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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. We demonstrate that the tumor-specific FAP + fibroblasts and SPP1 + macrophages were positively correlated in 14 independent CRC cohorts containing 2550 samples and validate their close localization by immuno-fluorescent staining and spatial transcriptomics. This interaction might be regulated by chemerin, TGF-β, and interleukin-1, which would stimulate the formation of immune-excluded desmoplasic structure and limit the T cell infiltration. Furthermore, we find patients with high FAP or SPP1 expression achieved less therapeutic benefit from an anti-PD-L1 therapy cohort. Our results provide a potential therapeutic strategy by disrupting FAP + fibroblasts and SPP1 + macrophages interaction to improve immunotherapy. Tumour microenvironment profiling during colorectal cancer progression may enable the discovery of therapeutic targets. Here, single cell and spatial RNA sequencing of tumour and adjacent normal tissues reveals an interaction between FAP + fibroblasts and SPP1 + macrophages that could be disrupted as an immunotherapy strategy.

Regulatory T (Treg) cells are one of the major immunosuppressive cell types in cancer and a potential target for immunotherapy, but targeting tumor-infiltrating (TI) Treg cells has been challenging. Here, using single-cell RNA sequencing of immune cells from renal clear cell carcinoma (ccRCC) patients, we identify two distinct transcriptional fates for TI Treg cells, Fate-1 and Fate-2. The Fate-1 signature is associated with a poorer prognosis in ccRCC and several other solid cancers. CD177, a cell surface protein normally expressed on neutrophil, is specifically expressed on Fate-1 TI Treg cells in several solid cancer types, but not on other TI or peripheral Treg cells. Mechanistically, blocking CD177 reduces the suppressive activity of Treg cells in vitro, while Treg-specific deletion of Cd177 leads to decreased tumor growth and reduced TI Treg frequency in mice. Our results thus uncover a functional CD177 + TI Treg population that may serve as a target for TI Treg-specific immunotherapy. Regulatory T (Treg) cells are important modulators of the tumor microenvironment. Here the authors perform transcriptome profiling of immune cells from patients with renal clear cell carcinoma to find a Treg signature that correlates with poorer prognosis, with CD177 being implicated as the main mediator for related alterations in Treg activity and tumor outcome.

Intestinal immune homeostasis and microbiome structure play a critical role in the pathogenesis and progress of inflammatory bowel disease (IBD), whereas IBD treatment remains a challenge as the first‐line drugs show limited therapeutic efficiency and great side effect. In this study, a colon‐targeted adhesive core–shell hydrogel microsphere is designed and fabricated by the ingenious combination of advanced gas‐shearing technology and ionic diffusion method, which can congregate on colon tissue regulating the gut immune‐microbiota microenvironment in IBD treatment. The degradation experiment indicates the anti‐acid and colon‐targeted property of the alginate hydrogel shell, and the in vivo imaging shows the mucoadhesive ability of the thiolated‐hyaluronic acid hydrogel core of the microsphere, which reduces the systematic exposure and prolongs the local drug dwell time. In addition, both in vitro and in vivo study demonstrate that the microsphere significantly reduces the secretion of pro‐inflammatory cytokines, induces specific type 2 macrophage differentiation, and remarkably alleviates colitis in the mice model. Moreover, 16S ribosomal RNA sequencing reveals an optimized gut flora composition, probiotics including Bifidobacterium and Lactobacillus significantly augment, while the detrimental communities are inhibited, which benefits the intestinal homeostasis. This finding provides an ideal clinical candidate for IBD treatment. A colon‐targeting and mucoadhesive hydrogel core–shell microsphere is fabricated by advanced gas‐shearing technology for treatment of inflammatory bowel disease. The oral‐administrated microsphere targets the colon where the alginate shell collapses and the HA‐SH‐Ag hydrogel core is released, which congregates on the inflamed colon mucosa for regulation of macrophage differentiation and optimization of gut flora.

The functional integrity of CD8+ T cells is tightly coupled to metabolic reprogramming, but how oxidative stress directs CD8+ T cell metabolic fitness in the tumor microenvironment (TME) remains elusive. Here, we report that SUMO-specific protease 7 (SENP7) senses oxidative stress to maintain the CD8+ T cell metabolic state and antitumor functions. SENP7-deficient CD8+ T cells exhibited decreased glycolysis and oxidative phosphorylation, resulting in attenuated proliferation in vitro and dampened antitumor functions in vivo. Mechanistically, CD8+ T cell-derived ROS triggered cytosolic SENP7-mediated PTEN deSUMOylation, thereby promoting PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, lowering T cell-intrinsic ROS restricted SENP7 cytosolic translocation and repressed CD8+ T cell metabolic and functional activity in human colorectal cancer samples. Our findings reveal that SENP7, as an oxidative stress sensor, sustains CD8+ T cell metabolic fitness and effector functions and unveil an oxidative stress-sensing machinery in tumor-infiltrating CD8+ T cells.

