t(11;14) (q13;q32) occurs in approximately 15%-25% of multiple myeloma (MM) cases and has traditionally been regarded as a standard cytogenetic risk factor. However, recent evidence suggests that MM with t(11;14) exhibits heterogeneous biological characteristics and clinical outcomes distinct from those associated with other cytogenetic risk categories. In a post hoc analysis of the prospective JSH-MM-15 study, we investigated the prognosis of newly diagnosed MM patients to identify prognostic features unique to t(11;14)-positive cases and to evaluate treatment factors influencing outcomes. Among 482 patients evaluated for t(11;14), 131 (27%) were positive. Overall survival (OS) in t(11;14)-positive patients was intermediate between standard- and high-risk groups, whereas progression-free survival (PFS) was comparable to that of high-risk cases. Deep response rates, including ≥ complete response (CR)/stringent CR and ≥ very good partial response, were lower in t(11;14)-positive MM than in other risk groups, and these responses were not associated with survival in t(11;14)-positive cases, in contrast to t(11;14)-negative MM. Compared with t(11;14)-negative MM, t(11;14)-positive patients more frequently expressed CD20 and less frequently expressed CD56 on myeloma cells. Exploratory analyses showed that, despite higher ≥ CR rates, OS was worse in patients with CD20-negative/CD56-negative tumors among t(11;14)-positive MM. Among CD20-positive patients, PI-containing regimens were associated with better OS, although no significant PFS benefit was observed. These findings support the biological and clinical heterogeneity of t(11;14)-positive MM and highlight the need for prospective validation of subgroup-specific treatment outcomes.

Noncoding RNAs, including circular RNAs (circRNAs), have been demonstrated to play vital roles in tumorigenesis. Uncovering the functions of circRNAs in tumorigenesis and their underlying regulatory mechanisms may suggest new approaches to the development of novel diagnostic and therapeutic strategies for human cancer. Here we report the important role of hsa_circ-0080018 in diffuse large B-cell lymphoma (DLBCL) progression and the potential impact of hsa_circ-0080018 in DLBCL tumorigenesis. Hsa_circ-0080018 was evidently upregulated in newly diagnosed DLBCL patient plasma, and as a reference to classify GCB and non-GCB subtypes. The high expression of hsa_circ-0080018 also appeared in plasma exosome and can transport to tumor microenvironment (TME). In addition, we found that at the molecular level hsa_circ-0080018 acted as a decoy for miR-625-5p and regulated tumor associated macrophage (TAM) polarization by suppressing miR-625-5p that led to IGF-1/IGF-1R pathway activation. The activated IGF-1/IGF-1R pressed macrophage polarizing to M2 and ultimately promoted tumor progression. Our results provided a new potential biomarker in DLBCL plasma that is correlated with cell of origin (COO). The mechanism of circ-0080018 in tumor progression was plasma generated circ-0080018 delivered to TME by exosome and pushed macrophage polarization. Our research may provide a new target for the DLBCL treatment and prognosis in future.

Small-cell lung carcinoma (SCLC) is a highly aggressive tumor with a dismal prognosis among lung cancers. Treatment is failing because of primary or rapidly developing secondary resistance. Recent molecular studies have suggested four SCLC subtypes with unique therapeutic vulnerabilities-ASCL1, NEUROD1, POU2F3, and YAP. These subtypes still distinguish themselves by considerable intra-tumoral heterogeneity and the influence of the microenvironmental context, which are both considered to be responsible for treatment resistance. We integrated in situ hybridization-based spatial transcriptomics with histological and protein-expression analyses of 18 specimens, comprising 16 SCLCs, one atypical carcinoid, and one normal lung specimen. Systematic case-by-case analysis revealed multiple coexisting tumor states, including neuroendocrine and non-neuroendocrine components, regional hypoxic states, and case-specific FABP7-positive and loss-of-chromosome-Y-associated populations. Integrative transcriptome clustering, copy number estimation, and exploratory trajectory analysis revealed transcriptional relationships among spatially coexisting tumor states, including phenotypically distinct tumor components with molecular features consistent with close clonal relationships in selected heterogeneous tumors. Furthermore, we identified immune signatures and uncovered a previously unrecognized MMP12-positive tumor-associated macrophage population, enriched at the tumor interface and spatially associated with necrotic and hypoxic regions. In vitro co-culture experiments further showed that direct contact with SCLC cells increased MMP12 expression in macrophages, with hypoxia further enhancing its expression under specific conditions. Together, our study delineates the complex spatial architecture of SCLC by defining specific cellular programs and adjacent immune phenotypes that provide an organizational framework for understanding its marked intratumoral heterogeneity.

