Reliably predicting brain metastasis (BM) and brain metastasis‑free survival (BMFS) in patients with primary small cell carcinoma of the esophagus (PSCCE) remains a clinical challenge.

To develop and externally validate predictive nomograms for assessing BM probability and BMFS in patients with PSCCE.

A retrospective model development and external validation study.

Using a training cohort, we constructed two separate nomograms. The first was developed using univariable and multivariable logistic regression to predict the probability of BM. The second was built using a Fine‑Gray competing-risk model to estimate BMFS, treating death without BM as a competing event. The performance of both nomograms was evaluated using the area under the receiver operating characteristic (ROC) curve/time-dependent ROC curve, calibration plots, and decision curve analysis (DCA). External validation was subsequently performed using an independent validation cohort.

The study sample included 492 patients in the training cohort (mean age at diagnosis 61.97 ± 8.86 years; 133 (27%) female) and 344 patients in the external validation cohort (mean age at diagnosis 62.97 ± 8.14 years; 108 (31%) female). Age, N stage, and M stage emerged as independent predictors and were included in a nomogram to estimate BM risk. Adding lesion length and initial treatments (radiotherapy, chemotherapy, and surgery) to these three factors allowed the model to predict BMFS. Both nomograms showed strong predictive performance in the training cohort, with area under the ROC curve values of 0.76 and 0.843, respectively, supported by calibration plots and DCA. These results were confirmed in the external validation cohort. The logistic regression‑based nomogram accurately predicted BM probability, while the Fine-Gray model provided reliable estimates of BMFS.

We successfully developed and externally validated two complementary nomograms that reliably predict BM probability and BMFS in patients with PSCCE. These tools may aid in risk stratification and inform personalized surveillance strategies.

Immune checkpoint inhibitors (ICIs) have revolutionized lymphoma treatment, yet resistance driven by complex regulatory networks remains a major hurdle. Circular RNAs (circRNAs) have emerged as central signaling hubs that integrate metabolic, inflammatory, and oncogenic cues to fine-tune immune checkpoints such as PD-L1 and CD47 in lymphoma. Here, we systematically dissect the molecular mechanisms by which circRNAs govern immune checkpoints in lymphoma, including nuclear transcriptional control, interactions with RNA-binding proteins (RBPs), competitive endogenous RNA (ceRNA) networks, and micropeptide translation. We differentiate between cell-extrinsic, exosome-mediated reprogramming of the tumor microenvironment and cell-intrinsic circRNA circuits within lymphoma cells spatially. Subtype-specific investigations demonstrate the importance of Epstein-Barr virus (EBV)-encoded circRNAs in immune evasion and the synergistic interactions between 9p24.1 amplification and circRNAs in classical Hodgkin lymphoma (cHL). While therapeutic approaches including antisense oligonucleotides, CRISPR-Cas13, and nanodelivery technologies demonstrate preclinical synergy with ICIs, circulating circRNAs show potential as dynamic indicators for predicting ICI responses. We also critically examine ongoing discussions about the flaws of current model systems, the technological constraints of current validation techniques, and the physiological significance of the ceRNA hypothesis. Positioning circRNAs as multimodal regulatory hubs, this review provides a theoretical framework for developing circRNA-based immunotherapies to overcome resistance in lymphoma.

Intravascular large B-cell lymphoma (IVLBCL) is an uncommon and aggressive subtype of non-Hodgkin lymphoma defined by the proliferation of large malignant B cells confined within small blood vessels. This neoplasm can present with different nonspecific symptoms, including fever, altered mental status, livedoid skin rashes, hepatosplenomegaly, and cytopenias, often complicating its diagnosis. The main categories are classical (formerly designated as Western), hemophagocytic variant (formerly designated as Asian), and primary cutaneous IVLBCL. A distinctly severe manifestation is hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory syndrome characterized by exaggerated immune activation and macrophage activation manifested by phagocytosis of hematopoietic cells including neutrophils, red blood cells, and platelets. We describe a 72-year-old female who presented with features reminiscent of an autoinflammatory syndrome including fever and hyperferritinemia followed by clinical features concerning for HLH. She developed a reticulated skin rash. Following skin biopsy, a diagnosis was rendered of IVLBCL complicated by HLH. The pathophysiology and other aspects of the literature pertaining to IVLBCL and HLH are reviewed.

