The evolutionarily conserved Hippo signaling pathway is a key regulator of stem cell self-renewal, differentiation, and organ size. While alterations in Hippo signaling are causally linked to uncontrolled cell growth and a broad range of malignancies, genetic mutations in the Hippo pathway are uncommon and it is unclear how the tumor suppressor function of the Hippo pathway is disrupted in human cancers. Here, we report a novel epigenetic mechanism of Hippo inactivation in the context of hepatocellular carcinoma (HCC). We identify a member of the microrchidia (MORC) protein family, MORC2, as an inhibitor of the Hippo pathway by controlling upstream Hippo regulators, neurofibromatosis 2 (NF2) and kidney and brain protein (KIBRA). Mechanistically, MORC2 forms a complex with DNA methyltransferase 3A (DNMT3A) at the promoters of NF2 and KIBRA, leading to their DNA hyper-methylation and transcriptional repression. As a result, NF2 and KIBRA are crucial targets of MORC2 to regulate confluence-induced activation of Hippo signaling and contact inhibition of cell growth under both physiological and pathological conditions. The MORC2-NF2/KIBRA axis is critical for maintaining self-renewal, sorafenib resistance, and oncogenicity of HCC cells in vitro and in nude mice. Furthermore, MORC2 expression is elevated in HCC tissues, associated with stem-like properties of cancer cells, and disease progression in patients. Collectively, MORC2 promotes cancer stemness and tumorigenesis by facilitating DNA methylation-dependent silencing of Hippo signaling and could be a potential molecular target for cancer therapeutics.

Objective RNA-binding motif protein 28(RBM28)plays a critical regulatory role in various malignancies,yet,its expression pattern and functional role in gastric cancer remain unclear.This study aims to investigate the effect and molecular mechanism of RBM28 on the development and progression of gastric cancer(GC).Methods① Study materials and clinical sample grouping:Patients who visited Department of Gastroenterology of Daping Hospital between December 2021 and December 2023 and from whom tissue samples were collected in this study.Among them,14 normal gastric mucosal tissues were assigned to Normal group,and 17 gastric cancer tissue samples were assigned to GC group.By integrating the data from The Cancer Genome Atlas(TCGA)database and our in-house RNA-seq data,differentially expressed members of the RBM family were screened,and RBM28 was identified as a significantly altered candidate gene.② Tissue-level validation and prognostic analysis:Immunohistochemistry was performed to detect RBM28 protein expression in the Normal and GC groups.In addition,transcriptomics,and survival data of GC patients from the Kaplan-Meier Plotter database(n=876)were used to analyze the association between RBM28 expression and patient prognosis.③ Cell model construction and functional assays:GC cell lines HGC-27 and AGS were employed as experimental models.Stable RBM28-knockdown cell lines and their corresponding control cells were established via lentiviral infection.Cell proliferation was assessed using CCK-8 assay at days 1,2,3,and 5 after seeding,with 6 replicate wells per group.Colony formation assay was also performed to evaluate clonogenic proliferative capacity.④ Cell cycle analysis:Propidium iodide(PI)staining combined with flow cytometry was utilized to observe cell cycle distribution of the control and RBM28-knockdown groups,and to determine the effect of RBM28 on G1/S phase progression.⑤ Mechanistic investigation and rescue validation:Pathway enrichment analysis was conducted to identify key genes associated with RBM28-related cell cycle and DNA replication pathways.A DONSON overexpression rescue model was further constructed,including the Control,shRBM28,and shRBM28+DONSON groups.DONSON expression was verified by RT-qPCR.Subsequently,CCK-8 assay,colony formation assay,and flow cytometry were performed to evaluate the changes in cell proliferation and cell cycle distribution after DONSON rescue,thereby determining whether RBM28 regulates G1/S phase progression and malignant proliferation of GC cells through DONSON.Results ① Integrated analysis of the TCGA database and our in-house dataset,as well as immunohistochemical validation,demonstrated that the protein level of RBM28 was significantly upregulated in GC tissues(P＜0.000 1),and high RBM28 expression was significantly associated with poor prognosis(HR=2.36,95％CI:1.45 to 3.85,P=0.000 4).② Knockdown of RBM28 significantly inhibited the proliferative capacity of GC cells(P＜0.01).③ Mechanistically,we found that high RBM28 expression was closely associated with the cell cycle DNA replication pathways.RBM28 knockdown induced G1 phase arrest in GC cells(P＜0.05),and DONSON was identified as a key regulatory factor involved in this process.④Furthermore,overexpression of DONSON following RBM28 knockdown significantly reversed G1/S phase arrest and restored the suppressed proliferative capacity of GC cells(P＜0.05).Conclusion RBM28 is highly expressed in GC tissues,and promotes G1/S phase progression by upregulating DONSON expression,thereby enhancing the proliferative capacity of GC cells and driving tumor progression.The RBM28/DONSON axis may serve as a potential novel target for GC molecularly targeted therapy.

