Immune checkpoint blockade (ICB) remains ineffective in most colorectal cancers (CRC) due to intrinsic immune resistance. We identify guanylate-binding protein 2 (GBP2) as a key enhancer of ICB response through modulation of the gasdermin D (GSDMD)-Yes-associated protein (YAP) axis. Analyses of CRC cohorts, patient samples, organoids, and mouse models revealed that GBP2 directly binds GSDMD, inhibiting its cleavage-dependent activation and preventing YAP nuclear translocation. Activated GSDMD facilitates YAP nuclear accumulation, which represses CXCL9/10/11 transcription and limits CD8⁺ T-cell infiltration. Mechanistically, GBP2 disrupts this process by restraining non-pyroptotic GSDMD activity and maintaining YAP in its inactive cytoplasmic state. Genetic or pharmacologic inhibition of GSDMD restored YAP inactivation and sensitized tumors to anti-PD-L1 therapy. These findings define a GBP2-GSDMD-YAP signaling axis that inhibits immune evasion and represents a therapeutic target to overcome ICB resistance in CRC.

Objectives: Gastric Cancer (GC) poses a significant global health challenge, necessitating effective biomarkers for early detection and prognosis. This study investigates the relationship between SDC2 expression and GC patient outcomes. Methods: We analyzed SDC2 expression in GC and its association with patient outcomes using Kaplan-Meier survival and Cox regression analyses. A pan-cancer analysis was performed to assess cross-tumor SDC2 expression patterns. Validation included immunohistochemistry and single-cell data analyses to confirm SDC2 expression in GC tissues and cell types, with findings supported by independent cohort studies. Results: Elevated SDC2 expression correlates with poor prognosis in GC patients, marked by lower survival rates, enhanced tumor microenvironment heterogeneity, decreased tumor mutational burden, and reduced immunotherapy efficacy. Kaplan-Meier and Cox regression analyses confirm that higher SDC2 expression is associated with shorter overall survival, establishing it as an independent prognostic risk factor. Pan-cancer analysis reveals consistent SDC2 expression patterns across multiple cancers, indicating broad clinical relevance. Validation through immunohistochemistry and single-cell data analysis confirms SDC2 expression in GC tissues and cell types. Independent cohort studies further support these findings. Conclusion: In summary, this study underscores the potential of SDC2 as a promising target for early diagnosis and therapeutic intervention in GC, with implications for other malignancies.

Abstract Still’s disease (SD) is a chronic and systemic autoinflammatory disorder, with the possibility of resulting in life-threatening complications, including macrophage activation syndrome (MAS). The metabolic–immune interplay underlying the immunopathology of SD/MAS remains largely unexplored. In this study, we identified itaconate — a myeloid cell-specific metabolite derived from the tricarboxylic acid cycle via the enzyme ACOD1 — as a dual regulator of inflammation and chemokine-driven tissue injury in SD/MAS. Clinical metabolomics revealed elevated serum itaconate in patients with SD, attributable to peripheral blood monocytes and correlated with disease severity. This was consolidated by the identification of the Acod1–itaconate axis in monocytes and macrophages in both a mouse model of MAS and in vitro cell cultures. Although itaconate suppressed IL-1β, IL-6, CXCL1 and CCL2 in vitro, it paradoxically amplified CXCL10 secretion in vitro and in vivo. This was in line with the observations of elevated plasma CXCL10 levels in patients with MAS. In the CpG ODN 1826-induced MAS mouse model, ablation of Acod1 ameliorated disease manifestations and hepatic inflammation, accompanied by a reduced CXCL10 level as well as attenuated hepatic infiltration of CD8+ T cells. Collectively, our study reveals a previously unrecognized metabolic–immune crosstalk in AOSD/MAS, positioning monocyte/macrophage-derived itaconate as a dual regulator that suppresses canonical pro-inflammatory cytokines while licensing CXCL10-mediated CD8+ T cell-driven tissue injury. Therefore, discovery from this study calls for scrutiny of an itaconate-based anti-inflammatory strategy in chronic inflammatory diseases.

