Understanding the complexity of the tumor microenvironment is vital for improving immunotherapy outcomes. Here, we report that the T cell costimulatory molecule OX40 was highly expressed in tumor endothelial cells (ECs) and was negatively associated with the prognosis of patients, which is irrelevant to T cell activation. Analysis of conditional OX40 loss- and gain-of-function transgenic mice showed that OX40 signal in ECs counteracted the antitumor effects produced in T cells by promoting angiogenesis. Mechanistically, leucine-rich repeat–containing GPCR5 (Lgr5 ⁺ ) cancer stem cells induced OX40 expression in tumor ECs via EGF/STAT3 signaling. Activated OX40 interacted with Spns lysolipid transporter 2 (Spns2), obstructing the export of sphingosine 1-phosphate (S1P) and resulting in S1P intracellular accumulation. Increased S1P directly bound to Yes 1–associated protein (YAP), disrupting its interaction with large tumor suppressor kinase 1 (LATS1) and promoting YAP nuclear translocation. Finally, the YAP inhibitor verteporfin enhanced the antitumor effects of the OX40 agonist. Together, these findings reveal an unexpected protumor role of OX40 in ECs, highlighting the effect of nonimmune cell compartments on immunotherapy.

Given the global prevalence of colorectal cancer (CRC), advancements in prompt and accurate diagnosis are crucial. Long non-coding RNAs (lncRNAs) in serum exosomes are emerging as potential diagnostic biomarkers. This study evaluated the feasibility of using serum exosomal lncRNAs for early-stage CRC diagnosis in clinical practice. Candidate serum exosomal lncRNAs were identified through an integrated analysis of two GEO datasets (GSE100206 and GSE100063) containing non-coding RNA expression profiles in serum exosomes. Exosomes isolated from participants' serum were validated using transmission electron microscopy (TEM) and immunoblotting. The expression levels of serum exosomal PCAT1 were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Diagnostic accuracy was assessed using receiver operating characteristic (ROC) analysis. Serum exosomal PCAT1 levels were evaluated in 150 CRC patients, 66 patients with benign colorectal lesions, and 128 healthy controls. ROC analysis demonstrated high diagnostic efficacy of serum exosomal PCAT1 for CRC. Notably, the predictive performance was sufficient to distinguish early-stage CRC patients. Additionally, the diagnostic value was significant for CRC patients with low serum carcinoembryonic antigen (CEA) levels. Measuring serum exosomal PCAT1 could complement CEA assessment, enhancing CRC diagnostic accuracy. Serum exosomal PCAT1 can complement CEA assessment, aiding in early CRC diagnosis and helping to differentiate the disease, especially in patients with low CEA levels.

Background: Colorectal cancer (CRC) is prevalent worldwide and novel diagnostic and prognostic biomarkers are needed to improve precision medicine. Circulating circular RNAs (circRNAs) are currently being considered as emerging tumor biomarkers. Methods: Candidate circRNA was selected by integrating analysis of Gene Expression Omnibus (GEO) database using GEO2R program. The expression data of serum circ_001659 were obtained from the quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic curves were applied to evaluate the clinical applications of circ_001659. Finally, biological functions and potential mechanisms of circ_001659 in tumor progression were investigated in CRC progression. Results: The results showed that the diagnostic performance of serum circ_001659 were excellent for CRC detection. The predictive values and likelihood ratios were satisfactory for the diagnosis of CRC, including patients in early-stage disease or patients with carcinoembryonic antigen (CEA)-negative status. Serum levels of circ_001659 declined significantly 3 months after surgery in both preoperative CEA-positive and CEA-negative patients. Functionally, circ_001659 influenced tumor cell metastasis via regulating epithelial-mesenchymal transition (EMT) and cytoskeleton organization. Conclusion: Our findings demonstrate that circ_001659 could be a useful serum biomarker for CRC diagnosis and prognosis. Targeting circ_001659 and its pathway may be meaningful for treating patients with CRC.

Background: Colorectal cancer (CRC) is prevalent worldwide and novel diagnostic and prognostic biomarkers are needed to improve precision medicine. Circulating circular RNAs (circRNAs) are currently being considered as emerging tumor biomarkers. Methods: Candidate circRNA was selected by integrating analysis of Gene Expression Omnibus (GEO) database using GEO2R program. The expression data of serum circ_001659 were obtained from the quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic curves were applied to evaluate the clinical applications of circ_001659. Finally, biological functions and potential mechanisms of circ_001659 in tumor progression were investigated in CRC progression. Results: The results showed that the diagnostic performance of serum circ_001659 were excellent for CRC detection. The predictive values and likelihood ratios were satisfactory for the diagnosis of CRC, including patients in early-stage disease or patients with carcinoembryonic antigen (CEA)-negative status. Serum levels of circ_001659 declined significantly 3 months after surgery in both preoperative CEA-positive and CEA-negative patients. Functionally, circ_001659 influenced tumor cell metastasis via regulating epithelial-mesenchymal transition (EMT) and cytoskeleton organization. Conclusion: Our findings demonstrate that circ_001659 could be a useful serum biomarker for CRC diagnosis and prognosis. Targeting circ_001659 and its pathway may be meaningful for treating patients with CRC.