Search Results (436)

Richter transformation (RT) represents a rare but highly lethal evolution of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), most frequently manifesting as diffuse large B-cell lymphoma (DLBCL). Despite therapeutic advances in CLL, DLBCL-RT remains characterized by rapid progression, profound treatment refractoriness, and short survival with conventional chemoimmunotherapy, underscoring the need for a refined biological and therapeutic framework. A defining feature of RT is clonal relatedness: most cases arise through linear or branched evolution of the antecedent CLL clone and carry an inferior prognosis compared with clonally unrelated cases that resemble de novo DLBCL. Recent multi-omic data further indicate that clonally related RT commonly originates from minute, transformation-primed subclones detectable years before clinical emergence, shifting RT from a late stochastic event to an early-established evolutionary trajectory. At transformation, recurrent genetic lesions of TP53, CDKN2A/B, NOTCH1, and MYC cooperate with B-cell receptor-associated programs, epigenetic reconfiguration, and metabolic rewiring toward OXPHOS- and mTOR-driven states, collectively promoting genomic instability and aggressive growth. In parallel, RT develops within a profoundly immunosuppressive microenvironment marked by PD-1-expressing malignant B cells, PD-L1-rich myeloid niches, exhausted T cells, expanded regulatory T cells, and M2-skewed macrophages interconnected by redundant checkpoint and cytokine networks. Therapeutic strategies are rapidly evolving, including pathway inhibitors, immune checkpoint blockade, T-cell-engaging bispecific antibodies, CAR-T therapies, and antibody–drug conjugates. This review integrates current insights into RT pathogenesis, immune escape, and emerging therapies, highlighting opportunities for biomarker-driven patient stratification, rational combinations, and earlier interception of transformation-prone disease. Full article

Background: Osteosarcoma remains largely refractory to immune checkpoint inhibitor (ICI) monotherapy, and strategies to modulate the tumor immune microenvironment are being actively explored. Mild hyperthermia has been reported to influence antitumor immune responses; however, its impact in combination with PD-1 blockade in osteosarcoma has not been well characterized. Methods: Murine LM8 osteosarcoma cells were subjected to mild thermal stimulation, and changes in PD-L1 expression were evaluated. LM8-bearing mice were treated with mild hyperthermia, anti-PD-1 antibody, or their combination. Tumor growth, lung metastasis, and survival were assessed. Tumor-infiltrating immune cells were profiled using single-cell RNA sequencing to descriptively characterize immune-associated transcriptional features under each treatment condition. Results: Mild thermal stimulation (42 °C, 30 min) increased PD-L1 expression in LM8 cells in vitro. In vivo, combination therapy significantly suppressed primary tumor growth compared with control (χ² = 29.75, p = 1.6 × 10⁻⁶) and reduced lung metastasis burden, with a significant decrease in metastatic nodules (p < 0.01). Kaplan–Meier analysis demonstrated a significant survival benefit in the combination group (log-rank p < 0.001). Single-cell RNA sequencing revealed an increased proportion of CD8⁺ T cells with reduced exhaustion-associated gene expression and a shift toward pro-inflammatory (M1-like) macrophage transcriptional profiles. Conclusions: PD-1 blockade combined with mild hyperthermia was associated with enhanced antitumor efficacy and immune-associated transcriptional remodeling in a murine osteosarcoma model, supporting further preclinical evaluation of this combination strategy. Full article

