Cancer letters最新文献

Perineural invasion (PNI) is a major contributor to the aggressiveness and poor prognosis of cholangiocarcinoma (CCA). However, the crosstalk among tumor cells, the peripheral nervous system, and tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) remains incompletely defined. Using in vitro and in vivo models of PNI, we demonstrate that tumor-derived exosomal LINC01978 mediates neural reprogramming and TAM-associated extracellular matrix (ECM) remodeling. Subsequent analyses of clinical cohorts confirm that high LINC01978 expression is significantly associated with PNI and poorer survival. This mechanism is further validated in human specimens by IHC and IF. Mechanistically, we propose a nerve-coupled dual-loop model that drives PNI in CCA. In the first loop, tumor-derived exosomes deliver LINC01978 to neural cells. This process promotes neurite outgrowth via autocrine glial cell line-derived neurotrophic factor (GDNF) signaling, which in turn activates the RET/STAT3 signaling pathway in CCA cells, thereby promoting malignant phenotypes. After this loop is established, a second loop emerges at the invasive front. Invaded nerves secrete CCL2, thereby preferentially recruiting CCR2+ inflammatory monocytes (IMs) to PNI sites, where they differentiate into TAMs and secrete CTSB to degrade the perineural ECM. Together, the two loops act sequentially and reinforce each other, creating a self-amplifying program that escalates PNI.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. This study aimed to develop and validate a regulatory T cell (Treg)-associated magnetic resonance imaging (MRI) radiomics model and assess its prognostic value, cross-species similarity, and interpretability across multicenter cohorts. Tregs retained prognostic significance for patients with GBM under World Health Organization CNS 5 classification. In murine models, Treg depletion suppressed tumor growth and reduced the infiltration of myeloid-derived suppressor cells, tumor-associated macrophages, and exhausted CD8⁺T cells. The in vitro co-culture of Tregs with GL261 cells significantly reduced radiation-induced apoptosis. We constructed a Treg-associated radiomics model comprising six features and validated the prognostic value of the radiomics score (RS) across multicenter clinical imaging cohorts (First Affiliated Hospital of Fujian Medical University, n = 111, hazard ratio [HR] = 2.178, 95% confidence interval [CI]: 1.269-3.740; Second Affiliated Hospital of Zhejiang University School of Medicine, n = 126, HR = 1.664, 95% CI: 1.049-2.640; The Cancer Genome Atlas, n = 86, HR = 1.811, 95% CI: 1.089-3.010). Treg depletion experiments also confirmed causal associations between two radiomic features and Treg infiltration. RS stratification correlated with hypoxia, glycolysis, interleukin (IL)-2/signal transducer and activator of transcription (STAT) 5, and IL-6/Janus kinase/STAT3 signaling pathways and immune checkpoints and genomic alterations. The MRI radiomics model enables noninvasive prediction of Treg infiltration and serves as a robust, generalizable prognostic biomarker for GBM. These findings provide evidence for biological causal associations and cross-species similarities between radiomics features and Treg infiltration.

Homologous recombination deficiency (HRD) has emerged as a key vulnerability in selected cancer types and is associated with response to platinum and PARPi-based treatment strategies. However, additional biomarkers and targeted therapy options are needed to broaden the range of patients that could benefit from this therapeutic niche. Here, we show that the SARC-HRD signature, composed of ten genes of the homologous recombination repair pathway, stratifies a cohort of sarcoma patients, and associates with genomic biomarkers of HRD, with disease progression and with the CINSARC prognostic signature. Equivalently to CINSARC, high levels of SARC-HRD are associated with poor metastasis-free survival, underscoring the potential of SARC-HRD to predict disease outcome. By pharmacotyping patient-derived cell models, we identified promising drug targets within the DNA damage response for sarcoma with HRD traits. Inhibition of ATR, CHK1 and WEE1 elicited synthetic lethality in sarcoma cells with HRD, which concomitantly showed an upregulation of ATR signaling. Combinatorial drug testing further revealed synergistic drug combinations between ATRi, WEE1i, PARP1/2i and chemotherapeutic agents with potential clinical impact. Mechanistically, targeting ATR signaling at multiple levels induced a replication defect, mitotic abnormalities and apoptotic cell death. Taken together, our results demonstrate the therapeutic benefit of targeting DDR mechanisms in sarcoma with HRDness traits and their potential clinical utility for treating a broader spectrum of tumor types.

Pharmacological targeting of ATR (ataxia telangiectasia and Rad3-related kinase), the master regulator of replication stress response, is emerging as a promising anticancer strategy. Despite the documented immune-modulatory effects of ATR inhibitors (ATRi), the immune evasion mechanisms constraining their therapeutic efficacy remain undefined. Here, we demonstrate that ATRi upregulates Galectin-9 (Gal-9), a ligand for the TIM-3 immune checkpoint, in tumor cells and host antigen-presenting cells (dendritic cells/macrophages) via STING-type I interferon (IFN-I) innate immune pathway. Notably, combining Gal-9 blockade with ATRi ceralasertib elicits potent anti-tumor effects and induces durable immunologic memory in syngeneic mouse models. In immune checkpoint-refractory lung cancer, the triple combination of ATRi, anti-Gal-9 and anti-PD-1 demonstrates superior efficacy. Mechanistically, Gal-9 blockade synergizes with ATRi to activate dendritic cells/macrophages and promote CD8⁺ T cell differentiation toward stem-like memory phenotypes with enhanced functional capacity. CD8⁺ T cell depletion completely abrogates the anti-tumor effects, suggesting their essential role in mediating therapeutic responses. These findings establish Gal-9 upregulation as a critical adaptive immune resistance mechanism constraining ATRi efficacy, providing a compelling rationale for clinical translation of ceralasertib/Gal-9 blockade combinations.