This review synthesizes recent research findings and proposes an integrated "microbiota-metabolite-immune-oncology" framework, highlighting how gut-derived metabolites regulate the dynamics of tumor immunity and informing the development of next-generation immunotherapies. Key metabolites-including short-chain fatty acids (SCFAs), bile acids (BAs), trimethylamine N-oxide (TMAO), indole-3-propionic acid (IPA), and urolithin A-exert bidirectional effects on antitumor immunity through multiple mechanisms. These include histone acetylation-driven epigenetic reprogramming, aryl hydrocarbon receptor (AhR)- and farnesoid X receptor (FXR)-mediated metabolic reprogramming, and direct regulation of immune effectors such as CD8⁺ T cells and myeloid-derived suppressor cells. Emerging evidence highlights specific roles of these metabolites within the tumor microenvironment (TME): microbial dysbiosis can amplify immunosuppressive circuits, whereas targeted enrichment of certain metabolites may enhance the efficacy of immune checkpoint blockade. Integrative multi-omics analyses have revealed the vascular remodeling effect of TMAO and the spatiotemporal heterogeneity of BAs, thereby connecting the gut-liver-tumor axis and achieving overall immune regulation. By mapping a precision-oriented metabolic roadmap, this review identifies underexplored therapeutic avenues-such as metabolite-targeted interventions and engineered probiotics-that, when combined with immune checkpoint inhibitors, may enable personalized, microbiome-based strategies with the potential to improve outcomes in cancer immunotherapy.

Nucleolar Protein 14 (NOP14), a highly conserved factor in eukaryotes, is essential for pre-18S rRNA processing and small ribosomal subunit assembly. Emerging evidence underscores its pivotal regulatory role in the progression of various malignancies. Nevertheless, its functional involvement in Diffuse large B-cell lymphoma (DLBCL), particularly its capacity to modulate the tumor immune microenvironment, remains to be fully elucidated.

Genomic and clinical data from DLBCL patients were retrieved from the GEO database (GSE12195, GSE32018, GSE181063 and GSE10846) for integrated bioinformatics analysis. NOP14 expression was quantified via qRT-PCR, western blot, and immunohistochemistry (IHC). Stable NOP14-knockdown cell lines were established using lentiviral vectors to assess proliferation through EdU, colony formation, and CCK-8 assays in vitro, as well as in the A20 syngeneic mouse model of DLBCL in vivo. To explore the underlying mechanism of NOP14, RNA sequencing was performed followed by KEGG enrichment analysis. Furthermore, flow cytometry was utilized to determine the correlation between NOP14 expression and the infiltration of immune cells. Finally, we developed cRGD-modified lipid nanoparticles encapsulating NOP14-siRNA (NOP14-siRNA@LNP) to assess its synergistic potential with anti-PD-1 therapy.

NOP14 was significantly overexpressed in DLBCL tissues and cell lines, with elevated levels correlating with shorter overall survival and unfavorable clinicopathological features. Our findings reveal that NOP14 exerts a prominent dual role in driving tumor proliferation and facilitating immune evasion in DLBCL. Characterized as a cell-intrinsic oncogene, NOP14 directly sustains tumor growth, whereas its depletion significantly compromises DLBCL cell proliferation both in vitro and in vivo. Concurrently, NOP14 functions as an extrinsic regulator of the tumor microenvironment by impairing CD8⁺ T cell infiltration and cytotoxic function to mediate immune escape. Mechanistically, NOP14 ablation inactivates the Wnt/β-catenin/c-Myc signaling cascade, which subsequently downregulates PD-L1 expression. This molecular shift successfully reverses the immunosuppressive state, markedly boosting tumor-infiltrating CD8⁺ T cells and stimulating their IFN-γ production. Notably, the specific depletion of CD8⁺ T cells significantly attenuated the effect of NOP14 on tumor growth. Additionally, cRGD-modified NOP14-siRNA@LNP successfully targets DLBCL via αvβ3 integrin recognition with excellent biocompatibility. NOP14-siRNA@LNP monotherapy effectively restricts tumor progression, and its combination with anti-PD-1 blockade exhibits strong synergy, maximizing CD8⁺ T cell infiltration and activation by simultaneously neutralizing the function of NOP14.