Triple-negative breast cancer (TNBC) is an aggressive and clinically challenging subtype of breast cancer characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression. This molecular phenotype narrows the availability of targeted therapies and contributes to high rates of early relapse, therapeutic resistance, and poor clinical outcomes. Mounting evidence pinpoints the tumor microenvironment (TME) as a central driver of TNBC progression, immune evasion, and resistance to treatment. The TME encompasses a complex and dynamic network of immune and stromal cells, extracellular matrix components, and soluble mediators that collectively shape tumor behavior and influence therapeutic response. Notably, TNBC often displays an immunologically active microenvironment, marked by high levels of tumor-infiltrating lymphocytes and immune checkpoint expression, opening a window for immune-based therapeutic strategies. This narrative review summarizes current knowledge on the cellular, molecular, and structural features of the TNBC tumor microenvironment, with particular focus on immunosuppressive mechanisms mediated by tumor-associated macrophages, myeloid-derived suppressor cells, cancer-associated fibroblasts, and dysfunctional T cells. We describe the clinical development and therapeutic impact of monoclonal antibodies, including immune checkpoint inhibitors and antibody–drug conjugates. Additionally, we discuss strategies aimed at modulating the TME to enhance monoclonal antibody efficacy, including immune cell reprogramming, extracellular matrix remodeling, cytokine/chemokine blockade, and combination treatment strategies. Finally, we highlight the role of biomarker-driven patient stratification and personalized therapeutic strategies, addressing current challenges and future directions in TME-targeted drug development. Together, these insights underscore the potential of integrating immune modulation and monoclonal antibody-based therapies to improve outcomes for TNBC patients. Full article

Tumor-associated macrophages (TAMs) and dendritic cells (DCs) play pivotal roles in shaping the tumor immune microenvironment, often contributing to immunosuppression and therapy resistance. Recent advances in nanotechnology have enabled precise modulation of these immune populations, offering a promising avenue to enhance the efficacy of cancer immunotherapy. Nano-enabled platforms can reprogram TAMs from a pro-tumorigenic M2-like phenotype to an anti-tumorigenic M1-like state, thereby restoring their capacity to phagocytose tumor cells and produce pro-inflammatory cytokines. Concurrently, nanomaterials can enhance DC activation and antigen presentation, promoting robust T-cell priming and adaptive immune responses. Various nanocarriers, including liposomes, polymeric nanoparticles, and inorganic nanostructures, have been engineered to deliver immune modulators, nucleic acids, or tumor antigens selectively to TAMs and DCs within the tumor microenvironment. These strategies have demonstrated synergistic effects when combined with immune checkpoint blockade or cytokine therapy, resulting in improved tumor regression and long-term immunological memory in preclinical models. Despite these promising outcomes, challenges remain regarding nanomaterial biocompatibility, targeted delivery efficiency, and potential off-target immune activation. Ongoing research is focused on optimizing nanoparticle physicochemical properties, surface functionalization, and multi-modal delivery systems to overcome these limitations. This review highlights recent advances in nano-enabled modulation of TAMs and DCs, emphasizing mechanistic insights, therapeutic outcomes, and translational potential. By integrating nanotechnology with immunotherapy, these approaches offer a powerful strategy to overcome tumor immune evasion, paving the way for more effective and personalized cancer treatments. Full article

Triggering receptor expressed on myeloid cells-2 (TREM2) is a key myeloid immune checkpoint for macrophage plasticity. However, its functional landscape in urology is still incomplete. This review addresses this gap by providing the first systematic synthesis of TREM2 in urological malignancies (bladder, prostate, and renal cell carcinomas) and benign conditions. We find a strong correlation between TREM2 upregulation and adverse clinical outcomes in these cancers. Importantly, we highlight the phenomenon of “mechanistic convergence”: unlike the high context-dependency of other organ systems, TREM2 appears to drive progression in urological malignancies by a common convergent signaling hub, the PI3K/AKT pathway. This contrasts sharply with its metabolic role in benign prostatic hyperplasia and its protective role in non-malignant renal injury. We also consider the translational potential of TREM2 as a prognostic biomarker (specifically urine detection) and as a therapeutic target to reverse immunotherapy resistance. Full article

