Ke Chen

Dendritic cells (DCs) function as a double-edged sword in tumor immunity, capable of both activating and tolerizing CD8⁺ cytotoxic T lymphocytes (CTLs). While conventional type 1 dendritic cells (cDC1s) are well-established mediators of cross-presentation for initiating anti-tumor CTL responses, existing reviews—largely overlook the tolerogenic potential of cDC1s and the context-dependent immunostimulatory capacity of cDC2s, monocyte-derived DCs (moDCs), and plasmacytoid DCs (pDCs). Furthermore, no prior synthesis has systematically reconciled the divergent functions of DC subsets across steady-state versus inflammatory conditions, migratory versus resident phenotypes, and human versus mouse model systems. The tumor microenvironment (TME) and tumor-derived exosomes further drive DCs toward an immunosuppressive phenotype, facilitating immune escape. Here, we establish a multi-dimensional framework that dissects the dichotomous roles of diverse DC subsets in regulating CTL immunity and tolerance, resolving key biological contradictions—including recent in vivo evidence that cDC2s can cross-present immune-complexed antigens via a WDFY4-dependent pathway shared with cDC1s—an activity that complements, but does not replace, the cDC1-restricted cross-presentation of cell-associated antigens. We also provide a hierarchical analysis of strategies to restore DC-mediated anti-tumor activity, extending the DC–CTL regulatory paradigm to autoimmunity and solid organ transplantation. A comprehensive summary table categorizes DC-based therapeutic approaches by clinical development stage. By elucidating this dynamic balancing mechanism, we offer refined insights for optimizing cancer immunotherapy design and cross-disciplinary therapeutic applications.

This study examined how 1-hydroxypyrene (1-OHP) affects bladder cancer (BCa) progression and tumor-associated immunosuppression. Public transcriptomic data and target-prediction databases were used to screen for targets related to 1-OHP and BCa. Machine learning was then used to narrow down the candidate genes. Molecular docking and single-cell RNA sequencing were also used to examine the selected targets and related pathways. The role of the main target was tested in vitro. CCK-8, colony formation, EdU, and Transwell assays were used to assess cell growth, migration, and invasion. Protein expression was examined by Western blotting. A tumor cell–CD8⁺ T-cell co-culture system was used to evaluate changes in CD8⁺ T-cell function. We identified 29 targets shared by 1-OHP and BCa. Machine learning further narrowed these targets to six genes, and macrophage migration inhibitory factor (MIF) was chosen for experimental validation. Treatment with 1-OHP increased BCa cell viability, proliferation, migration, and invasion. Silencing MIF partly reduced these effects. 1-OHP also increased MIF and CD74/CD44 expression and enhanced PI3K/AKT/mTOR signaling. These changes were reduced after MIF silencing. In the co-culture system, 1-OHP-treated BCa cells reduced CD8⁺ T-cell proliferation and function. Ki67, GZMB, and IFNG levels were decreased. MIF knockdown partly reversed these changes. Collectively, our findings show that 1-OHP promotes bladder cancer progression and tumor-associated immunosuppression, at least in part, through a MIF-dependent mechanism. By linking environmental exposure to activation of the CD74/CD44–PI3K/AKT/mTOR axis and impaired CD8⁺ T-cell function, our study provides new insight into the molecular basis of environmentally associated bladder carcinogenesis.

Bladder cancer, particularly muscle-invasive disease, has a high metastatic potential and limited treatment options, highlighting the need for new therapeutic targets. CD276 (B7-H3), a type I transmembrane protein of the B7 family, is traditionally considered an immunomodulatory ligand with an unidentified receptor. Here, we investigated the role of CD276 in bladder cancer and sought to identify its binding partner. Using a high-throughput human proteome microarray, we identified the secreted lectin galectin-1 (LGALS1) as a high-affinity binding partner of CD276, suggesting that CD276 may function as a receptor. Mechanistically, we uncovered a novel LGALS1-CD276 axis in endothelial cells, where CD276 serves as a functional receptor for tumor cell-derived LGALS1, with their interaction mediated by N-linked glycosylation at the N433 site within the D4 domain of CD276. This interaction activates the MAP4-dependent PI3K/AKT signaling pathway, thereby promoting angiogenesis and bladder cancer progression. Disruption of the LGALS1-CD276 interaction or inhibition of the downstream MAP4/PI3K/AKT pathway markedly suppressed endothelial proliferation, migration, and tube formation. In subcutaneous and orthotopic bladder cancer mouse models, anti-CD276 monoclonal antibody treatment significantly inhibited tumor angiogenesis, delayed tumor growth, and extended survival. Consistently, Cd276^-/- and/or Lgals1^-/- mouse models confirmed that the tumor-promoting effect of LGALS1 depends on CD276 expression. Clinically, elevated CD276 and LGALS1 expression was associated with poor prognosis and positively correlated with angiogenesis. Together, our findings identify CD276 as a functional cell-surface receptor and demonstrate that LGALS1 binding to CD276 promotes tumor angiogenesis through MAP4-mediated activation of the PI3K/AKT signaling pathway. These findings establish a new mechanistic foundation for bladder cancer therapy and highlight the potential of targeting the LGALS1-CD276 axis for anti-angiogenic treatment.