Although collagen type 1 alpha 1 (COL1A1)-platelet-derived growth factor B-chain (PDGFB) gene fusion is a characteristic driver alteration in fibrosarcomatous dermatofibrosarcoma protuberans (FS-DFSP), an aggressive DFSP variant, the tumor microenvironment (TME) underlying the aggressive phenotype remains unclear. We investigated microenvironmental and molecular differences between pure-DFSP and FS-DFSP using integrated histopathologic and transcriptomic analyses of archival samples from 122 patients, including 39 with FS-DFSP. Histopathologic evaluation, immunohistochemistry, and transcriptomic analyses were performed to assess vascular features, cancer-associated fibroblasts (CAFs), macrophage infiltration, and angiogenesis-related molecular alterations. FS-DFSP demonstrated increased CD31-positive vascular structures without a corresponding increase in αSMA-positive vascular structures, suggesting immature vascular features. CAF markers, including periostin and fibroblast activation protein, were significantly upregulated in intratumoral and invasive front regions of FS-DFSP. Gene expression analysis was performed separately for the fibrosarcomatous and DFSP components of the FS-DFSP cases and for the pure-DFSP cases. By targeted transcriptomic profiling, the DFSP and fibrosarcomatous components within the FS-DFSP cases shared molecular features, suggesting early tumor microenvironment-associated alterations that preceded overt fibrosarcomatous morphology. Integrated transcriptomic and protein analyses revealed upregulation of angiogenesis-related molecules, including vascular endothelial growth factor A (VEGFA), C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine receptor 4 (CXCR4) in FS-DFSP. Periostin-positive CAFs coexpressed VEGFA and CCL2, potentially contributing to angiogenic features within the tumor microenvironment. These findings reveal that FS-DFSP is characterized by coordinated angiogenic and stromal remodeling involving tumor cells and CAFs and suggest that the tumor microenvironment may represent a potential focus for future therapeutic investigation.

Triple-negative breast cancer (TNBC) is an aggressive subtype with high metastatic potential and poor prognosis, yet the molecular mechanisms driving metastasis remain incompletely understood. Here, we performed integrated transcriptomic, metabolomic, and imaging mass cytometry (IMC) analyses on tumor tissues from 52 TNBC patients stratified into NonMeta (long-term survival without metastasis, n = 39) and MetaPoor (metastasis-related death within 36 months after metastatic diagnosis, n = 13) groups. Transcriptomic analysis revealed significant enrichment of epithelial-mesenchymal transition (EMT), WNT signaling pathway, and angiogenesis pathways in MetaPoor tumors, with EMT identified as the top enriched hallmark by GSEA. Metabolomic profiling showed decreased branched-chain amino acids (BCAAs) and arginine derivatives, alongside elevated glycerophosphorylcholine (GPC), indicating enhanced metabolic demand and membrane remodeling. IMC-based spatial proteomics identified distinct tumor cell subpopulations, with MetaPoor tumors harboring higher proportions of stem-like and EMT-like cells characterized by upregulated HADHA (BCAA oxidation) and P38, and downregulated ATP5A (oxidative phosphorylation). Multi-omics integration revealed strong correlations between GPC and EMT markers, and between BCAA depletion and HADHA expression. Collectively, our multi-omics study demonstrates that metastatic TNBC is characterized by EMT activation, metabolic reprogramming toward altered BCAA metabolism and oxidative phosphorylation-related protein expression, and remodeling of the tumor immune microenvironment, suggesting candidate molecules that warrant independent validation and further mechanistic investigation.

Immune checkpoint blockade (ICB) has demonstrated efficacy in clinical cancer therapy; however, a significant proportion of cancer patients do not respond to ICB. One contributing factor to this lack of response is the impairment of IFN-γ signaling within cancer cells. A20 acts as a negative regulator of IFN-γ signaling. Our study aimed to investigate the mechanism by which A20 exerts its negative regulatory effect on IFN-γ signaling in hepatocellular carcinoma (HCC) cells. Bioinformatic analysis revealed that A20 expression in HCC cell lines is inversely associated with the activation of IFN-γ signaling. Functional loss and gain experiments demonstrated that A20 inhibits IFN-γ signaling in HCC cells. The interaction between A20 and STAT1 was assessed using Co-Immunoprecipitation (Co-IP) assays and bimolecular fluorescence complementation (BioFC) assays. Our results also indicated that A20 suppresses the expression of downstream molecules involved in IFN-γ signaling, such as CXCL9, CXCL10, and HLA-ABC, in HCC cells. Additionally, enforced expression of A20 in HCC cells inhibited anti-tumor immunity in a mouse model of HCC. Bioinformatic analysis suggests that A20 may negatively regulate IFN-γ signaling in HCC cells from human HCC cohorts. Collectively, our study uncovers a novel mechanism whereby A20 inhibits IFN-γ signaling in HCC cells through direct binding with STAT1. These findings enhance our understanding of the regulatory mechanisms of IFN-γ signaling in cancer cells and provide insights for designing strategies to enhance the effectiveness of ICB therapy.