Glioblastoma multiforme (GBM) is the most aggressive primary brain cancer (with a median survival time of 14.5 months), characterized by heterogeneity. Identifying prognostic molecular subtypes could provide a deeper exposition of GBM biology with potential therapeutic implications. In this study, we classified GBM into two prognostic subtypes, C1-GBM (n = 57; OS: 313 days) and C2-GBM (n = 109; OS: 452 days), using pathway-based signatures derived from RNA-seq data. Unsupervised consensus clustering revealed that only binary classification (cluster number, CN = 2; mean cluster consensus score = 0.84) demonstrated statistically prognostic differences. We characterized C1 and C2 based on oncogenic pathway and immune signatures. Specifically, C1-GBM was categorized as an immune-infiltrated “hot” tumor, with high infiltration of immune cells, particularly macrophages and CD4⁺ T cells, while C2-GBM as an “inherent driving” subtype, showing elevated activity in G2/M checkpoint genes. To predict the C1 or C2 classification and explore therapeutic interventions, we developed a neural network model. By using Weighted Correlation Network Analysis (WGCNA), we obtained the gene co-expression module based on both gene expression pattern and distribution among patients in TCGA dataset (n = 166) and identified nine hub genes as potentially prognostic biomarkers for the neural network. The model showed strong accuracy in predicting C1/C2 classification and prognosis, validated by the external CGGA-GBM dataset (n = 85). Based on the classification of the BP neural network model, we constructed a Cox nomogram prognostic prediction model for the TCGA-GBM dataset. We predicted potential therapeutic small molecular drugs by targeting subtype-specific oncogenic pathways and validated drug sensitivity (C1-GBM: Methotrexate and Cisplatin; C2-GBM: Cytarabine) by assessing IC₅₀ values against GBM cell lines (divided into C1/C2 subtypes based on the nine hub genes) from the Genomics of Drug Sensitivity in Cancer database. This study introduces a pathway-based prognostic molecular classification of GBM with “hot” (C1-GBM) and “inherent driving” (C2-GBM) tumor subtypes, providing a prediction model based on hub biomarkers and potential therapeutic targets for treatments. Full article

Slow-growing and locally invasive, chordoma is a rare malignant bone tumor, with a reported annual worldwide incidence of 0.08 per 100,000 cases. It accounts for about 3 percent of all bone tumors and about 20 percent of primary spinal tumors. The incidence rates vary between countries and races, with white/Caucasian males in the 5th or 6th decade of life having a higher prevalence. Chordoma poses significant challenges because of its high recurrence rate and resistance to several standard treatment techniques. All cancers, including chordomas, have altered energy metabolism processes that contribute to their unchecked growth and survival. The significance of non-coding RNAs, particularly circular RNAs (circRNAs), as key regulators at the intersection of cellular metabolism and immune function has been highlighted by recent discoveries. By focusing on important glycolytic enzymes in tumor cells and altering metabolic reprogramming pathways, CircRNAs can influence cancer metabolic adaptability. Furthermore, via influencing immune cell functions as immunological checkpoint signaling and macrophage polarization, circRNAs influence immune evasion in the tumor microenvironment. These frequently happen via regulating important pathway signals, like PI3K/AKT/mTOR and NRF2, or by processes like miRNA sponging, creating a tumor microenvironment that is immunosuppressive and metabolically friendly. The translational pathway of circRNA-targeted therapeutics is promoted as a developing pharmacological entity in this review, which also highlights recent information on the control of circRNA-mediated immunometabolism in chordoma and examines numerous important molecular axes. There are promising opportunities to develop novel precision treatments for chordoma by considering circRNAs as dual regulators of immunological and metabolic networks. Full article

T-cell immunoglobulin and mucin domain 3 (TIM-3), a well-known immune checkpoint molecule, is increasingly recognized for its regulatory functions beyond T cell exhaustion, particularly in macrophages. Recent advances have revealed the important role of this molecule in various pathological and physiological conditions. The demand for a comprehensive study of TIM-3 is increasing, particularly as a result of ongoing clinical trials targeting TIM-3 in oncology. This review is devoted to the role of TIM-3 in macrophage biology, focusing on associations between TIM-3 expression and macrophage polarization states and functional activity, as well as its involvement in the pathogenesis of different diseases and reproductive immunology. The review examines known effects and molecular mechanisms by which TIM-3 regulates macrophage functional phenotype and the contribution of TIM-3-expressing macrophages to cancer, pregnancy, inflammation, infectious and autoimmune diseases, and fibrosis. Findings highlight the controversial role of TIM-3 in the regulatory function of macrophages and suggest that TIM-3 functions differently depending on the context. The review also touches on gaps and unexplored parts of the topic. A summary of current data allows us to conclude that TIM-3 is an important modulator of macrophage functions and can be considered a potential therapeutic target in various pathological conditions. Full article