Background:Hepatic encephalopathy (HE), especially overt HE (OHE), is the most common transjugular intrahepatic portosystemic shunt (TIPS) complication, affecting quality of life. Existing noninvasive models have suboptimal predictive performance. Aim:To develop a novel model integrating preoperative and intraoperative indicators to predict post-TIPS OHE. Methods:We included 455 TIPS patients from three centers (Army Medical Center, Xinqiao Hospital, and West China Hospital) between March 2018 and September 2024, randomly allocated into 7:3 development and validation cohorts. LASSO and multivariate logistic regression identified independent risk factors, with model discrimination/calibration evaluated against traditional models (Child-Pugh, model for end-stage liver disease [MELD], albumin-bilirubin [ALBI], and Freiburg index of post-TIPS survival [FIPS]). Results:A total of 455 patients were included. During follow-up, 91 patients (28.4%) in the development cohort and 41 (30.4%) patients in the validation cohort developed OHE. The analysis identified the following independent risk factors: peripheral blood monocyte count (odds ratio [OR] = 1.40, 95% confidence interval [CI]: 1.22-1.63, P < 0.001), thrombin time (TT; OR = 1.35, 95% CI: 1.15-1.59, P < 0.001), age (OR = 1.08, 95% CI: 1.05-1.12, P < 0.001), history of diabetes (OR = 7.64, 95% CI: 3.50-17.55, P < 0.001), ascites grade [mild-moderate ascites (OR = 2.35, 95% CI: 1.19-4.77, P = 0.02), severe ascites (OR = 3.76, 95% CI: 1.15-12.64, P = 0.03)]. Stent underdilated (8-mm stent dilated to 6-mm) was a strong independent protective factor (OR = 0.12, 95% CI: 0.05-0.26, P < 0.001). The six-factor prediction model achieved area under the curve values of 0.864 (development cohort) and 0.812 (validation cohort), significantly outperforming Child-Pugh (0.617/0.656), MELD (0.551/0.569), ALBI (0.607/0.662), and FIPS (0.667/0.608) scores (all P < 0.05). Conclusion:The prediction model incorporating stent dilatation status, peripheral blood monocyte count, TT, age, ascites severity, and history of diabetes demonstrates high predictive accuracy for assessing OHE risk after TIPS. Notably, the model was derived in a mainly hepatitis B virus-cirrhosis Asian population, which may limit generalizability to alcoholic/nonalcoholic steatohepatitis-dominant western populations.

Acute activation of mTORC1 by amino acids (AAs) is pivotal for growth regulation, yet it remains unclear how the intracellular nutrient-sensing machinery might be rewired by environmental cues to execute distinct functions. Here we report that, despite nutrient insufficiency, cancer-intrinsic AA-sensing mTORC1 signalling is hijacked by inflammatory cytokines in the tumour microenvironment (TME). ZBTB5 translates inflammatory signals to restore mTORC1 pathway via disrupting the GATOR1 complex. Mechanistically, inflammatory cues promote phosphorylation of ZBTB5-S127, thereby recruiting the Cullin3ZBTB5 E3 ubiquitin ligase to degrade NPRL2 within GATOR1 and reactivate mTORC1 signalling. Consequently, tumoural AA uptake is boosted to exacerbate nutrient restriction and death of CD8+ T cells, leading to immunoevasion, tumour progression and inferior response to immune-checkpoint inhibitors. As such, blocking ZBTB5-pS127 ameliorates primary and acquired resistance to checkpoint blockade. Thus, targeting aberrant nutrient-sensing via the ZBTB5-pS127-mTORC1 axis represents a proof-of-concept strategy to sensitize cancer immunotherapy by alleviating AA restriction in the TME.