Hepatic angiomyolipoma (HAML) is a rare variant of perivascular epithelioid cell neoplasms (PEComas). Unlike its more common renal angiomyolipoma (RAML), the unique spatial microenvironment of HAML and its specific progression mechanisms remain poorly characterized. Here, we integrated single-nucleus RNA-sequencing and spatial transcriptomics from three sporadic HAML cases. We mapped functionally heterogeneous PEComas subpopulations and their localized tissue niches. Transcriptomic alignment and spatial colocalization demonstrated a high similarity between endothelial cells and a subset of PEComas, supporting a potential transition trajectory. Furthermore, spatial intercellular communication analysis identified an endothelial-derived PDGFD-PDGFRB axis. We propose that this paracrine signaling engages downstream Ras cascades to sustain localized autophagic flux in adjacent PEComas, potentially acting as a compensatory survival mechanism parallel to intrinsic TSC-mTOR defects. While definitive in vivo functional fate-mapping and perturbation studies are requisite, this multi-omics atlas provides a novel spatial framework for HAML pathogenesis and highlights the endothelial-PEComa signaling network as a potential therapeutic vulnerability.

Biliary tract cancer (BTC) is a rare abdominal cancer with poor prognosis. Circulating tumor DNA (ctDNA) analysis with liquid biopsy offers a minimally invasive approach for cancer detection and disease monitoring. Given limited reports, this study aims to evaluate minimal residual disease (MRD) and longitudinal ctDNA monitoring in BTC patients. A total of 124 BTC patients were enrolled, with 111 evaluable for ctDNA analysis using a tumor-informed approach. Baseline tumor tissue and plasma samples were collected for comprehensive genomic profiling (CGP). A customized ctDNA panel was developed based on CGP of resectable BTC tumors and public genomic databases for MRD assessment and longitudinal monitoring. ctDNA sequencing was performed using ultradeep targeted next-generation sequencing. Associations between ctDNA detection and outcomes were analyzed. Preoperative ctDNA detection was associated with advanced pathological stage and significantly worse relapse-free survival (RFS) and overall survival. Using this ctDNA panel, preoperative ctDNA was detected in 51.4% of cases, with TP53, KRAS, ARID1A, and SMAD4 being the most frequently mutated genes. During longitudinal monitoring, 57.8% of patients showed persistent ctDNA positivity or subsequent ctDNA detection before radiological recurrence. RFS was significantly shorter among patients with ctDNA positivity during longitudinal monitoring than among those with undetectable ctDNA (HR = 9.04; 95% CI, 3.56-23.97; p < 0.001). Our customized panel detected BTC-specific mutations in plasma using liquid biopsy, and ctDNA positivity was strongly associated with recurrence and survival outcomes. This panel has the potential to improve MRD assessment and longitudinal monitoring in BTC, enabling earlier intervention and improved patient stratification.

Treatment options remain limited for unresectable or advanced lung squamous cell carcinoma (LSqCC) that progresses after immune checkpoint inhibitor (ICI)-based therapy. Although combination therapy with cisplatin, gemcitabine, and necitumumab (CGN) represents a potential second-line regimen, no prospective data in a post-ICI setting have been reported. This open-label, multicenter single-arm Phase II study enrolled patients with LSqCC after platinum-based chemotherapy plus ICI, including concurrent chemoradiotherapy. The primary endpoint was objective response rate (ORR), with the null and alternative hypotheses set at 23% and 40%, respectively. Secondary endpoints included the disease-control rate (DCR), progression-free survival (PFS), overall survival (OS), the impact of platinum-free interval (PFI), eligibility for anti-angiogenic therapies, and safety. Forty-six patients were evaluable for efficacy. ORR was 26.1% (80% CI, 17.7-36.2) and DCR was 87.0% (95% CI, 73.7-95.1). Median PFS and OS were 4.4 months (95% CI, 4.1-5.5) and 12.2 months (95% CI, 9.4-15.2), respectively. Common adverse events included hematological toxicities, acneiform rash, and hypomagnesemia. No pneumonitis or treatment-related deaths were observed. The safety profile was consistent across prior treatment types and anti-angiogenic therapies eligibility. PFI analysis showed that longer PFI durations were associated with improvements in PFS and OS, and the optimal PFI cutoff value was approximately 4 months. Although the predefined response threshold was not met, CGN demonstrated modest antitumor activity with a high DCR and a manageable toxicity after ICI-based therapy. CGN may be a feasible treatment option for second-line after ICI-based therapy, including for patients unsuitable for anti-angiogenic therapies, although further validation is warranted. Trial Registration: jRCTs051200138.