Tertiary lymphoid structures (TLSs) are immune cell aggregates that emerge in nonlymphoid tissues during various disease states, including chronic inflammation, autoimmunity, and cancer. TLSs are structurally and functionally analogous to secondary lymphoid organs, and exhibit a maturation continuum (progressing from initial aggregation to mature structures with germinal centers). TLS formation is synergistically regulated by local chemokine networks (e.g. CXCL13, CCL19, and CCL21), lymphotoxin signaling axes, stromal cells, metabolic reprogramming, and the microbiome. This review comprehensively elucidates the biological foundations of TLSs, including their cellular composition, spatial architecture, and developmental dynamics of maturation. We explore the crucial roles of TLSs as favorable prognostic factors and predictors of the immunotherapy response in various solid tumors, including melanoma, breast cancer, lung cancer, hepatocellular carcinoma, and colorectal cancer. Additionally, we analyze their "pathogenic" role in causing tissue damage and disease progression in autoimmune disorders such as rheumatoid arthritis and Sjögren's syndrome, as well as chronic inflammatory diseases such as COPD, IgA nephropathy, and atherosclerosis. In addition, we thoroughly examine TLS research methodologies, covering a wide range of approaches from conventional hematoxylin and eosin (H&E) and immunohistochemical staining to advanced multiplex fluorescence staining, imaging mass spectrometry, and spatial transcriptomic techniques. We summarize multiple gene expression signatures (e.g. the 12-chemokine signature and TLS score) for TLS identification and quantification. Finally, we highlight multiple strategies for artificially inducing TLS formation, including cytokine delivery, immunotherapy, engineered scaffolds, microbiome modulation, and organoid technologies, designed to enhance antitumor immunity or reverse immunopathology. This review provides a comprehensive framework for understanding the complex functions of TLSs in human disease and explores their clinical translation potential as biomarkers and therapeutic targets.

Clear cell renal cell carcinoma (ccRCC), the most common and lethal subtype of renal cell carcinoma, exhibits marked intratumoral heterogeneity and complicates clinical management. Although long noncoding RNAs (lncRNAs) regulate diverse cellular processes, their landscape and biomarker potential in ccRCC remain poorly defined. Here we performed single-nucleus and bulk transcriptomic, proteomic, and metabolomic analyses on a cohort of 100 ccRCC patients. The expression pattern of lncRNAs were described based on metacells. Malignant cells displayed broader but lower lncRNA expression, likely reflecting copy number alterations, whereas low-abundance lncRNAs in normal epithelial cells showed individual variability. Multi-omics integration was used to establish a preliminary lncRNA functional inference pipeline, identifying lncRNAs involved in metabolic and immune processes and validating their roles through functional and in vivo experiments. Candidate biomarkers lncRNAs were identified to build diagnostic (DMRlnc) and prognostic models (PMRlnc), which were validated in TCGA, CheckMate, and IMmotion151 cohorts. DMRlnc achieved high diagnostic accuracy in both discovery and TCGA-KIRC cohorts (AUC 0.98 and 0.93). PMRlnc stratified patients into distinct risk groups with significant differences (p < 0.0001) across TCGA-KIRC and IMmotion151 cohorts. PMRlnc further indicated that low-risk patients may benefit more from nivolumab, while high-risk patients might respond better to atezolizumab plus bevacizumab.

Supplementary data related to Figure 1-2

Supplementary data related to Figure 3

Restoration of MLYCD reversed resistance to ENZ in PCa, related to Figure 7