Acute pancreatitis (AP) is a severe inflammatory disorder characterized by a complex molecular pathophysiology involving premature zymogen activation, organelle dysfunction, and systemic immune dysregulation. Current therapeutic strategies remain largely supportive, underscoring the critical need for specific molecular-targeted interventions. Baicalein, a bioactive flavonoid derived from Scutellaria baicalensis Georgi, has emerged as a potent pleiotropic agent. This review comprehensively synthesizes the molecular mechanisms underlying baicalein’s therapeutic efficacy in AP. Its capacity to intercept the pathological cascade at multiple checkpoints is elucidated, from mitigating the initiating cytosolic calcium overload and preserving mitochondrial integrity to suppressing the cytokine storm via the TLR4/NF-κB/MAPK signaling axis. Crucially, baicalein modulates the pancreatic immune microenvironment by driving the phenotypic polarization of macrophages from pro-inflammatory M1 to reparative M2 states and regulating neutrophil dynamics, specifically by inhibiting infiltration and neutrophil extracellular trap formation. Furthermore, its role in orchestrating regulated cell death pathways is highlighted, specifically by blocking pyroptosis and ferroptosis while modulating apoptosis, and its function as a biophysical scavenger of circulating histones and pancreatic lipase to neutralize systemic toxins. Consequently, this review emphasizes the multi-target biological activities of baicalein, providing a mechanistic rationale for its development as a precision therapeutic candidate for AP. Full article

Background: Prostate cancer (PCa) is a prevalent malignancy with a rising incidence. Advanced PCa, often resistant to therapy, remains a major clinical challenge, underscoring the need to identify novel molecular drivers. Methods: Utilizing transcriptomic data from the TCGA and GEO databases, we identified APOBEC3C (A3C) as a key candidate through WGCNA, differential expression analysis, and LASSO regression. Its clinical relevance was assessed via Kaplan–Meier survival analysis. Then, we validated A3C expression patterns using immunohistochemistry and Western blot in normal and malignant prostate cell lines. The functional effects of A3C on proliferation, migration, and invasion and mechanisms of such were evaluated through in vitro gain- and loss-of-function assays (CCK-8, Ki67 staining, wound healing, Transwell, Western blot, etc.). Results:A3C was significantly downregulated in PCa, and this low expression strongly correlated with adverse clinicopathological features, including advanced T stage, higher Gleason scores, and worse survival. Bioinformatically, high A3C expression was associated with an activated anti-tumor immune microenvironment, characterized by enhanced CD8+ T cell infiltration, reduced M2 macrophage abundance, and upregulation of the immune checkpoint CD40. In vitro, A3C overexpression effectively suppressed PCa cell proliferation, migration, and invasion, while its knockdown promoted these malignant phenotypes. Mechanistically, A3C enhances the expression of the STING1 and its downstream related molecules Caspase-1, IL-18, and IL-1β; upregulates DNA damage-protective genes (GSTP1 and GPX3); and enhances the expression of cell cycle regulator GAS1. Conclusions: This study establishes A3C as a suppressor in PCa, which impedes tumor progression by regulating key molecules involved in cellular inflammation, cell cycle arrest, and DNA damage response. Full article

Hepatocellular carcinoma (HCC) ranks among the top causes of cancer-related mortality worldwide, and its complex tumor microenvironment (TME) contributes to poor responses to immunotherapy. Although PD-1/PD-L1 blockade has emerged as an effective treatment strategy, therapeutic resistance frequently limits its clinical benefit. Here, we uncover a distinct macrophage population associated with anti-PD-1 resistance in HCC. Single-cell transcriptomic profiling reveals an NFKBIZ⁺ M0 macrophage subset predominantly present in non-responders. Notably, these macrophages exhibit a hypoxia-induced phenotype characterized by the secretion of VEGFA and HBEGF, which cooperatively enhance tumor angiogenesis, alongside an elevated expression of the inflammatory chemokines CXCL2, CXCL3, and CXCL8 that consolidate an immunosuppressive, pro-tumorigenic microenvironment. Transcriptional regulatory network analysis further identified FOSB–VEGFA and FOS–HBEGF axes as key drivers of this pathogenic macrophage phenotype. Our findings define a distinct NFKBIZ⁺ macrophage population that mechanistically links hypoxia, angiogenesis, and immune evasion to PD-1 blockade resistance. This work provides new insights into the cellular and molecular basis of immunotherapy failure in HCC and highlights potential targets for overcoming treatment resistance. Full article