Altered DNA methylation (DNAm) patterns have been proven to play a key role in Crohn’s disease (CD) pathogenesis. However, DNAm and its association with disease status in Chinese CD remain unclear. This study systematically examines DNAm patterns in Chinese patients with CD and their association with disease status. By elucidating specific DNAm alterations involved in CD pathogenesis, it aims to provide a molecular foundation for early diagnosis, prognosis assessment, and personalized treatment strategies. In this study, 24 adult treatment-naïve patients with CD were enrolled between January 2022 and May 2023. We performed reduced representation bisulfite sequencing (RRBS) on paired inflamed and non-inflamed intestinal mucosa samples from these patients, and inflammation-specific and disease severity-specific differential methylation signatures were identified. A total of 17,097 differentially methylated sites (DMCs) and 2,687 differentially methylated regions (DMRs) were identified in inflamed mucosa. Biological association analysis revealed that inflammation-associated DMRs were enriched in immune function, with 123 DMRs annotating 89 genes involved in immune cell function while 173 DMRs annotating 117 genes participated in cell adhesion function. Analysis of DNAm profiles of inflamed mucosal samples by disease severity revealed that 389 DMRs were associated with the Simple Endoscopic Score for Crohn’s Disease (SES-CD) and 327 DMRs with the Crohn Disease Activity Index (CDAI). Of these, six genes, KDM4B , CLDN15 , PGGHG , SLC25A10 , KIAA2013 , and N4BP1 , were significantly associated with inflammation, SES-CD and CDAI. Hence, DNAm reflects immunological changes in the gut of CD patients and discriminates patients based on disease severity, highlighting its potential as a predictive marker for disease management.

Stable gut colonization of probiotics is essential for sustained therapeutic effects, however traditional oral probiotic supplements often fail to adapt to the gut environment. Here, based on the observation that multicellular microcolonies instead of planktonic bacteria display a more advantageous gene pattern for colonization, we design a system encapsulating multicellular self-organized probiotic microcolonies, termed Express Microcolony Service (EMS), for efficient oral delivery and enhanced gut colonization of probiotics. Utilizing the stress-relaxing and acid-resistant property of the covalent-ionic crosslinking alginate hydrogel microsphere, the micro-cargo provides tunable nutrient supply and extracellular matrix support to facilitate microcolony self-organization. Notably, we show that the variable spatial constraints of the stress-relaxing hydrogel could modulate the viability and colonization potential of microcolonies. In vitro, bacteria microcolonies in EMS show remarkable resistance to gastric acid, bile salts, and antibiotics, compared with planktonic probiotics. In vivo, the EMS strategy exhibits 89- and 52-fold higher colonization rate in the cecum and colon of mice, compared to conventional oral probiotics. The multicellular self-organized EMS system offers an innovative, efficient and clinically transformable alternative for probiotic therapy. Here, the authors develop a microcargo system encapsulating multicellular self-organized probiotic microcolonies called Express Microcolony Service (EMS), showing it facilitate efficient oral delivery and enhanced gut colonization of probiotic by mimicking biofilm formation.

Endoplasmic reticulum stress (ERS) plays crucial roles in maintaining Treg stability and function, yet the underlying mechanism remains largely unexplored. Here, we demonstrate that (Tmed4ΔTreg) mice with Treg-specific KO of ERS-related protein transmembrane p24 trafficking protein 4 (TMED4) had more Tregs with impaired Foxp3 stability, Treg signatures, and suppressive activity, which led to T cell hyperactivation and an exacerbated inflammatory phenotype and boosted antitumor immunity in mice. Mechanistically, loss of Tmed4 caused defects in ERS and a nuclear factor erythroid 2-related factor 2-related (NRF2-related) antioxidant response, which resulted in excessive ROS that reduced the Foxp3 stability and suppressive function of Tregs in an IRE1α/XBP1 axis-dependent manner. The abnormalities could be effectively rescued by the ROS scavenger, NRF2 inducer, or by forcible expression of IRE1α. Moreover, TMED4 suppressed IRE1α proteosome degradation via the ER-associated degradation (ERAD) system including the ER chaperone binding immunoglobulin protein (BIP). Our study reveals that TMED4 maintained the stability of Tregs and their suppressive function through IRE1α-dependent ROS and the NRF2-related antioxidant response.