Our findings establish NOP14 as a crucial oncogene and a key mediator of immune evasion in DLBCL that operates through the Wnt/β-catenin/c-Myc axis. Targeted NOP14 via NOP14-siRNA@LNP not only inhibits tumor growth but also sensitizes DLBCL to immune checkpoint blockade, offering a promising strategic framework for precision immunotherapy.

Inhibitor of differentiation 1 (ID1) has emerged as a crucial regulator in the pathogenesis and progression of lung cancer, influencing various aspects of tumor biology, including tumor cell proliferation, invasion, metastasis, and immune modulation, within the complex tumor microenvironment. This review comprehensively examines the molecular mechanisms by which ID1 contributes to lung cancer, emphasizing its role in driving these processes. Despite significant advancements in lung cancer biology, the interactions between tumor cells and their surrounding microenvironment remain incompletely understood. This presents challenges for developing effective therapeutic strategies. We then examine the pathophysiology of malignant pleural effusion (MPE), a devastating complication of advanced lung cancer. Based on the striking mechanistic overlap between ID1-driven processes and the core drivers of MPE-vascular hyperpermeability, immunosuppression, and tumor cell seeding-we propose a unifying, testable hypothesis that ID1 may act as aputative key orchestrator of MPE formation, a proposition that currently awaits direct experimental validation. While direct evidence is currently lacking, we outline indirect clues and propose specific experimental approaches to test this hypothesis. By integrating recent findings from both basic research and clinical studies, this article emphasizes ID1 as a pivotal mediator in lung tumorigenesis and microenvironment remodeling. It also highlights its potential as a novel biomarker and therapeutic target, aiming to promote the development of improved diagnostic and therapeutic approaches for lung cancer, particularly in addressing challenges related to tumor progression and MPE.

EGFR exon 20 insertion (ex20ins) NSCLC typically shows limited response to immunotherapy. We report a rare case of a smoker with metastatic EGFR ex20ins (p.S768_D770dup) and high PD-L1 expression (TPS 50%) who achieved exceptional survival (OS = 63 months). Following progression on chemotherapy and intolerance to afatinib, the patient received paclitaxel plus tislelizumab. This combination yielded durable disease control. While the overall benefit of immune checkpoint inhibitors (ICIs) in EGFR-mutant NSCLC remains limited, this case suggests that chemo-immunotherapy (particularly taxane + PD-1 inhibition) may provide significant benefit in ex20ins tumors with high PD-L1 expression and smoking history. These findings highlight the critical value of targeted molecular profiling and offer a viable precision oncology strategy when novel targeted agents are inaccessible.

