Search Results (41)

Over the last decades, a significant improvement in cancer patient outcomes has occurred due to advances in cancer cell biology, systemic immunity, tumor-immune microenvironment (TIME) and precision cancer therapy. Despite this explosion of knowledge, its usefulness in clinical practice has been limited by the ability to translate multidimensional data into clinical care. Progress in artificial intelligence (AI) opens up a new frontier, with the promise of achieving synergistic and comprehensive integration. The classification of cancer biology and immunobiology into hallmarks of cancer by Hanahan and Weinberg provides a framework for organizing this information. This systematic classification has enabled the understanding of the interplay and cross-talk between its parts. Targeted cancer therapies and immunotherapies have achieved considerable success, yet their combinatorial potential is still being uncovered. Molecular diagnostics has worked hand-in-hand with precision oncology in deploying new therapies in a cancer-informed and patient-specific way. Harnessing the full power of the advances in these three fields with the aid of AI promises a transformation of molecular diagnostics. This review conceptualizes molecular diagnostics in the context of cancer hallmarks using nonsmall cell lung cancer (NSCLC) as a template, highlighting the potential of a new diagnostic science through the integrative power of AI. Full article

Background/Objectives: Immunotherapy has improved outcomes for selected patients with advanced non-small-cell lung cancer (NSCLC), yet the predictive value of individual biomarkers such as PD-L1 remains limited. Systemic inflammatory indices derived from routine blood tests may complement molecular and immunohistochemical features, offering a broader view of host–tumor immunobiology. Methods: We conducted a retrospective study of 298 patients with stage IIIB–IV NSCLC treated with immune checkpoint inhibitors (ICIs) at a tertiary oncology center between 2022 and 2024. Baseline neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune–inflammation index (SII) were collected alongside PD-L1 expression and molecular alterations (EGFR, KRAS, ALK, TP53). Patients were stratified into inflammatory–molecular clusters integrating these parameters. Associations with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated using Kaplan–Meier and multivariate Cox analyses. Results: Four distinct inflammatory–molecular clusters demonstrated significantly different outcomes (p < 0.001). Patients with low NLR and high PD-L1 expression (Cluster A) showed the highest ORR (41%), longest median PFS (13.0 months), and OS (22.5 months). The EGFR/ALK-driven, inflammation-dominant cluster (Cluster C) exhibited poor response (ORR 7%) and shortest survival (PFS 4.3 months). High NLR (HR 2.12), PD-L1 < 1% (HR 1.91), and EGFR mutation (HR 2.36) independently predicted shorter PFS. A combined model incorporating NLR, PD-L1, and molecular status outperformed individual biomarkers (AUC 0.82). Conclusions: Integrating systemic inflammatory indices with PD-L1 expression and molecular alterations identifies clinically meaningful NSCLC subgroups with distinct immunotherapy outcomes. This multidimensional approach improves prediction of ICI response and may enhance real-world patient stratification, particularly in settings with limited access to extended molecular profiling. Full article

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with limited therapeutic options despite rapid progress in the immunotherapy era. The balance among CD4⁺ helper T cells (Th), CD8⁺ cytotoxic T cells (Tc), and regulatory T cells (Tregs) is a central determinant of tumor immune dynamics and clinical outcomes. The profound immune suppression in PDAC, driven largely by regulatory T cells (Tregs), remains a major barrier to successful immunotherapy response. Tregs enforce tolerance, shape fibroblasts’ immunosuppressive effect, and reprogram the tumor metabolic niche. This study describes the effect of the relative abundance of effector T cell subtypes and Tregs on survival outcomes in metastatic pancreatic cancer patients and reviews how Tregs and other effector T cell subtypes regulate PDAC immunobiology and influence clinical outcomes. Methods: This retrospective study provides immunohistochemical profiling of 62 metastatic PDAC patients, revealing differential prognostic associations among intratumoral and peritumoral subsets of Th, Tc, and Tregs. For each immunostaining, the immune cell infiltrates were evaluated by counting the number of positive cells under the objective of X20 magnification per 0.125 mm². Results: While high intratumoral Th (>16.8) and Tc (>19.6) abundances correlated with improved overall survival and progression-free survival, Treg infiltration (both IT and PT) showed no significant prognostic effect. Conclusions: The effector Th and Tc are the dominant prognostic T cell subsets in PDAC, whereas Treg abundance alone is an incomplete surrogate of immunosuppression. These findings describe the immunobiological landscape of PDAC. Full article