Background: Crohn’s disease (CD) involves chronic intestinal inflammation, frequently requiring surgical intervention. CD patients undergoing surgery often undergo increased psychological stress. One of the outcomes of persistent stress is post-traumatic stress (PTS), a mental health concern associated with immune dysregulation and disease progression. However, research on PTS in CD patients following surgery is limited. Objectives: This study aims to explore the incidence and associated factors of PTS in CD patients after surgery. Design: A retrospective cross-sectional study. Methods: This retrospective cross-sectional study investigated 124 patients with CD who underwent surgery between September 2015 and July 2023. Online questionnaires, including the PTSD checklist, 5th edition (PCL-5), Crohn’s and Colitis Knowledge Score, and Short Generic Patient Experience Questionnaire, were employed. The potential risk factors for PTS were evaluated through univariate and multivariate analyses. Results: Among sampled individuals, 44 patients (35.5%) were classified into the PTS group. The patients in the PTS group had a significant lower monthly income (27.3% vs 8.8%, p = 0.006), higher Harvey–Bradshaw Index score (3.82 ± 3.25 vs 2.31 ± 2.50, p = 0.009), more occurrence of perianal lesions (36.4% vs 20%, p = 0.047), higher ostomy (36.4% vs 20%, p = 0.047), and laparotomy rates (31.8% vs 15%, p = 0.028). Through logistic regression analysis, we identified postoperative complications and a history of multiple surgeries as independent risk factors for PTS (p = 0.002 and p = 0.019, respectively). Conclusion: PTS is common in CD patients requiring bowel resection and multiple surgeries, as well as other postoperative related factors, can invoke psychological and mental stress. These findings provide insights for formulating medical service strategies that prioritize patient mental health.

Emerging evidence indicates that a vicious cycle between inflammation and microthrombosis catalyzes the pathogenesis of inflammatory bowel disease (IBD). Over‐stimulated inflammation triggers a coagulation cascade and leads to microthrombosis, which further complicates the injury through tissue hypoxia and ischemia. Herein, an injectable protein hydrogel with anti‐thrombosis and anti‐inflammation competency is developed to impede this cycle, cross‐linked by silver ion mediated metal‐ligand coordination and electronic interaction with sulfhydryl functionalized bovine serum albumin and heparin, respectively. The ex vivo experiments show that the hydrogel, HEP‐Ag‐BSA, exhibits excellent self‐healing ability, injectability, biocompatibility, and sustained drug release. HEP‐Ag‐BSA also demonstrates anti‐coagulation and anti‐inflammation abilities via coagulation analysis and lipopolysaccharide stimulation assay. The in vivo imaging confirms the longer retention time of HEP‐Ag‐BSA at inflammatory sites than in normal mucosa owing to electrostatic interactions. The in vivo study applying a mouse model with colitis also reveals that HEP‐Ag‐BSA can robustly inhibit inflammatory microthrombosis with reduced bleeding risk. This versatile protein hydrogel platform can definitively hinder the “inflammation and microthrombosis” cycle, providing a novel integrated approach against IBD. A microthrombosis and inflammation balancing protein hydrogel, HEP‐Ag‐BSA, is crosslinked by silver ion mediated metal‐ligand coordination and electronic interaction with sulfhydryl functionalized bovine serum albumin and heparin. This injectable hydrogel has prolonged retention at inflamed site, reduces the release of proinflammatory cytokines, and robustly inhibits microthrombosis, which exerts a definitive therapeutic effect on the pathogenesis of inflammatory bowel disease with guaranteed safety.

Background Inflammatory bowel diseases (IBDs) are characterized by sustained inflammation and/or ulcers along the lower digestive tract, and have complications such as colorectal cancer and inflammation in other organs. The current treatments for IBDs, which affect 0.3% of the global population, mainly target immune cells and inflammatory cytokines with a success rate of less than 40%. Results Here we show that berberine, a natural plant product, is more effective than the frontline drug sulfasalazine in treating DSS (dextran sulfate sodium)-induced colitis in mice, and that berberine not only suppresses macrophage and granulocyte activation but also promotes epithelial restitution by activating Lgr5 + intestinal stem cells (ISCs). Mechanistically, berberine increases the expression of Wnt genes in resident mesenchymal stromal cells, an ISC niche, and inhibiting Wnt secretion diminishes the therapeutic effects of berberine. We further show that berberine controls the expression of many circadian rhythm genes in stromal cells, which in turn regulate the expression of Wnt molecules. Conclusions Our findings suggest that berberine acts on the resident stromal cells and ISCs to promote epithelial repair in experimental colitis and that Wnt-β-Catenin signaling may be a potential target for colitis treatment.