Guanylate-binding protein 2 (GBP2) has been reported to be involved in the progression of various human malignancies, but its specific functions and underlying molecular mechanisms in pancreatic cancer remain poorly understood. The expression level of GBP2 in pancreatic cancer tissues and cell lines was detected, and the correlation between GBP2 expression and clinicopathological features as well as patient prognosis was analyzed. In vitro and in vivo experiments were performed to investigate the effect of GBP2 on pancreatic cancer cell proliferation and cell cycle progression. RNA-sequencing was conducted to screen downstream regulatory targets of GBP2, and molecular mechanism assays (including ubiquitination assay, co-immunoprecipitation) were carried out to verify the regulatory relationship between GBP2, SP1, TRIM25 and SKP2. GBP2 was significantly upregulated in pancreatic cancer tissues and cell lines, and high GBP2 expression was closely associated with a poor prognosis, an advanced TNM stage and a higher tumor grade. Functional experiments showed that GBP2 promotes pancreatic cancer cell proliferation by inducing cell cycle progression. Mechanistically, GBP2 competes with the E3 ubiquitin ligase TRIM25 for binding to transcription factor SP1, thereby inhibiting SP1 ubiquitination and proteasomal degradation. The stabilized SP1 further enhances its binding to the SKP2 promoter, upregulates SKP2 transcription, and activates the SKP2/p27 signaling axis to drive tumor progression. This study reveals a novel GBP2–SP1–SKP2–p27 signaling pathway that promotes pancreatic cancer progression. GBP2 may serve as a potential therapeutic target for pancreatic cancer, which requires further validation through pharmacological studies and patient-derived organoid models.

The prognostic evaluation of advanced CRC patients places increased importance on longitudinal peripheral blood immune status. This study aimed to identify prognosis associated longitudinal immune markers and construct dynamic prognostic models for advanced CRC patients with first-line chemotherapy. Metastatic CRC patients treated with standard first-line palliative chemotherapy were retrospectively collected at Shanghai General Hospital from May 2013 to May 2020. Lymphocyte subsets, inflammatory indices, and tumor markers in peripheral blood were repeatedly assessed before each chemotherapy cycle. Joint models were used to identify significant longitudinal prognostic markers. A dynamic prognostic model was established using random forests for time-dependent predictors, and internally validated using tenfold cross-validation. Increased levels of CRP, CEA, CA199, and IL-6, as well as the CD4 + CD29 + cell proportion and the CD4 + CD45RO + /CD4 + ratio were identified as significant risk factors for overall survival (OS) in metastatic CRC patients. Conversely, the increased levels of CD3-CD19 + cell proportion and the CD4 + CD45RA + /CD4 + ratio were identified as favorable factors for OS. A dynamic prognostic model demonstrated good discriminative ability, with AUC values of 0.827, 0.787, 0.726, and 0.693 for 2-, 3-, 4-, and 5-year predictions, respectively. A high ratio of CD4 + CD45RA + /CD4 + before the third to fourth chemotherapy cycle was associated with significantly better OS. Normal CRP and IL-6 levels in the early phase of first-line chemotherapy indicated a good prognosis. This study highlights the prognostic significance of measuring longitudinal immune status in advanced CRC patients and develops an internally validated dynamic prediction model. External validation is needed before clinical implementation.

PURPOSE:Resistance to bevacizumab (Bev) remains a major challenge in the management of glioblastoma multiforme (GBM). Our previous work indicated that brain and muscle ARNT-like 1 (BMAL1) participates in lactate metabolism in GBM and may be involved in the mechanisms underlying Bev resistance. However, the specific roles of BMAL1 and lactate in this process require further investigation. EXPERIMENTAL DESIGN:This study employed a comprehensive strategy combining in vitro GBM cell line models, patient-derived xenografts (PDX), and in vivo mouse studies. Functional assays (Cell Counting Kit-8 and 3D spheroid invasion), molecular techniques [chromatin immunoprecipitation-quantitative polymerase chain reaction, coimmunoprecipitation, and immunoprecipitation and mass spectrometry (IP-MS)], and biochemical analyses were performed to dissect the mechanism. The clinical relevance of our findings was validated in five independent GBM cohorts and through the analysis of human GBM tissues. RESULTS:We identified a previously unrecognized signaling axis in which lactate promotes BMAL1 expression via H3K18la modification at its promoter. In addition, lactate induces BMAL1 protein lactylation at lysine 123, which facilitates its nuclear translocation. IP-MS further showed that lactylated BMAL1 displays a strengthened interaction with tubulin alpha 1c (TUBA1C), a protein essential for its nuclear import. This lactylation-dependent BMAL1/TUBA1C complex subsequently enhances vascular endothelial growth factor A (VEGFA) transcription, thereby driving Bev resistance. Importantly, targeting this pathway either by silencing BMAL1, inhibiting lactate transporters, or introducing a lactylation-deficient BMAL1-K123 mutant effectively restored Bev sensitivity in vitro and in vivo. CONCLUSIONS:These findings reveal a novel mechanism through which lactate-mediated lactylation of BMAL1 promotes Bev resistance in GBM, supporting the lactate/BMAL1/TUBA1C/VEGFA axis as a promising therapeutic target for overcoming Bev resistance in patients with GBM.