Cancer cells undergo metabolic reprogramming to meet the demands of rapid proliferation, survival and chemotherapy resistance. Targeting cancer-specific metabolic vulnerabilities offers a compelling strategy for therapeutic intervention. Owing to the Warburg effect and the unique tumor microenvironment, pancreatic ductal adenocarcinoma (PDAC) cells exhibit a high demand for glucose to sustain their energy metabolism. Here, we identify a novel regulatory mechanism controlling the cell surface abundance of glucose transporter 1 (GLUT1), mediated by RAB8A-dependent vesicular trafficking. RAB8A, a member of the RAS oncogene family, enhances GLUT1 membrane localization and thereby increases glucose uptake in PDAC cells. Mechanistically, we demonstrate that ubiquitin-specific peptidase 20 (USP20) negatively regulates RAB8A activation by selectively removing K48-linked polyubiquitin chains from its inactive form. Functional assays in vitro and in vivo validate the tumor-suppressive role of the USP20-RAB8A signaling axis. Furthermore, using primary PDAC cells derived from KPC (Kras^G12D/+; Trp53 R172H^flox/flox; Pdx1-Cre) mice, we show that dual knockdown of Rab8a and Glut1 markedly attenuates tumor-promoting effects driven by oncogenic Kras and Trp53 loss. Collectively, our findings reveal that the USP20-RAB8A-GLUT1 axis regulates glucose uptake and metabolic reprogramming in PDAC, thereby inhibiting tumor growth and metastasis. Targeting this signaling axis provides a novel insight into metabolic therapy for pancreatic cancer.

Pancreatic cancer has a dismal prognosis, largely due to resistance to all current therapeutic modalities, including prevailing immunotherapy. Deciphering the mechanisms underlying the immunosuppressive tumor microenvironment is pivotal for developing effective therapeutic strategies. In this study, we found that the expression of CCL20 is negatively correlated with the infiltration of CD8⁺ T cells, and consistently, patients with higher CCL20 expression have a worse prognosis. CCL20, as a secreted ligand protein regulated by SP5, can bind to its cognate receptor CCR6 in the tumor microenvironment and is mainly produced by tumor cells, as confirmed by single-cell RNA sequencing and immunofluorescence staining of tumor tissues. Compared with CCL20 wild-type tumors, CCL20 knockout tumors exhibited impaired growth, decreased infiltration of CCR6⁺ Tregs, and concomitantly increased infiltration of CD8⁺ T cells. Importantly, this altered immune infiltration phenotype was abolished in Treg-specific CCR6 knockout mice. Furthermore, CCR6 inhibition potentiated the efficacy of anti-PD1 immune checkpoint blockade. Taken together, our data demonstrate that tumor cell-derived CCL20 shapes an immunosuppressive microenvironment in pancreatic cancer by recruiting CCR6⁺ Tregs, suggesting that targeting the CCL20-CCR6 axis offers a promising therapeutic strategy, particularly when combined with immune checkpoint blockade.

Acute myocardial infarction (MI) is a relatively rare but life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Information regarding the clinical characteristics, outcomes, and prognostication of post-transplant MI is lacking. We conducted a nationally representative cohort study at 34 centers in China. Patients with MI were retrospectively identified among those who underwent allo-HSCT. The diagnosis and classification of MI were reviewed according to established guidelines. One hundred thirteen patients were analyzed, including 23 patients with T1MI, 87 patients with T2MI, and three patients with T3MI. Patients with T2MI had a significantly higher mortality rate. Thrombotic microangiopathy (TMA) frequently coexisted with T2MI and adversely affected the overall survival. Disease relapse or progression, a platelet count <20 × 10⁹/L, active TMA at MI onset, and Killip class 3-4 were identified as independent risk factors for 2-month mortality. We divided these patients into a low-risk group (without risk factors), an intermediate-risk group (1-2 risk factors), and a high-risk group (3-4 risk factors). Significantly different 2-month mortality rates were observed across these groups (11.1 %, 59.3 %, and 100.0 %, respectively). Available angiographic imaging data and antiplatelet therapy after MI onset may be associated with improved outcome, but the survival benefits and optimized medication use in patients with post-transplant MI require further validation. These findings may facilitate refined monitoring and management strategies of MI in the post-transplant population.

This study analyzes the global burden of primary liver cancer among young adults (15-49 years) from 1990 to 2021, revealing a 46.0% rise in incidence and 59.0% increase in prevalence, yet declining age-standardized mortality (Estimated Annual Percentage Change-EAPC = -1.27). Middle-SDI regions faced the highest burden, with East Asia accounting for 66,472 prevalent cases and stark national disparities (e.g., Mongolia ASR = 1846.83/100,000 vs. Morocco ASR = 16.73). Population growth drove 42.8-47.8% of case increases, while metabolic risks and alcohol use (surpassing smoking in 2021) emerged as dominant factors. Males showed a 3.5-fold higher smoking-related risk than females. Deaths rose notably among those ≥30 years, with a 20.6% increase in 30-34-year-olds, signaling earlier onset. A shift from hepatitis B to metabolic/behavioral risks underscores evolving etiology. Projections suggest 133,561 cases by 2050, urging prioritized early screening and equitable resource allocation beyond traditional viral hepatitis frameworks.