This study characterized the genomic profile of esophageal squamous cell carcinoma (ESCC) via circulating tumor DNA (ctDNA) to identify predictive biomarkers for efficacy of definitive radiotherapy combined with systemic therapy. In this prospective cohort of 40 ESCC patients, 7 tumor tissues and 71 serial plasma samples were analyzed using a 340-gene panel. TP53 (45%) and PIK3CA (12.5%) were the most frequent SNVs, followed by NOTCH1/2 (7.5%). The 11q13.2-13.4 amplification (including CCND1/FGF19) occurred in 12.5% of cases. TP53 mutation rate was significantly higher in cT4 than cT2-3 stages (60% vs. 20%, p = 0.010). Notably, patients with persistent TP53 positivity posttreatment had significantly shorter PFS than those converting to negativity (HR = 5.090, p = 0.035); the 2-year PFS rates were 33.3% vs. 75%, respectively, with OS showing a borderline difference (p = 0.053). Posttreatment ctDNA-based minimal residual disease (MRD) positivity was 18.8%, correlating with a trend toward worse PFS (HR = 3.027, p = 0.067). Among the 31 patients with paired pre- and post-treatment plasma samples, the positive detection rate of nucleosome-positioning (left-shifted profile) decreased from 67.9% at baseline to 35.7% after treatment (χ[2] = 5.793, p = 0.016). This work based on plasma ctDNA profiling demonstrated that posttreatment clearance of TP53 mutations may represent a favorable prognostic biomarker in ESCC treated with definitive radiotherapy and systemic therapy. ctDNA-derived MRD status and nucleosome positioning constitute promising non-invasive biomarkers for treatment response monitoring and risk stratification for ESCC. Trial Registration:This study was registered with the Chinese Clinical Trial Registry (ChiCTR) on December 6, 2019 (Registration No. ChiCTR1900027936).

PABPC1, long recognized as a constitutive translational housekeeper, has emerged as a stress-responsive translational reprogramming hub in cancer. This review synthesizes recent paradigm shifts that redefine PABPC1 function: From global translation maintenance to selective oncogenic mRNA amplification via liquid-liquid phase separation; from binary protein-RNA interactions to complex regulatory networks involving lncRNAs and circRNAs that modulate PABPC1 stability, localization, and target selectivity; and from diffuse cytoplasmic distribution to functionally compartmentalized condensates. PABPC1 integrates diverse post-translational modifications, including SUMOylation, acetylation, and ubiquitination, that enable stress adaptation, and actively regulates alternative polyadenylation to influence 3'UTR length and gene expression. Positioned at the convergence point of multiple oncogenic signaling pathways (PI3K/AKT, Wnt/β-catenin, NF-κB, and etc.), PABPC1 converts upstream signals into translational outputs that drive tumor progression, metastasis, and therapy resistance across malignancies. Its functional duality, context-dependent activities, and paralog-specific roles underscore both the complexity and therapeutic potential of targeting this multifaceted RNA-binding protein.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by reinvigorating antitumor immunity; however, a substantial proportion of patients show primary resistance or later relapse. To investigate T cell states associated with reduced ICI efficacy, we performed single-cell RNA sequencing (scRNA-seq) on tumor-infiltrating lymphocytes (TILs) from a patient experiencing rapid recurrence under PD-1 blockade. Our analysis identified elevated expression of the ZFP36 family of RNA-binding proteins within exhausted CD8[+] T cells (Tex cells) in this progressing tumor. The ZFP36 family is known to destabilize target mRNAs by binding to AU-rich elements in their 3' untranslated regions (3' UTRs). In EL4 T cells, Zfp36 overexpression accelerated the decay of the effector cytokine mRNAs Tnf, Il2, and Ifng, thereby impairing cytokine production. This process is exacerbated by hypoxia. Furthermore, high ZFP36 family expression correlates with poor prognosis in ICI-treated patients in a public bulk tumor transcriptomic dataset. These findings suggest that tumor microenvironment (TME)-induced hypoxia upregulates the ZFP36 family in Tex cells, which in turn suppresses cytokine production via post-transcriptional regulation, potentially contributing to impaired antitumor effector function.