To evaluate the feasibility and safety of using colorectal mucosal grafts (CMG) harvested via endoscopic submucosal dissection (ESD) for ureteral reconstruction in patients with ureteral stricture. Eight patients with ureteral stricture underwent robotic ureteral reconstruction using CMG harvested by ESD. Preoperative assessments included clinical history, physical examination, and various imaging studies. The ESD procedure was performed with standard precautions to obtain sufficient graft material. Postoperative follow-up involved endoscopic examinations and retrograde pyelograms to assess colorectal complication and ureteral patency. The average age of patients was 44 years, and the median BMI was 24.6 kg/m². The causes of stricture included ureteral stones, urinary tract infections, and ureteral polyps. The median stricture length was 3.5 cm. The average size of the harvested CMG was 4 × 2.4 cm. The success rate of the grafting procedure was 100%, with no gastrointestinal complications observed. Endoscopic examination one week postoperatively revealed well-healed wounds. No recurrent ureteral strictures were noted during a median follow-up period of 5 months. The average glomerular filtration rate (GFR) of the affected kidneys was 61 ml/min. Harvesting CMG via ESD for ureteral reconstruction is feasible and safe, with minimal complications and promising short-term outcomes. This technique provides a viable alternative for patients contraindicated for oral mucosal grafts, potentially reducing morbidity associated with traditional intestinal mucosa harvesting methods.

Background: Inflammatory bowel disease (IBD) is characterized by chronic mucosal inflammation and intestinal epithelial barrier disruption. However, the molecular mechanisms driving intestinal inflammation and anti-TNFα therapy resistance remains poorly understood. Methods: Bioinformatics analysis was used to identify candidates that contributes to IBD pathogenesis. Guanylate-binding protein 2 (GBP2) expression was validated in external IBD cohorts and acute colitis mice. Intestinal epithelium-specific GBP2 knockout mice and in vitro experiments with TNFα-injured cells were conducted were used to confirm the role of GBP2 in colitis pathogenesis. Immunoprecipitation-Mass Spectrometry (IP-MS), competitive Co-IP, and SUMOylation assays were performed to further elucidate the molecular mechanisms in depth. Findings: GBP2 is significantly upregulated in the inflamed mucosa of IBD patients and acute colitis mice. Intestinal epithelial cell-specific GBP2 knockout mice are resistant to dextran sodium sulfate-induced colitis, characterized by markedly improved integrity of the intestinal epithelial barrier and markedly reduced epithelial cell ferroptosis. Consistently, knockdown of GBP2 alleviated lipid peroxidation and ferroptosis in vitro under TNFα-induced inflammation. Mechanistically, GBP2 competes with SAE1 for binding to GPX4 via its GTP-binding domain. This competition attenuates GPX4 SUMOylation and promotes its ubiquitin-independent proteasomal degradation, thereby triggering ferroptosis and exacerbating intestinal inflammation. Notably, increased GBP2 expression and ferroptosis correlate with resistance to anti-TNF therapy in both IBD patients and animal models. Interpretation: Our study reveals a GBP2–GPX4 axis that drives ferroptosis in IBD pathogenesis, and identifies GBP2 as a promising predictive biomarker for anti-TNF responsiveness and a potential therapeutic target.

>To the Editor: Chylothorax is a serious disease characterized by rupture of the thoracic tube and milky exudation from the pleural cavity,which can lead to a variety of pathological symptoms and is life threatening[1].Chylothorax is common after thoracic surgery or trauma.The non-traumatic chylothorax is rare in the clinical practice,and the etiology is complex and often associated with the primary disease[2].Chylothorax is a rare complication of patients with advanced cirrhosis[3],most of which are manifested as dyspnea,cough,chest pain,and the medical treatment effect is relatively poor.We performed orthotopic liver transplantation (OLT) in a patient with advanced cirrhosis combined with massive chylothorax and chyloperitoneum.The 2-year follow-up showed that the patient’s liver function was stable and no recurrence of chylothorax.