METTL3, a key RNA N6-methyladenosine (m6A) methyltransferase, plays essential roles in cell fate regulation and tissue homeostasis, yet therapeutic strategies to enhance its activity remain unexplored. Here, we profile the S-palmitoylation landscape during embryonic stem cell differentiation and observe increased METTL3 S-palmitoylation at cysteine 376 during mesodermal commitment. This modification is catalyzed by ZDHHC24 and reversed by ABHD17A. METTL3 C376S mice exhibit cartilage defects and exacerbated osteoarthritis (OA). Through AI-guided screening, we identify Isoborneol as a small molecule that enhances METTL3 S-palmitoylation by disrupting its interaction with ABHD17A. Isoborneol treatment alleviates joint degeneration and preserves cartilage integrity in OA models. Mechanistically, S-palmitoylation promotes METTL3 condensate formation in proximity to ribosomes, facilitating its cytoplasmic spatial compartmentalization. This condensate state suppresses chaperone-mediated autophagy, thereby enhancing METTL3 protein stability. Our findings reveal S-palmitoylation as a regulatory mechanism governing METTL3 localization and turnover and establish a pharmacological strategy for restoring METTL3 activity in OA.

Ferritin is a heteropolymer or homopolymer composed of 24 polypeptides forming a cage-shaped sphere. Its main function is to maintain soluble and non-toxic states of iron ions in the body. In mammals, ferritin is primarily located in the cytoplasm and the mitochondria. Cytoplasmic ferritin consists of heavy (H) and light (L) subunits, whereas mitochondrial ferritin is a homopolymer composed exclusively of a single subunit type. A notable feature of ferritin is its ability to self-assemble into nanocages in vitro, which is reversible and controllable. This unique property has enabled its widespread application in various fields including drug delivery, disease diagnosis, and vaccine development. In this review, we provide a comprehensive overview of ferritin, focusing on the following aspects: 1) structural characteristics, biological functions, dynamics, and molecular mechanisms underlying ferritin self-assembly, 2) recent advances and applications of ferritin-based self-assembled nanocages in biomedicine and bioengineering, and 3) progress in the molecular modification of ferritin using genetic engineering techniques. Additionally, we critically examined the current limitations of ferritin in research and practical applications, and proposed potential strategies for further improvement, with the aim of providing insights into the future development and utilization of ferritin in medical and scientific contexts. This work integrates the kinetics and molecular mechanisms of ferritin self-assembly with advanced genetic engineering strategies, offering a systematic framework for the rational design of ferritin-based multifunctional platforms.

Inflammatory bowel disease(IBD)is characterized by complex etiology and highly heterogeneous manifestations,which poses significant challenges to precise diagnosis and individualized therapy due to difficulties in early differential diagnosis,incomplete standardization of endoscopic and imaging criteria,insufficient sensitivity and specificity of biomarkers,imperfect predictive systems for treatment response,and poor patient adherence.In recent years,the incidence of IBD has continued to rise both globally and in China,with diagnostic delay being common,necessitating the urgent development of systematic diagnostic and therapeutic strategies.The critical steps in diagnosis are as follows:① screening high-risk populations(age at onset of 15 to 35 years or 60 to 75 years,family history in first-degree relatives,persistent diarrhea with hematochezia,perianal lesions,etc.),and initiating colonoscopy and imaging assessment as early as possible;② elucidating the three core manifestations—diarrhea,abdominal pain,and wasting—while recognizing extraintestinal manifestations[arthritis,erythema nodosum,primary sclerosing cholangitis(PSC),etc.]and special presentations(anal fistulas,failure to improve after appendectomy,etc.);③ establishing a logical chain of imaging assessment from 3 dimensions:the bowel wall,mesenteric marginal vessels,and mesenteric lymph nodes,with computed tomography enterography(CTE)and intestinal ultrasound each offering distinct advantages;④ systematically excluding intestinal tuberculosis,ischemic bowel disease,drug-induced enteropathy,and rare inherited immune disorders in differential diagnosis,integrating information from epidemiology,serum biomarkers,dynamic endoscopic evolution,and precise histopathology.In terms of treatment:① emphasizing the"treat-to-target"paradigm,with therapeutic goals shifting from symptom relief to mucosal healing and even to histological healing.Drug selection should be individualized based on disease phenotype,biomarkers,endoscopic activity,and patient characteristics.Mesalazine serves as first-line therapy for mild-to-moderate UC;corticosteroids are used only as a"bridge"in the acute phase;biologics(anti-TNF-α,anti-integrin,anti-IL-12/23)are indicated for moderate-to-severe patients;JAK inhibitors and sphingosine-1-phosphate receptor(S1PR)modulators represent small-molecule precision options.Management of special populations requires a precise balance between efficacy and risk,with vedolizumab preferred during pregnancy,cautious use of corticosteroids and JAK inhibitors in elderly patients,and prerequisite antiviral or anti-tuberculosis therapy for patients with concurrent hepatitis B or latent tuberculosis infection.② For difficult-to-treat and refractory IBD,a paradigm shift from phenotype-driven to multi-omics molecular subtyping is proposed,along with dynamic non-invasive monitoring technologies such as AI-assisted capsule endoscopy and plasma cell-free DNA(cfDNA)methylation profiling,and integrated management model of multidisciplinary team(MDT).IBD is essentially a systemic immune disorder;diagnosis and treatment require grasping clinical clues and evaluating the 3 imaging dimensions(bowel wall,mesenteric vessels and lymph nodes).The principles of"early diagnosis","individualized precision therapy",and"whole-disease-cycle management"should be implemented in diagnosis and treatment of IBD,gradually shifting from symptom relief toward mucosal and histological healing,thereby improving patients'quality of life.