Pediatric oral rhabdomyosarcoma (RMS) is a rare and aggressive cancer of the head and neck, characterized by a complex and mostly immunosuppressive tumor–immune microenvironment. Unlike adult cancers, pediatric RMS typically exhibits a “cold” immune profile, characterized by minimal T-cell infiltration, a low mutational burden, and resistance to immune checkpoint blockade. The tumor’s location in the oral cavity adds difficulty to treatment because of anatomical and functional limitations. Additionally, the presence of fusion oncogenes, such as PAX3:FOXO1, hampers immunogenicity and treatment response by disrupting antigen presentation and reducing immune cell infiltration. Advances in immuno-oncology have introduced new strategies, including immune checkpoint inhibitors, chimeric antigen receptor (CAR) therapies, cancer vaccines, and oncolytic viruses. However, these approaches face specific challenges in the pediatric population due to developmental immune factors. This narrative review highlights recent findings on the immunobiology of pediatric oral RMS, focusing on tumor–immune interactions and their impact on disease progression and treatment resistance. We reviewed the cellular components of the TIME, the mechanisms of immune evasion, and the expression of immune checkpoints, including PD-L1 and B7-H3. Emerging immunotherapies, including CAR-T, CAR-NK, and CAR-CIK cell therapies; checkpoint inhibitors; oncolytic viruses; and cancer vaccines, are discussed, with an emphasis on their current limitations and potential to transform the pediatric RMS immune landscape. Full article

Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates often found in chronic inflammatory conditions, including cancer. These structures, which share many cellular and functional features with secondary lymphoid organs, can profoundly influence the tumor microenvironment by promoting local anti-tumor immune activation. TLSs have been observed in various cancers, including melanoma, and are associated with improved responses to immunotherapy and clinical outcomes. However, our understanding of the molecular mechanisms underlying TLS formation and function remains incomplete. This review summarizes the current findings on TLSs in human melanoma, drawing from multiple studies to provide an updated overview. We discuss the cellular composition, spatial distribution, and genetic signatures of TLSs at different stages of melanoma pathogenesis and in subtypes including acral, uveal, and desmoplastic melanoma. Additionally, we examine the influence of tumor mutational burden (TMB) and complement activation on TLS formation, as well as the role of TLSs in immune checkpoint inhibitor therapy. We also highlight the potential of TLSs as indicators for disease progression and treatment response, and review preclinical strategies aimed at inducing TLSs to improve therapeutic outcomes. This synthesis aims to support ongoing research into the role of TLSs in melanoma immunobiology. Full article

Background: Structurally active phospholipoproteomic formulations that lack pharmacodynamic targets or systemic absorption present unique challenges for validation. Designed for immune compatibility or structural modulation—rather than therapeutic effect—these platforms cannot be evaluated through conventional clinical or molecular frameworks. Methods: This study introduces a standardized, non-invasive ex vivo protocol using real-time kinetic imaging to document biological behavior under neutral conditions. Eight human tumor-derived adherent cell lines were selected for phenotypic stability and imaging compatibility. Phospholipoproteomic preparations were applied under harmonized conditions, and cellular responses were recorded continuously over 48 h. Results: Key parameters included signal continuity, morphological integrity, and inter-batch reproducibility. The system achieved high technical consistency without labeling, endpoint disruption, or destructive assays. Outputs included full kinetic curves and viability signals across multiple cell–fraction pairings. Conclusions: This method provides a regulatorily compatible foundation for functional documentation in non-pharmacodynamic programs where clinical trials are infeasible. It supports early-stage screening, batch comparability, and audit-ready records within SAP, CTD, or real-world evidence (RWE) ecosystems. By decoupling validation from systemic exposure, the protocol enables scalable, technically grounded decision-making for structurally defined immunobiological platforms. Full article