As a T-cell receptor co-stimulatory protein, signaling lymphocyte activation molecule family 6 (SLAMF6) is a member of the immune cell activating receptor family and is expressed on T cells, B cells, natural killer cells (NK cells), and tumor cells. To date, the biological functions and clinical significance of SLAMF6 in certain solid tumors remain to be elucidated. We analyzed the transcriptional expression pattern of SLAMF6 and its relationship with clinical outcomes using clinical specimens and pancancer databases. Next, multispectral immunofluorescence was applied to assess the correlation between SLAMF6 expression and CD8[+] T-cell activation and infiltration in clinical samples, with additional validation through immune-infiltration analysis. In parallel, using a colorectal cancer xenograft model, we examined how upregulation of SLAMF6 combined with immune-checkpoint blockade (anti-PD-L1) influences immunotherapy efficacy. Ultimately, our findings indicate that SLAMF6 modulates CD8[+] T-cell activation and infiltration through the STAT1/CXCL10 axis, thereby enhancing the recruitment of these effector cells to tumor sites.

To investigate the expression pattern, biological functions and regulatory mechanisms of inhibin beta B (INHBB) in colorectal cancer (CRC), and to clarify its role in mediating CD8[+] T cell exhaustion via the INHBB-ACVR2B-SMAD signaling axis for identifying a novel therapeutic target in CRC targeted immunotherapy, we analyzed the expression profile and prognostic value of INHBB in CRC tissues using The Cancer Genome Atlas database. Stable INHBB knockdown and overexpression CRC cell lines were constructed, and the malignant phenotypes were evaluated by Transwell assays, flow cytometry and other functional experiments. The interaction between INHBB and ACVR2B was verified by co-immunoprecipitation and immunofluorescence, and the in vivo regulatory effects of this pathway were determined using mouse xenograft tumor models combined with SMAD inhibitors. INHBB was upregulated in CRC tissues and associated with poor prognosis. Functional assays demonstrated that INHBB promoted the proliferation and invasion and suppressed the apoptosis of CRC cells. Mechanistically, INHBB bound to ACVR2B on CD8[+] T cells, activated SMAD signaling, and triggered CD8[+] T cell exhaustion, whereas blockade of the SMAD pathway reversed INHBB-mediated immunosuppression and tumor progression. Collectively, INHBB dually regulates the malignant phenotypes of CRC cells and CD8[+] T cell function through the INHBB-ACVR2B-SMAD axis, and targeting this axis may represent a promising therapeutic strategy for CRC immunotherapy.

In the phase 3 AEGEAN study, perioperative durvalumab plus neoadjuvant chemotherapy significantly improved the primary endpoints of event-free survival (EFS) and pathological complete response (pCR) in patients with resectable NSCLC versus neoadjuvant chemotherapy alone. We report prespecified exploratory Japanese subgroup analyses of EFS, disease-free survival (DFS), and overall survival (OS) (interim analyses; data cut-off [DCO] May 10, 2024); pCR (final analysis; DCO November 10, 2022); and safety. In this double-blind, placebo-controlled study, 79 treatment-naïve Japanese patients (stage II-IIIB[N2]) were randomized (1:1) to neoadjuvant chemotherapy plus durvalumab/placebo (every 3 weeks [Q3W], 4 cycles) pre-surgery, then adjuvant durvalumab/placebo (Q4W, 12 cycles). Efficacy was analyzed in the modified intention-to-treat population (N = 64; durvalumab arm n = 30, placebo arm n = 34), which excluded patients with documented EGFR/ALK aberrations. At the corresponding data cutoffs, EFS benefit favored the durvalumab arm (unstratified HR, 0.63; 95% CI, 0.26-1.45; median follow-up, 42 months [censored patients]), and the pCR rate was numerically higher with durvalumab versus placebo (33.3% vs. 5.9%). A clinically meaningful DFS improvement favored the durvalumab arm (unstratified HR 0.47, 95% CI 0.16-1.21); however, no difference in OS was observed (unstratified HR 1.01, 95% CI 0.40-2.51). Grade 3/4 adverse events occurred in 62.2% and 65.9% of patients with durvalumab and placebo, respectively. Improvements in EFS and pCR with perioperative durvalumab plus neoadjuvant chemotherapy versus neoadjuvant chemotherapy alone were comparable to, or greater than, those observed in the global study population, supporting this regimen as a treatment option for Japanese patients. Trial Registration: ClinicalTrials.Gov Identifier NCT03800134.