pathological examination often reveals sterilised nodes or immune infiltration without viable tumour. Consequently, conventional radiologic criteria for nodal metastasis demonstrate limited specificity in this context. The discordance between imaging findings and pathological outcomes raises important implications for staging accuracy, response assessment, and treatment planning. This review examines the biological basis of lymphatic involvement in dMMR colorectal cancer, evaluates the performance of current imaging modalities for nodal staging, and summarises emerging evidence from neoadjuvant immunotherapy trials. Particular emphasis is placed on the interpretation of lymph node findings in the era of immune checkpoint blockade and the implications for surgical decision-making, organ preservation, and future staging paradigms. Full article