Galectin-9 (Gal-9, LGALS9) is a member of the family of carbohydrate-binding lectins known as galectins. Galectins bind a diverse repertoire of galactose-bearing glycoprotein receptors expressed across multiple cell types. These interactions elicit a broad spectrum of pleiotropic effects important in both normal physiology and disease pathogenesis. Gal-9 contains two separate carbohydrate recognition domains with overlapping yet also divergent binding affinities for distinct glycostructures. This tandem repeat motif enables fine-tuning of its various biological functions. Additional control of Gal-9 activity is provided via multiple gene variants, protein isoforms, tissue distribution, and cell type-associated glycoprotein binding profiles. Within the tumor microenvironment, Gal-9 interacts with immune, non-immune, and cancer cells to influence malignant progression. Its binding of the premier immune checkpoint glycoreceptors, T-cell immunoglobulin and mucin-domain-containing-3 (TIM-3) and programmed cell death protein 1 (PD-1), places Gal-9 apart as a burgeoning target for immunotherapy. In this review, we delve into important aspects of Gal-9 immunobiology in tumorigenesis, including glycobiological and lineage-dependent functions. We further examine Gal-9 as a promising new glyco-immune checkpoint target for cancer therapy. Full article

Dendritic cells (DCs) play a central role in the immunopathogenesis of rheumatoid arthritis (RA), yet their regulation by tumor necrosis factor alpha (TNF) and associated receptors remains poorly characterized. We applied a single-cell multi-omics approach (CITE-seq) to profile peripheral blood mononuclear cells (PBMCs) from RA patients and healthy donors, before and after in vitro TNF stimulation. Using integrated analysis of surface protein expression and transcriptomic data, we focused on phenotypic and transcriptional changes in dendritic cell populations. DCs from RA patients exhibited elevated surface expression of CD14 and CD16, indicative of an inflammatory phenotype, and showed marked responsiveness to TNF. Upon stimulation, RA-derived DCs upregulated genes involved in antigen presentation (CD83, LAMP3), lymph node migration (CCR7, ADAM19), and inflammation (TRAF1, IL24) whereas such activation was absent in healthy controls. Our data reveal a TNF-responsive, pro-inflammatory transcriptional program in dendritic cells from RA patients and underscore the relevance of the TNF receptor profile in shaping DC function. These findings provide new insights into the immunobiology of RA and identify dendritic cells as potential targets for personalized immunomodulatory therapy. Full article

Background: Glioblastoma is a highly malignant brain tumor with limited treatment options and a poor prognosis, largely driven by its complex immune microenvironment. This study aimed to identify and characterize an immune-related gene signature associated with prognosis and immune regulation in glioblastoma. Methods: We performed integrative analyses using bulk and single-cell RNA sequencing data to identify prognostically significant immune-related genes. A five-gene signature (THEMIS2, SIGLEC9, CSTA, LILRB3, and MS4A6A) was derived and its expression patterns were analyzed in association with immune cell infiltration and macrophage subtypes. Functional enrichment and pathway analyses were conducted, followed by drug sensitivity profiling to explore potential therapeutic implications. Results: The five-gene signature was significantly associated with worse survival outcomes and increased immune cell infiltration. Functional analyses revealed involvement in key immune pathways, including antigen presentation, cytokine signaling, and immune cell activation. Single-cell RNA sequencing demonstrated high expression of the signature in tumor-associated macrophages, particularly immune-suppressive and proliferation-associated subtypes. The high expression in proliferation TAMs suggests a role in promoting tumor angiogenesis and growth. Drug sensitivity analysis revealed distinct vulnerabilities between high- and low-risk groups based on signature expression. Conclusions: This Macrophage-Associated Prognostic Signature (MAPS) provides new insights into glioblastoma immunobiology and identifies potential biomarkers and therapeutic targets. It may serve as a valuable tool to guide personalized immunotherapy-based strategies for glioblastoma patients. Full article