Tissue invasion is an initiating step of the cancer metastatic cascade. Unraveling the mechanisms underlying intracellular signaling pathway rewiring that activates downstream transcriptional machinery to drive invasiveness could help identify improved strategies to prevent and treat metastasis. Through an unbiased genome-wide CRISPR screen in a mouse model of gastric adenocarcinoma (GAC), an E3 ubiquitin ligase, tripartite motif-containing protein 49 (TRIM49), was identified as a potent suppressor of cancer invasiveness. In two thirds of GAC, TRIM49 expression was downregulated in invading cancer cells, in which TRIM49 deficiency correlated with deeper tumor infiltration and lymph node metastasis and was indicative of shorter overall patient survival. In multiple orthotopic GAC mouse models, TRIM49-deficient cancer cells were highly infiltrative, leading to multiorgan metastasis. Mechanistically, galectin-3, a putative regulator of cancer invasion, was stabilized in TRIM49-deficient cancer, largely because of the failure to undergo TRIM49-mediated polyubiquitination and proteasomal degradation. Consequently, galectin-3 assembled a complex with EGR1, thereby regulating transcriptional activities of a proinvasive gene module. As the galectin-3/EGR1 complex acted as a key node relaying proinvasive signaling, its disruption using GB1107, an oral galectin-3 inhibitor, suppressed tissue infiltration and metastasis of patient-derived xenografts. Taken together, a proinvasive galectin-3/EGR1 transcriptional complex was exploited by TRIM49-deficient GAC to fuel tissue invasion, representing an Achilles' heel that is potentially targetable to prevent metastasis.Significance: A proinvasion galectin-3/EGR1 transcriptional complex is a therapeutic vulnerability in the highly invasive TRIM49-deficient gastric adenocarcinoma, which can be disrupted by the oral galectin-3 inhibitor GB1107 to prevent cancer spreading.

Baseline characteristics associated with pathological response

Flow diagram of trial enrollment and analysis

Depression is a psychiatric disorder which affects many aspects of the social life of patients; however, the molecular biological mechanisms underlying its development are not fully understood. Our research reveals that depression onset is associated with BRD2 LLPS-mediated activation of ATG7 super-enhancers (SEs), and we studied BRD2 liquid-liquid phase separation (LLPS) and super-enhancers in depression using chronic mild stress (CMS)-induced rat models and corticosterone-stimulated PC12 cell models. SEs enrichment, core transcription factor ARID5A and target gene ATG7 were found in the prefrontal cortex of depressed rats by ChIP-seq; through in vitro construction of phase separation droplets, fluorescent bleach recovery experiments (FRAP), and verification of the dual luciferase reporter gene, we found that BRD2 mediates transcription through LLPS, driving ATG7 transcriptional activation; while the BET inhibitor JQ1 reverses abnormal ATG7 activation and alleviates depressive behaviors and saving ferritinophagy in animal models of CMS.Our work is the first to elucidate the “phase separation-SEs-ferritinophagy” axis in depression pathogenesis, offering novel therapeutic strategies targeting epigenetic and phase separation mechanisms. It provides new ideas for the pathogenesis and treatment of depression.