Bone is one of the most common sites of distant metastasis in solid tumors, particularly breast cancer, prostate cancer, and lung cancer. Bone metastatic lesions frequently exhibit persistent resistance to multiple systemic therapies, including chemotherapy, targeted therapy, endocrine therapy, and immune checkpoint inhibitors (ICIs). Accumulating evidence suggests that metabolic reprogramming within the bone microenvironment contributes to this resistance, yet the upstream mechanisms remain incompletely understood. Intercellular mitochondrial transfer has emerged as a potential link between the bone marrow niche and tumor metabolic adaptation. Bone marrow mesenchymal stem cells (BMSCs) have been reported to deliver functional mitochondria to tumor cells through tunneling nanotubes (TNTs), extracellular vesicles (EVs), and gap junctions, a process proposed to be regulated by metabolic stress, chemokine signaling (CXCL12/CXCR4), and inflammatory cues. The bone marrow microenvironment-characterized by hypoxia, high cell density, and lipid abundance-together with the intrinsic transfer capacity of BMSCs, may facilitate efficient mitochondrial delivery. Following transfer, exogenous mitochondria have been shown, largely in vitro and preclinical models, to restore oxidative phosphorylation (OXPHOS) through respiratory chain reassembly, mitochondrial DNA (mtDNA) replication, and membrane potential recovery, which may drive a metabolic shift from the Warburg phenotype toward a mixed state with enhanced fatty acid β-oxidation (FAO), glutaminolysis, and branched-chain amino acid oxidation. The resulting high adenosine triphosphate (ATP) pool and reshaped redox homeostasis have been proposed to support multiple resistance mechanisms, including ATP-dependent drug efflux, enhanced DNA damage repair, apoptosis resistance, metabolic bypass of targeted therapies, immunosuppressive nutrient competition, and cancer stem cell (CSC) maintenance with therapy-induced dormancy. Mitochondrial dynamics remodeling and metabolic-epigenetic crosstalk may further establish a "metabolic memory" sustaining the resistant phenotype. Notably, transfer patterns appear to exhibit tumor type specificity across breast cancer, prostate cancer, and lung cancer, with multiple myeloma (MM) considered here as a mechanistically informative, marrow-resident comparator rather than a parallel solid-tumor setting. Conceptually proposed therapeutic strategies targeting this axis encompass transfer blockade, OXPHOS and FAO inhibition, and bone-targeted nanodelivery systems, none of which has yet demonstrated efficacy specifically against mitochondrial transfer in patients with bone metastasis. Importantly, several controversies remain unresolved, including the durability and functional integrity of transferred mitochondria, the risk of dye-tracing artifacts, in vivo detection sensitivity, and the clinical translation of pathway-specific inhibitors. This review systematically examines the reported molecular mechanisms of mitochondrial transfer between BMSCs and tumor cells, its proposed role in OXPHOS reprogramming and drug resistance in bone metastasis, and emerging therapeutic strategies, aiming to provide a critical framework for developing metabolism-targeted interventions to overcome bone metastatic resistance.

In the wake of the 10-year anniversary since the introduction of chimeric antigen receptor-T (CAR-T) cell therapies to the market, the field of B cell lymphoma has seen remarkable advances since these therapies first arrived at the bedside in 2017. Modern data from longitudinal readouts attests to the high depth and durability of response to CAR-T therapies in many patients with B cell lymphomas; however, approximately 50% of patients continue to have relapsed/refractory disease even after receipt of conventional CAR-T constructs. In this review, we discuss the mechanisms underlying primary and secondary refractoriness to conventional single-targeting CAR-T therapies for B cell lymphomas and explore the ongoing challenges with existing CAR constructs. We discuss the prospects for adaptable multi-antigen targeting via the use of bivalent CAR and bicistronic CAR functionalities as informed by recent advances in synthetic immunobiology. We explore contemporary efforts, mostly Phase 1 and 2 trials, involving bivalent CAR and bicistronic CAR constructs at the cutting edge of clinical translation. Finally, we propose evidence-based solutions to help improve the translational success of multi-antigen CAR-T therapy, including optimizing construct architecture, expanding the targetable antigen landscape, and improving scalability. These solutions for multi-antigen targeting in next-generation CARs may have substantial benefits in the coming years.

Relapse of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is associated with poor prognosis and remains the most common cause of treatment failure following allogeneic hematopoietic stem cell transplantation (alloHSCT). Over the past two decades, hypomethylating agents (HMAs), particularly azacytidine, have evolved from an experimental approach to the current therapeutic backbone of relapse therapy following alloHSCT, although future treatment paradigms may further evolve with emerging targeted and immunotherapeutic approaches. The RELAZA studies demonstrated that preemptive therapy with azacytidine in molecular relapse can significantly delay the onset of hematologic relapse. However, sustained disease control generally requires additional immunological mechanisms. Against this backdrop, the combination of azacytidine-either alone or in combination regimens-with donor lymphocyte infusions (DLI) has been established as a successful salvage strategy. Numerous studies have consistently shown over the years that a low disease burden, molecular rather than hematological relapse, and a longer interval between transplant and relapse are associated with better response rates and prolonged survival. This underscores the great importance of MRD monitoring for enabling early intervention. Prognostic models such as the APSS-R score incorporate these factors. Additionally, the score takes into account pre-transplant therapy, thereby underscoring the importance of a biologically tailored treatment strategy to prevent the emergence of treatment-resistant clones. Recent combination therapies with targeted agents, such as FLT3 and IDH inhibitors, as well as with venetoclax or lenalidomide, are showing promising results. Future strategies will likely focus on individualized, biological1ly guided treatment approaches and a selective indication for second alloHSCT.