Over the past three decades, immunodeficient mouse models carrying human immune cells, with or without human lymphoid tissues, termed humanized immune system (HIS) rodent models, have been developed to recapitulate the human immune system and associated immune responses. HIS mouse models have successfully modeled many human-restricted viral infections, including those caused by human cytomegalovirus (HCMV) and human immunodeficiency virus (HIV). HIS mouse models have also been used to model human cancer immunobiology, which exhibits differences from murine cancers in traditional mouse models. Variants of HIS mouse models that carry human liver cells, lung tissue, skin tissue, or human patient-derived tumor xenografts and human hematopoietic stem cells-derived-human immune cells with or without lymphoid tissue xenografts have been developed to probe human immune responses to infections and human tumors. HCMV-based vaccines are human-restricted, which poses limitations for mechanistic and efficacy studies using traditional animal models. The HCMV-based vaccine approach is a promising vaccine strategy as it induces robust effector memory T cell responses that may be critical in preventing and rapidly controlling persistent viral infections and cancers. Here, we review novel HIS mouse models with robust human immune cell development and primary and secondary lymphoid tissues that could address many of the limitations of HIS mice in their use as animal models for HCMV-based vaccine research. We also reviewed novel HIS rat models, which could allow long-term (greater than one year) vaccinology studies and better recapitulate human pathophysiology. Translating laboratory research findings to clinical application is a significant bottleneck in vaccine development; HIS rodents and related variants that more accurately model human immunology and diseases could increase the translatability of research findings. Full article

Despite the great advancements in treatment strategies for hematological malignancies (HMs) over the years, their effective treatment remains challenging. Conventional treatment strategies are burdened with several serious drawbacks limiting their effectiveness and safety. Improved understanding of tumor immunobiology has provided novel anti-cancer strategies targeting selected immune response components. Currently, immunotherapy is counted as the fourth pillar of oncological treatment (together with surgery, chemo- and radiotherapy) and is becoming standard in the treatment regimen, alone or in combination therapy. Several categories of immunotherapies have been developed and are currently being assessed in clinical trials for the treatment of blood cancers, including immune checkpoint inhibitors, antigen-targeted antibodies, antibody–drug conjugates, tumor vaccines, and adoptive cell therapies. However, monoclonal antibodies (mAbs) and their derivatives have achieved the most notable clinical outcome so far. Since the approval of rituximab for treating B-cell malignancies, the availability of mAbs against tumor-specific surface molecules for clinical use has flourished. Antibody-based therapy has become one of the most successful strategies for immunotherapeutic cancer treatment in the last few decades, and many mAbs have already been introduced into standard treatment protocols for some hematologic malignancies. To further increase the efficacy of mAbs, they can be conjugated to radioisotopes or cytostatic drugs, so-called antibody–drug conjugates. Moreover, with the growing recognition of T-cell immunity’s role in cancer development, strategies aimed at enhancing T cell activation and inhibiting mechanisms that suppress T cell function are actively being developed. This review provides a comprehensive overview of the current status of immunotherapeutic strategies based on monoclonal antibodies and their derivatives, including antibody–drug conjugates, bispecific T-cell engagers, and checkpoint inhibitors, approved for the treatment of various HMs. Full article