OBJECTIVES:To assess the post-COVID-19 psychological condition of systemic lupus erythematosus (SLE) patients and the internal relationship between psychiatric symptoms. METHODS:A total of 619 SLE patients were included in this observational study, with 493 diagnosed with COVID-19 and 126 remaining uninfected. Visual analogue scale (VAS), Multi-dimensional Fatigue Inventory (MFI), Patient Health Questionnaire-9 (PHQ-9), and Pittsburgh Sleep Quality Index (PSQI) were utilised to assess pain, exhaustion, depression, and sleep quality, respectively. Network analysis found the core symptoms and bridge symptoms. Logistic regression was utilised to assess the impact of COVID-19 symptoms on later psychiatric symptoms. RESULTS:COVID-19 infected SLE patients had higher levels of pain, 'General Fatigue' (GF), PHQ-9, and PSQI ratings compared to others (p=0.006, 0.027, 0.003, and 0.049, respectively). The infected SLE patients' network of depression, fatigue, and sleep issues identified GF and 'Feeling down, hopeless' (PHQ2) as core symptoms with the greatest expected influence of 1.20. The symptoms 'Trouble sleeping' (PHQ3), GF and 'Daytime dysfunction' (DD) were bridge symptoms with greatest bridge expected influence of 0.72, 0.56 and 0.53, respectively. COVID-19 symptoms such as shortness of breath, weakness, and joint discomfort were linked to post-COVID-19 psychological condition. CONCLUSIONS:Our study demonstrated a worse long-term mental status in COVID-19 infected SLE patients. Early screening and specific therapies might help prevent mental issues in SLE patients.

BACKGROUND:The histone deacetylases 10 (HDAC10) is a HDAC family member, yet its importance in the context of colorectal cancer (CRC) development remains incompletely understood. The present study was thus developed to explore the mechanistic importance of HDAC10 as a regulator of CRC. AIM:To investigate the impact of HDAC10 on tumor growth and its regulation in tumor microenvironment (TME) in CRC, we conducted this study. METHODS:The study evaluated HDAC10 expression using immunohistochemistry analyses and assessed its prognostic value in CRC patients. HDAC10 depletion CRC cell lines were generated, and its biological functions were assessed through cell counting kit-8, wound healing, and colony formation assays. Furthermore, gene set variation analysis (GSVA) was employed to explore the potential molecular mechanisms of HDAC10 in CRC. The impact of HDAC10 on TME was subsequently assessed. Finally, the study investigated the influence of HDAC10 on the response to immunotherapy and chemotherapeutic drugs in CRC. RESULTS:HDAC10 expression was significantly elevated in CRC and correlated with poor prognosis in patients. Knockdown of HDAC10 reduced colon cancer cell proliferation and migration capabilities. GSVA revealed a strong association between high HDAC10 expression and immune suppression. Additionally, high HDAC10 levels were correlated with a non-inflamed TME. Finally, patients with high HDAC10 expression showed reduced sensitivity to immunotherapy. CONCLUSION:This study revealed the significance of HDAC10 in TME, therapy efficacy, and clinical prognosis in CRC, offering novel insights for therapeutic advancements in CRC.

BACKGROUND:Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). This study further elucidated the regulatory mechanism of microglia polarization in AD. METHOD:Microglia polarization was assessed using RT-qPCR, ELISA, and immunofluorescence (IF). Western blot (WB) analyzed inflammation-related, p-tau, and apoptosis-related proteins. Neuronal damage was evaluated by immunofluorescence, and neuronal apoptosis by flow cytometry and TUNEL assay. METTL3 and IκBα expression were detected using RT-qPCR and WB. N6-methyladenosine (m6A) levels were quantified with a colorimetric assay. RNA pull-down assay examined METTL3, IGF2BP2, and IκBα mRNA binding. IGF2BP expression was assessed by RT-qPCR. Learning and memory abilities were evaluated using morris water maze (MWM) test and novel object recognition (NOR) test. Inflammation-related proteins were detected using IF. RESULTS:Stimulation with Aβ1-42 led to microglia M1 polarization, upregulation of inflammation-related proteins, and exacerbation of neuronal injury and apoptosis, along with increased p-tau expression in neurons. METTL3/IGF2BP2 modulated IκBα m6A modification through binding to IκBα mRNA, enhancing its expression. Enhanced METTL3 or IGF2BP2 expression suppressed M1 polarization, inflammation, and neuronal apoptosis in microglia, reversed by knockdown of IκBα. AD model mice exhibited cognitive impairments, neuroinflammation, and elevated M1 polarization. METTL3 or IGF2BP2 overexpression improved cognitive function, reduced neuroinflammation, and inhibited M1 polarization, and this effect was similarly reversed by knockdown of IκBα. CONCLUSION:Our study demonstrates that the METTL3/IGF2BP2/IκBα axis is involved in neuroinflammation in AD by modulating microglia M1/M2 polarization, which sheds light on the treatment of AD.