Cell surface immune checkpoint receptors are objects for therapeutic intervention to stimulate immune cell attack of cancers. Interference between the checking ectodomain (ECD) and the natural ligand lowers constitutive restraints exerted on immune cells. This approach assumes that immune cells can do more, that a checkpoint blocker will make immune cells more effective at killing cancer cells, and that checkpoint molecules might have limited physiological roles. These assumptions may be warranted, as in the case of checkpoint-blockers towards the programmed death-ligand 1 (PD-L1) ECD, where clinical outcomes are consistently good. However, this does not appear to be the case for the universally expressed CD47 ECD. Much effort has been directed at engineering molecules that bind to the CD47 ECD to increase T cell and macrophage killing of cancers. But a wealth of clinical data do not indicate strong signals, improved killing, or meaningful survival advantages. This suggests that the CD47 ECD is a subpar target for cancer therapy. Consideration of reasons accounting for the modest benefits realized by molecules that bind to the CD47 ECD in cancer, also known as Plan A, is provided. This is followed by thoughts on what might be done, known as plan B, to identify advantages within the CD47 ECD for modulating tolerance in autoimmune diseases. Full article

Chronic HBV infection remains a global health challenge, driving liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Liver injury is primarily mediated by host immune responses rather than direct viral cytotoxicity. Macrophages, including Kupffer cells, play dual roles in antiviral defense and disease progression. HBV skews macrophages toward an M2-like, immunosuppressive phenotype, promoting viral persistence and fibrogenesis via cytokines such as Interleukin (IL)-10 and Transforming growth factor-beta (TGF-β). Therapeutic strategies targeting macrophage polarization, including Toll-like receptor (TLR) agonists, immune checkpoint inhibitors, and nanoparticle-based systems, are under investigation. Addressing macrophage heterogeneity and the immunosuppressive hepatic microenvironment using advanced models is essential. Modulating macrophages offers a promising avenue to control HBV, restore immune balance, and mitigate liver injury. This review highlights the central role of macrophages in chronic HBV infection and explores emerging therapeutic strategies. Full article

The tumor microenvironment (TME) plays an important role in the development, progression, and treatment response of pediatric cancers, yet remains less elucidated compared to adult malignancies. Pediatric tumors are unique with a low mutational burden, an immature immune landscape, and unique stromal interactions. The resultant “cold” immune microenvironments limits the effectiveness of conventional immunotherapies. This review summarizes the key cellular and non-cellular components of the pediatric TME—including T cells, NK cells, tumor-associated macrophages, cancer-associated fibroblasts, extracellular matrix remodeling, angiogenesis, and hypoxia—and describes how these elements shape tumor behavior and therapy resistance. The role of TME in common pediatric cancers like leukemia, lymphoma, neuroblastoma, brain tumors, renal tumors, and sarcomas is discussed. Emerging therapeutic strategies targeting immune checkpoints, macrophage polarization, angiogenic pathways, and stromal barriers are discussed. Full article

Cluster of Differentiation 47 (CD47), an innate immune checkpoint, facilitates immune escape by binding signal regulatory protein alpha (SIRPα) to inhibit macrophage phagocytosis. Its significance in colorectal cancer (CRC) has garnered heightened interest. This review summarizes five immunohistochemistry (IHC) studies and complementary transcriptomic analyses assessing CD47 in CRC. IHC results consistently indicated membrane overexpression, though positivity rates varied widely (16–91%) due to methodological heterogeneity. Transcriptomic results confirmed CD47 upregulation, especially in Consensus Molecular Subtype 1 (CMS1) and CMS4 subtypes and revealed co-expression with immune checkpoints and oncogenic pathways. Clinically, high CD47 levels were associated with advanced TNM stage, metastasis, poor differentiation, and altered immune infiltration; however, the prognostic significance varied among cohorts. Overall, CD47 appears to be a promising biomarker and therapeutic target, but clinical translation requires standardized evaluation, including harmonized antibody selection and scoring cut-offs, and prospective validation. Full article