Cancer immunobiology is one of the hot topics of discussion amongst researchers today, and immunotherapeutic modalities are among the selected few emerging approaches to cancer treatment that have exhibited a promising outlook. However, immunotherapy is not a new kid on the block; it has been around for centuries. The origin of cancer immunotherapy in modern medicine can be traced back to the initial reports of spontaneous regression of malignant tumors in some patients following an acute febrile infection, at the turn of the twentieth century. This review briefly revisits the historical accounts of immunotherapy, highlighting some of the significant developments in the field of cancer immunobiology, that have been instrumental in bringing back the immunotherapeutic approaches to the forefront of cancer research. Some of the topics covered are: Coley’s toxin—the first immunotherapeutic; the genesis of the theory of immune surveillance; the discovery of T lymphocytes and dendritic cells and their roles; the role of tumor antigens; relevance of tumor microenvironment; the anti-tumor (therapeutic) ability of Bacillus Calmette– Guérin; Melacine—the first therapeutic vaccine engineered; theories of immunoediting and immunophenotyping of cancer; and Provenge—the first FDA-approved therapeutic vaccine. In this review, head and neck cancer has been taken as the reference tumor for narrating the progression of cancer immunobiology, particularly for highlighting the advent of immunotherapeutic agents. Full article

Meningiomas are the most common primary intracranial tumors in adults and typically have a slow-growing and benign nature. However, there is also a substantial subset of meningiomas that shows aggressive clinical behavior and is refractory to standard treatment modalities, which are still limited to surgery and/or radiotherapy. Despite intensive research, no systemic treatment options are yet available in the clinic for these challenging tumors, resulting in poor patient outcome. Intensive research on the molecular pathogenesis of meningiomas has led to improved diagnostic tools, but so far there is no standardized implementation for the molecular profiling of these tumors for clinical practice. Recent research advances have also focused on the immunophenotyping of meningiomas, leading to several clinical trials examining the use of immune checkpoint blockade therapy in patients with clinically aggressive subtypes. In this review, we aim to summarize the current knowledge on the molecular and immunological landscape of meningiomas in detail and provide current and progressive ideas for future directions. Full article

Dendritic cells (DCs) are a heterogeneous group of antigen-presenting cells crucial for fostering allograft tolerance while simultaneously supporting host defense against infections and cancer. Within the tumor microenvironment, DCs can either mount an immune response against cancer cells or foster immunotolerance, presenting a dual role. In immunocompromised individuals, posttransplant malignancies pose a significant health concern, with DCs serving as vital players in immune responses against cancer cells. Both recipient- and donor-derived DCs play a critical role in the rejection process, infiltrating the transplanted organ and sustaining T-cell responses. The use of immunosuppressive drugs represents the predominant approach to control this immunological barrier in transplanted organs. Evidence has shed light on the immunopharmacology of these drugs and novel strategies for manipulating DCs to promote allograft survival. Therefore, comprehending the mechanisms underlying this intricate microenvironment and the effects of immunosuppressive therapy on DCs is crucial for developing targeted therapies to reduce graft failure rates. This review will delve into the fundamental immunobiology of DCs and provide a detailed exploration of their clinical significance concerning alloimmune responses and posttransplant malignancies. Full article

High-grade gliomas (HGGs) have a poor prognosis and are difficult to treat. This review examines the evolving landscape of endovascular therapies for HGGs. Recent advances in endovascular catheter technology and delivery methods allow for super-selective intra-arterial cerebral infusion (SSIACI) with increasing precision. This treatment modality may offer the ability to deliver anti-tumoral therapies directly to tumor regions while minimizing systemic toxicity. However, challenges persist, including blood–brain barrier (BBB) penetration, hemodynamic complexities, and drug–tumor residence time. Innovative adjunct techniques, such as focused ultrasound (FUS) and hyperosmotic disruption, may facilitate BBB disruption and enhance drug penetration. However, hemodynamic factors that limit drug residence time remain a limitation. Expanding therapeutic options beyond chemotherapy, including radiotherapy and immunobiologics, may motivate future investigations. While preclinical and clinical studies demonstrate moderate efficacy, larger randomized trials are needed to validate the clinical benefits. Additionally, future directions may involve endovascular sampling for peri-tumoral surveillance; changes in drug formulations to prolong residence time; and the exploration of non-pharmaceutical therapies, like radioembolization and photodynamic therapy. Endovascular strategies hold immense potential in reshaping HGG treatment paradigms, offering targeted and minimally invasive approaches. However, overcoming technical challenges and validating clinical efficacy remain paramount for translating these advancements into clinical care. Full article