Background & Aims Cancer stem cells (CSCs) can contribute to hepatocellular carcinoma (HCC) progression and recurrence following therapy. The presence of tumor-associated macrophages (TAMs) in patients with HCC is associated with poor outcomes. It is not clear whether TAMs interact with CSCs during HCC development. We investigated whether TAMs affect the activities of CSCs in the microenvironment of human HCCs. Methods HCCs were collected from 17 patients during surgical resection and single cell suspensions were analyzed by flow cytometry. CD14+ TAMs were isolated from the HCC cell suspensions and placed into co-culture with HepG2 or Hep3B cells, and CSC functions were measured. The interleukin 6 (IL6) receptor was blocked with a monoclonal antibody (tocilizumab), and STAT3 was knocked down with small hairpin RNAs in HepG2 cells. Xenograft tumors were grown in NOD-SCID/Il2Rgnull mice from human primary HCC cells or HepG2 cells. Results CD44+ cells from human HCCs and cell lines formed more spheres in culture and more xenograft tumors in mice than CD44− cells, indicating that CD44+ cells are CSCs. Incubation of the CD44+ cells with TAMs promoted expansion of CD44+ cells, and increased their sphere formation in culture and formation xenograft tumors in mice. In human HCC samples, numbers of TAMs correlated with numbers of CD44+ cells. Of all cytokines expressed by TAMs, IL6 was increased at the highest level in human HCC co-cultures, compared with TAMs not undergoing co-culture. IL6 was detected in the microenvironment of HCC samples and induced expansion of CD44+ cells in culture. Levels of IL6 correlated with stages of human HCCs and detection of CSC markers. Incubation of HCC cell lines with tocilizumab or knockdown of STAT3 in HCC cells reduced the ability of TAMs to promote sphere formation by CD44+ cells in culture and growth of xenograft tumors in mice. Conclusions CD44+ cells isolated from human HCC tissues and cell lines have CSC activities in vitro and form a larger number of xenograft tumors in mice than CD44− cells. TAMs produce IL6, which promotes expansion of these CSCs and tumorigenesis. Levels of IL6 in human HCC samples correlate with tumor stage and markers of CSCs. Blockade of IL6 signaling with tocilizumab, a drug approved by the Food and Drug Administration for treatment of rheumatoid arthritis, inhibits TAM-stimulated activity of CD44+ cells. This drug might be used to treat patients with HCC.

Aerobic glycolysis regulates T cell function. However, if and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity remains a question in cancer patients. Here we report that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNA101 and microRNA26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors, Numb and Fbxw7, via H3K27me3, and consequently stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, human shRNA-knockdown-EZH2-deficient T cells elicited poor anti-tumor immunity. EZH2+CD8+ T cells were associated with improved cancer patient survival. Together, the data unveil a novel metabolic target and mechanism of cancer immune evasion.

Myeloid-derived suppressor cells (MDSC) contribute to immune suppression in cancer, but the mechanisms through which they drive metastatic progression are not fully understood. In this study, we show how MDSC convey stem-like qualities to breast cancer cells that coordinately help enable immune suppression and escape. We found that MDSC promoted tumor formation by enhancing breast cancer cell stem-like properties as well as by suppressing T cell activation. Mechanistic investigations indicated that these effects relied upon crosstalk between the STAT3 and NOTCH pathways in cancer cells, with MDSC inducing IL-6-dependent phosphorylation of STAT3 and activating NOTCH through nitric oxide (NO), leading to prolonged STAT3 activation. In clinical specimens of breast cancer, the presence of MDSC correlated with the presence of cancer stem-like cells (CSC) and independently predicted poor survival outcomes. Collectively, our work revealed an immune-associated mechanism that extrinsically confers cancer cell stemness properties and affects patient outcome. We suggest that targeting STAT3-NOTCH crosstalk between MDSC and CSC could offer a unique locus to improve cancer treatment, by coordinately targeting a coupled mechanism that enables cancer stemness and immune escape.

Defect passivation has been demonstrated to be effective in improving the radiative recombination of charge carriers in perovskites, and consequently, the device performance of the resultant perovskite light‐emitting diodes (LEDs). State‐of‐the‐art useful passivation agents in perovskite LEDs are mostly organic chelating molecules that, however, simultaneously sacrifice the charge‐transport properties and thermal stability of the resultant perovskite emissive layers, thereby deteriorating performance, and especially the operational stability of the devices. We demonstrate that lithium halides can efficiently passivate the defects generated by halide vacancies and reduce trap state density, thereby suppressing ion migration in perovskite films. Efficient green perovskite LEDs based on all‐inorganic CsPbBr3 perovskite with a peak external quantum efficiency of 16.2 %, as well as a high maximum brightness of 50 270 cd m−2, are achieved. Moreover, the device shows decent stability even under a brightness of 104 cd m−2. We highlight the universal applicability of defect passivation using lithium halides, which enabled us to improve the efficiency of blue and red perovskite LEDs.

Hepatocellular carcinoma (HCC) is highly associated with inflammation. Myeloid cells, including tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), are abundant in HCC microenvironment and are often associated with poor prognosis. Myeloid cells in HCC play a vital role in supporting tumor initiation, progression, angiogenesis, metastasis and therapeutic resistance. Here, we summarize our current knowledge about myeloid cells in HCC, and focus on their immune suppressive activities and tumor promoting functions, as well as the relevance to potential new therapies in HCC.