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Background and Aims:We previously demonstrated that cancer-associated fibroblasts (CAFs) promote tumor growth through recruitment of myeloidderived suppressor cells (MDSCs). 5-lipoxygenase (5-LO) is highly expressed in myeloid cells and is critical for synthesizing leukotriene B4 (LTB4), which is involved in tumor progression by activating its receptor leukotriene B4 receptor type 2 (BLT2). In this study, we investigated whether and how CAFs regulate MDSC function to enhance cancer stemness, the driving force of the cancer aggressiveness and chemotherapy refractoriness, in highly desmoplastic intrahepatic cholangiocarcinoma (ICC). Approach and Results: RNA-sequencing analysis revealed enriched metabolic pathways but decreased inflammatory pathways in cancer MDSCs compared with blood MDSCs from patients with ICC. Co-injection of ICC patient-derived CAFs promoted cancer stemness in an orthotopic ICC model, which was blunted by MDSC depletion. Conditioned media (CM) from CAFeducated MDSCs drastically promoted tumorsphere formation efficiency and stemness marker gene expression in ICC cells. CAF-CM stimulation increased expression and activity of 5-LO in MDSCs, while 5-LO inhibitor

Enhanced gut permeability due to dysregulated epithelial tight junction is often associated with inflammatory bowel diseases (IBD), which have a greater risk for developing colorectal cancer. STAT6 activation was detected in inflamed colonic epithelium of active IBD patients, suggesting a role of epithelial STAT6 in colitis development. Here, we demonstrated that non-hematopoietic STAT6, but not hematopoietic STAT6, triggered DSS-induced colitis and subsequent tumorigenesis. This could be due to the enhancingeffect of STAT6 on gut permeability and microbiota translocation via interruption of epithelial tight junction integrity. Mechanistically, long-myosin light-chain kinase (MLCK1) was identified as a target of STAT6, leading to epithelial tight junction dysfunction and microbiota-driven colitis. Furthermore, neutralization of IL-13, which was primarily derived from type 2 innate lymphoid cells (ILC2) in a microbiota-dependent way, inhibited epithelial STAT6 activation and improved gut permeability and DSSinduced colitis. Importantly, pharmacological inhibition of STAT6 reduces murine intestinal tumor formation, and tumoral p-STAT6 levels positively correlated to the clinical stage and poor prognosis of human colorectal cancer. Thus, our study reveals a direct role of STAT6 in the disruption of epithelial tight junction integrity and colitis development, and suggests STAT6 as a potential therapeutic and prophylactic target for IBD and colitis-associated cancer.

The regulation of electrostatic electric fields through electrical stimulation is an efficient method to increase the catalytic activity of nanozymes and improve the therapeutic effect of nanozyme catalytic therapy. Piezoelectric materials, which are capable of generating a built-in electric field under ultrasound (US), not only improve the activity of nanozymes but also enable piezoelectric sonodynamic therapy (SDT). In this study, a sonosensitizer based on a Hf-based metal−organic framework (UIO-66) and Au nanoparticles (NPs) was produced. Under US irradiation, UIO-66 can generate a built-in electric field inside the materials, which promotes electron− hole separation and produces reactive oxygen species (ROS). The introduction of Au NPs facilitated the electron transfer, which inhibited the recombination of the electron−hole pairs and improved the piezoelectric properties of UIO-66. The value of the piezoelectric constant (d 33 ) increased from 71 to 122 pmV −1 after the deposition of Au NPs. In addition, the intrinsic catalase and peroxidase activities of the Au NPs were increased 2-fold after the stimulation from the built-in electric field induced through US exposure. In vivo and in vitro experiments revealed that the proposed sonosensitizer can kill cancer cells and inhibit tumor growth in mice through the enhanced piezoelectric SDT and nanozyme catalytic therapy. The piezoelectric sensitizer proposed in this work proved to be an efficient candidate that can be used for multiple therapeutic modalities in tumor therapy.