ABSTRACT Backgrounds Immunotherapy is a promising and effective approach that has achieved significant curative effects in colorectal cancer (CRC). Recently, retinoic acid‐inducible gene I (RIG‐I) has been shown to play a critical role in tumor immunity. However, the correlation between RIG‐I and immunotherapy in CRC remains unclear. Methods RIG‐I expression was measured in CRC and normal samples based on analysis of the public databases, a tissue microarray, and CRC cell lines. The correlation between RIG‐I and immune microenvironment was explored using well‐established biological algorithms and in vitro and in vivo experiments. Results We discovered that RIG‐I expression was downregulated in CRC compared with normal samples. The bioinformatic algorithms indicated that high RIG‐I‐expressing samples showed a positive correlation with IFN‐α response and enrichment of antitumor immune cells, especially CD8+ T cells. Furthermore, knockdown of RIG‐I expression efficiently reduced the cell death, STAT1 phosphorylation, and CXCL10/11 expression induced by IFN‐α in CRC cells. Finally, an in vivo study showed that the infiltration of CD3+ CD8+ T cells was significantly decreased in the RIG‐I knockout group. An animal model further confirmed that the inhibition of tumor growth induced by IFN‐α plus anti‐PD‐1 therapy was dependent on RIG‐I expression. Conclusion RIG‐I is a promising biomarker for CRC immunotherapy, which provides a novel concept for combinatorial immunotherapy.

IntroductionGliomas can be classified by their molecular characteristics, which are also closely associated with clinical outcomes. Cell-free DNA (cfDNA)-based liquid biopsy in gliomas is challenging because of the limited amount of tumor-derived cfDNA present in body fluids.MethodsIn this study, we identified the open chromatin states of gliomas using cfDNA and demonstrated the potential of this technique for glioma detection. The chromatin accessibility of gliomas was investigated using tumor tissues donated by four donors. cfDNA derived from paired cerebrospinal fluid (CSF) and plasma samples was also sequenced.ResultsA total of 72 accessible chromatin regions in the tumor tissues were identified as open chromatin regions using CSF cfDNA. Furthermore, 16 open chromatin regions with significant differences in glioma grade were found using cfDNA extracted from plasma. A glioma grade classifier was constructed with 16 plasma cfDNA-derived accessible chromatin features, which could accurately differentiate low-grade from high-grade samples in the training dataset Area Under Curve ((AUC) = 0.814). However, lower accuracy was obtained on the testing dataset (AUC = 0.736). The diversity of transcription factor binding sites among glioma patients was also illustrated using cfDNA.DiscussionIn conclusion, our study defines novel chromatin-accessibility-based biomarkers and illustrates their potential application in glioma liquid biopsy.

Adult-onset Still's disease (AOSD) is characterized by an overwhelming inflammatory response and hyperactivation of monocytes/macrophages, which may cause macrophage activation syndrome (MAS). Here, we demonstrate the forkhead box protein O3 (FOXO3), a transcriptional factor downregulated by interferon, as an important regulator of inflammation in AOSD-MAS. FOXO3 expression is downregulated in monocytes/PBMCs from patients with AOSD, especially in those developing MAS. A negative correlation between FOXO3 expression with disease activity and inflammatory level is identified. FOXO3 downregulation can be induced by TLR9 activation both in the murine MAS model and TLR9 agonist-stimulated macrophages in vitro, through transcriptional regulation and phosphorylation by AKT. Depletion of Foxo3 protected mice from hyperinflammatory response and organ damage in MAS, and mechanistically, alleviated NLRP3 inflammasome activation in macrophages. Our study reveals mechanisms of FOXO3 in facilitating AOSD-MAS development and identifies the critical role of FOXO3 in the self-negative regulation of inflammation in AOSD through suppression by TLR9 signaling.