Neoadjuvant and adjuvant treatment-related adverse events

Mesenchymal stem cells (MSCs) are multipotent stem cells that have a chondrogenic differentiation capacity. However, the molecular mechanism underlying the chondrogenic differentiation of MSCs has not been fully elucidated, which hinders further development of MSC-based cell therapies for cartilage repair in the clinic. Here, we showed that the E3 ubiquitin ligase Trim63 positively regulates the chondrogenic differentiation of MSCs by catalyzing the K27-linked cysteine ubiquitination of Myh11. Trim63 directly interacts with Myh11 and catalyzes K27-linked ubiquitination of cys382. Mutation of cys382 diminishes Trim63-catalyzed K27-linked ubiquitination and chondrogenic differentiation of MSCs. A deficiency in Trim63 significantly impairs the chondrogenic differentiation of MSCs. Trim63 enhances the repair of articular cartilage defects in vivo. Taken together, the results of our study demonstrated that Trim63 promotes the chondrogenic differentiation of MSCs by catalyzing K27-linked cysteine ubiquitination of Myh11, which provides an alternative therapeutic target for cartilage regeneration and repair.

Single cell transcriptome analysis of gastric adenocarcinoma tissues

BACKGROUND:Etrasimod is an oral, once-daily sphingosine 1-phosphate (S1P) receptor modulator for the treatment of active ulcerative colitis. In the randomised, placebo-controlled, double-blind phase 3 ENLIGHT UC study, also known as the ES101002 study, we aimed to evaluate the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis in East Asia. METHODS:Using a central interactive web response system, in the 12-week induction period, adults (aged 18-75 years, inclusive) with moderately to severely active ulcerative colitis (modified Mayo score [MMS] 4-9 with an endoscopic subscore ≥2 and a rectal bleeding subscore ≥1) and an inadequate response, loss of response, or intolerance to at least one ulcerative colitis treatment were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients and study staff were masked to treatment assignment. Patients were enrolled from 52 hospitals across China, Taiwan, and Souh Korea. Randomisation was stratified by previous treatment status and baseline disease activity. Patients who had an MMS clinical response at induction period week 12 were re-randomly assigned (1:1) to once-daily oral etrasimod 2 mg or placebo for the 40-week maintenance period. Randomisation was stratified by induction period treatment, previous exposure to biologicals or JAK inhibitors, and concomitant use of oral corticosteroids at induction period baseline. The primary efficacy outcome was MMS clinical remission (stool frequency subscore=0 [or stool frequency subscore=1 with a ≥1 point decrease from induction period baseline], rectal bleeding subscore=0, and endoscopic subscore ≤1 [excluding friability]), assessed in the induction and maintenance periods separately (at induction period week 12 and maintenance period week 40). The primary efficacy analyses used the full analysis set (FAS), which included all patients who were randomly assigned and received at least one dose of study treatment for the induction period, and all re-randomly assigned patients who showed clinical response at induction period week 12 and received at least one dose of study treatment for the maintenance period. The safety analyses for each treatment period used the safety analysis set (SAF), which included all patients who received any amount of study drug in the corresponding treatment period. ENLIGHT UC is registered with ClinicalTrials.gov (NCT04176588) and the study is complete. FINDINGS:606 patients were screened between Sept 25, 2019, and April 27, 2023, and 340 were randomly assigned for the induction period and treated (FAS: 228 patients [88 female and 140 male] assigned to etrasimod and 112 patients [44 female and 68 male] assigned to placebo). 157 patients who showed clinical response in the induction period were re-randomly assigned and treated in the maintenance period (FAS: 77 patients [35 female and 42 male] assigned to etrasimod and 80 patients [32 female and 48 male] assigned to placebo). A significantly greater proportion of patients treated with etrasimod than those treated with placebo, showed clinical remission at induction week 12 (57 [25·0%] of 228 patients vs six [5·4%] of 112 patients; adjusted difference 20·4%; 95% CI 13·4%-27·4%; p<0·0001) and maintenance period week 40 (37 [48·1%] of 77 patients vs 10 [12·5%] of 80 patients; adjusted difference 35·9%; 95% CI 22·5%-49·2%; p<0·0001). In the induction period, the most frequently reported treatment-emergent adverse event (TEAE) was increased ALT (22 [10%] in the etrasimod group vs one [1%] in the placebo group). In the maintenance period, the most frequently reported TEAE was upper respiratory tract infection (14 [18%] in the etrasimod group vs 14 [17%] in the placebo group). Across the induction and maintenance periods, most TEAEs were mild to moderate in severity. Five (2%) of 228 patients treated with etrasimod and four (4%) of 112 patients treated with placebo discontinued study treatment due to TEAEs during the induction period, and one (1%) of 77 patients treated with etrasimod and one (1%) of 81 patients treated with placebo discontinued study treatment due to TEAEs during the maintenance period. No grade 4 or higher TEAE, malignancies, or deaths were reported. INTERPRETATION:Etrasimod was effective and well tolerated as an oral induction and maintenance treatment in patients with moderately to severely active ulcerative colitis in East Asia. FUNDING:Everest Medicines. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

