An age-related decrease in leptin contributes to CD8 T cell aging in the tumor microenvironment.

T cell dysfunction with age underlies an increased incidence of cancer in elderly individuals; however, how T cell aging is triggered in the tumor microenvironment is unclear. Here, we show that an age-associated reduction in adipocyte-derived leptin contributes to the accumulation of tumor-infiltrating senescent CD8 T cells. Single-cell profiling of human and mouse cancer tissues reveals that the frequency of intratumoral senescent CD8 T cells increases with age, leading to a weak antitumor effect.

Diet-derived galactose reprograms hepatocytes to prevent T cell exhaustion and elicit antitumour immunity.

Dietary nutrients are inextricably linked to antitumour immune responses. However, the effect of diet-derived galactose on antitumour immunity remains unclear. Here we show that dietary galactose augments CD8 T cell immunity to suppress tumour progression.

A pan-KRAS inhibitor and its derived degrader elicit multifaceted anti-tumor efficacy in KRAS-driven cancers.

KRAS remains a challenging therapeutic target with limited effective inhibitors currently available. Here, we report the discovery of MCB-294, a potent dual-state pan-KRAS inhibitor capable of binding both the active (GTP-bound) and inactive (GDP-bound) forms of KRAS. MCB-294 engages the switch-II pocket through a water-mediated hydrogen-bond network and selectively inhibits KRAS over NRAS and HRAS.

Disruption of the Vagal TRPA1-Pulmonary Neuroendocrine Cell Axis Reduces Asthma Severity.

Background: Pulmonary neuroendocrine cells (PNECs) are adjacent to the vagus nerve, which innervates the lungs, and have been implicated in asthma pathogenesis. However, the neuroimmunomodulatory role of vagal-PNEC signaling in asthma remains poorly understood.

Methods: We developed an asthma model of C-fiber photoactivation and vagotomy to investigate the changes in PNECs.

Lactate dehydrogenase B facilitates disulfidptosis and exhaustion of tumour-infiltrating CD8 T cells.

The aberrant accumulation of intracellular disulfides promotes cancer cell disulfidptosis; however, how disulfide stress influences tumour-infiltrating CD8 T cell function remains unknown. Here we demonstrate that lactate dehydrogenase B (LDHB) facilitates intratumoural CD8 T cell disulfidptosis and exhaustion, leading to impaired antitumour immunity. SLC7A11-mediated cystine uptake by CD8 T cells induces disulfidptosis, which plays critical roles in the development of exhausted CD8 T cells.

Integration of Pan-Cancer Single-Cell and Spatial Transcriptomics Reveals Stromal Cell Features and Therapeutic Targets in Tumor Microenvironment.

Unlabelled: Stromal cells are physiologically essential components of the tumor microenvironment (TME) that mediates tumor development and therapeutic resistance. Development of a logical and unified system for stromal cell type identification and characterization of corresponding functional properties could help design antitumor strategies that target stromal cells. Here, we performed a pan-cancer analysis of 214,972 nonimmune stromal cells using single-cell RNA sequencing from 258 patients across 16 cancer types and analyzed spatial transcriptomics from 16 patients across seven cancer types, including six patients receiving anti-PD-1 treatment.

Dietary fructose-mediated adipocyte metabolism drives antitumor CD8 T cell responses.

Fructose consumption is associated with tumor growth and metastasis in mice, yet its impact on antitumor immune responses remains unclear. Here, we show that dietary fructose modulates adipocyte metabolism to enhance antitumor CD8 T cell immune responses and control tumor growth. Transcriptional profiling of tumor-infiltrating CD8 T cells reveals that dietary fructose mediates attenuated transition of CD8 T cells to terminal exhaustion, leading to a superior antitumor efficacy.

Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy.

Background & Aims: The tumour microenvironment (TME) is a crucial mediator of cancer progression and therapeutic outcome. The TME subtype correlates with patient response to immunotherapy in multiple cancers. Most previous studies have focused on the role of different cellular components in the TME associated with immunotherapy efficacy.

DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion.

RNA-binding proteins (RBPs) can recognize thousands of RNAs that help to maintain cell homeostasis, and RBP dysfunction is frequently observed in various cancers. However, whether specific RBPs are involved in tumor immune evasion by regulating programmed death ligand-1 (PD-L1) is unclear. Here, we perform targeted RBP CRISPR/Cas9 screening and identify density regulated re-initiation and release factor (DENR) as a PD-L1 regulator.

Single-cell and spatial analysis reveal interaction of FAP fibroblasts and SPP1 macrophages in colorectal cancer.

Colorectal cancer (CRC) is among the most common malignancies with limited treatments other than surgery. The tumor microenvironment (TME) profiling enables the discovery of potential therapeutic targets. Here, we profile 54,103 cells from tumor and adjacent tissues to characterize cellular composition and elucidate the potential origin and regulation of tumor-enriched cell types in CRC.

Profiling of immune features to predict immunotherapy efficacy.

Immune checkpoint blockade (ICB) therapies exhibit substantial clinical benefit in different cancers, but relatively low response rates in the majority of patients highlight the need to understand mutual relationships among immune features. Here, we reveal overall positive correlations among immune checkpoints and immune cell populations. Clinically, patients benefiting from ICB exhibited increases for both immune stimulatory and inhibitory features after initiation of therapy, suggesting that the activation of the immune microenvironment might serve as the biomarker to predict immune response.

Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer.

Background: The four major RNA adenosine modifications, i.e., mA, mA, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the "writer" enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis.

microRNA-23a contributes to asthma by targeting BCL2 in airway epithelial cells and CXCL12 in fibroblasts.

The deregulated cross-talk between airway epithelial cells with subepithelial fibroblasts during inflammation drives the pathogenesis of asthma. Bioinformatics analysis and luciferase activity assay suggested that B cell lymphoma-2 (BCL2) and CXC ligand 12 (CXCL12) are potential targets of miR-23a. The aim of this study was to elucidate the effect of microRNA-23a (miR-23a) on BCL2, and CXCL12 in asthma.

Specific regulation of PRMT1 expression by PIAS1 and RKIP in BEAS-2B epithelia cells and HFL-1 fibroblasts in lung inflammation.

Protein arginine methyltransferase 1 (PRMT1) catalyzes methylation of histones and other cellular proteins, and thus regulates gene transcription and protein activity. In antigen-induced pulmonary inflammation (AIPI) PRMT1 was up-regulated in the epithelium, while in chronic AIPI, increased PRMT1 shifted to fibroblasts. In this study we investigated the cell type specific regulatory mechanism of PRMT1.