BACKGROUND AIMS:Currently, there is limited evidence regarding the survival benefit of transjugular intrahepatic portal shunt (TIPS) placement in patients with advanced cirrhosis and recurrent ascites. This study aimed to assess whether TIPS improves the survival in such population compared with large volume paracenteses plus albumin (LVP + A). METHODS:This retrospective study included 462 patients with advanced cirrhosis and recurrent ascites who were treated with TIPS (N = 151) or LVP + A (N = 311) at 11 tertiary hospitals in China between September 2014 and September 2020. The Fine and Gray competing risk regression model was used to compare the outcomes between the two groups after adjusting for liver disease severity and other potential confounders. RESULTS:1-year overall survival was significantly higher in the TIPS group than in the LVP + A group (77.9% vs 47.3%; P < 0.001), with the relative risk of mortality reduced by 57% (adjusted HR = 0.43, 95% CI: 0.29 to 0.64; P < 0.001). Furthermore, TIPS group had a lower rate of further paracentesis (17.9% vs 100%; P < 0.001) and portal hypertension-related bleeding (5.8% vs 28.1%; P < 0.001) but a higher rate of overt hepatic encephalopathy (26.5% vs 6.4%; P < 0.001) compared with LVP + A group. CONCLUSIONS:In patients with advanced cirrhosis and recurrent ascites, TIPS improved the 1-year survival rates compared with LVP + A. Although TIPS increases the risk of overt hepatic encephalopathy, it can significantly decrease ascites recurrence and portal hypertension-related bleeding.

Background/Aims:Hepatic rupture in amyloidosis is a rare, highly lethal, and poorly understood condition. This study aimed to summarize the clinical features, therapeutic options, and prognosis of this rare disease. Methods:A literature search of the PubMed, Embase, Scopus, and Web of Science databases for relevant full-text studies was performed. Case reports directly addressing hepatic rupture in amyloidosis were retrieved. Additional studies were identified by reviewing the reference lists of the retrieved studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for data extraction and quality assessment were applied. Results:Thirty-one patients with hepatic rupture with amyloidosis (14 males [45.2%], 17 females [54.8%]; mean age: 49 years) were identified. Most patients had right lobe involvement (52.9%), followed by involvement of both lobes (29.4%), and left lobe involvement (17.6%). The 31 patients were treated with supportive therapy (54.8%), surgery (41.9%), angiographic embolization (35.5%), chemotherapy (29.0%), or liver transplantation (12.9%) and exhibited a high in-hospital mortality rate (45.2%). Conclusion:Hepatic rupture in the setting of amyloidosis is extremely ominous and is associated with high mortality rates. The combination of supportive therapy with hepatic artery embolization, surgery, chemotherapy, and liver transplantation has contributed to a decrease in the mortality rate of this disease.

Representativeness of Study Participants

BackgroundImmune checkpoint therapy for colorectal cancer (CRC) has been found to be unsatisfactory for clinical treatment. Fecal microbiota transplantation (FMT) has been shown to remodel the intestinal flora, which may improve the therapeutic effect of αPD-1. Further exploration of key genera that can sensitize cells to αPD-1 for CRC treatment and preliminary exploration of immunological mechanisms may provide effective guidance for the clinical treatment of CRC.MethodsIn this study, 16S rRNA gene sequencing was analyzed in the fecal flora of both responders and no-responders to αPD-1 treatment, and the therapeutic effect was experimentally verified.ResultsPseudomonas aeruginosa was found to be highly abundant in the fecal flora of treated mice, and Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) in combination with αPD-1 was effective in the treatment of CRC through the induction of CD8+ T-cell immunological effects.ConclusionThe clinical drug PA-MSHA can be used in combination with αPD-1 for the treatment of CRC as a potential clinical therapeutic option.