BackgroundGastric cancer is a serious disease that threatens human life; early diagnosis and treatment have been the focus of many studies. With advancements in imaging evaluation and machine learning, early detection and treatment of gastric cancer have become feasible. This study aimed to explore research trends and hotspots in the field of gastric cancer and machine learning through bibliometric analysis and to provide new insights for related clinical applications.MethodsLiterature on gastric cancer and machine learning published from 2004 to 2023 was retrieved from the Web of Science database. Microsoft Excel 2019 was used for statistical analysis of influential articles, journals, authors, organizations, countries (regions), and co-citation references in this research domain. VOSviewer (version 1.6.16) and CiteSpace (version 5.8.R3) were utilized to visualize the corresponding data.ResultsWe analyzed and evaluated 425 articles authored by 2,899 researchers from 825 organizations across 52 countries (regions). The People’s Republic of China, the Chinese Academy of Sciences, and the University of the Chinese Academy of Sciences were identified as leaders in this field. The article “Genome-wide cell-free DNA fragmentation in patients with cancer,” published in Nature, was the most frequently cited work. The diagnosis and treatment of gastric cancer have consistently been research hotspots, with a shift in focus from laboratory-based studies to clinical applications. This trend highlights the transition from etiology-oriented research to studies emphasizing treatment and practical applications.ConclusionsThis study offers a comprehensive visual analysis of research on gastric cancer and machine learning, representing the most detailed bibliometric study in this domain. With the continuous advancement of research, artificial intelligence-assisted early diagnostic methods for gastric cancer and corresponding treatment strategies may emerge as a pivotal direction for future research in this area.

Microglia and exosomes are intimately connected with the pathogenesis of Alzheimer's disease (AD). We aim to investigate the role and potential mechanisms of M2-like (anti-inflammatory) microglia-derived exosomes (M2-Exos) in AD. We utilized an Aβ1-42-induced AD model in HT-22 neurons and mouse. The effects of M2-Exo on mitochondrial damage, ferroptosis, oxidative stress, and inflammation levels in the AD cell/animal models were evaluated using transmission electron microscopy, immunoblotting, and biochemical assay kits. Cognitive function in mouse was assessed through behavioral tests. In the AD cell/animal models, the effects of M2-Exo on the Wnt/β-catenin pathway were investigated through immunofluorescence and immunoblotting. AD cells were treated with HLY78 (Wnt/β-catenin pathway activator) to explore the modulation of the pathway. After knocking down TREM2 in M2-Exo, mitochondrial damage, ferroptosis, oxidative stress, and inflammation markers were reevaluated in AD cell and animal models. Aβ1-42 induced mitochondrial shrinkage and deformation in neurons, upregulated ACSL4, PTGS2, Fe2+/Fe, lipid peroxide (LPO), ROS, MDA, IL-6, IL-1β, and TNF-α, while it downregulated GPX4, FTH1, and GSH-PX. M2-Exo reversed the effects induced by Aβ1-42 both in vitro and in vivo, and M2-Exo improved cognitive function in AD mouse. HLY78 also reversed the effects induced by Aβ1-42. M2-Exo increased the levels of β-catenin. BV2 cells converting to M2-like type increased TREM2 levels. Knocking down TREM2 in M2-Exos resulted in decreased neuronal β-catenin levels, reversing the beneficial effects of M2-Exo on AD cell and mouse models. M2-Exo TREM2 alleviates neuronal ferroptosis, inflammation, and oxidative stress in AD by activating the Wnt/β-catenin signaling pathway.

INTRODUCTION:MCAM, alternatively referred to as CD146, is an integral membrane glycoprotein belonging to the immunoglobulin superfamily. However, its importance in the tumorigenesis of colorectal cancer is still partially understood. Therefore, this study was designed to investigate the significance of MCAM in colorectal cancer. METHODS:MCAM expression was analyzed by TCGA and GEO databases. qRT-PCR and IHC analysis were conducted to validate MCAM expression in patient tissues. The tumor-inhibiting ability of MCAM was further assessed by CCK-8 assay, colony formation assay, and wound-healing assay. qRT-PCR and WB analysis were conducted to evaluate the expression of EMT markers and MMP2/9. qRT-PCR analysis was utilized to detect the polarization status of macrophages. Kaplan-Meier curve, univariate, and multivariate cox analyses were employed to verify the ability of MCAM in prognosis prediction. TIDE scores were used to assess the impact of MCAM on immunotherapy. RESULTS:The expression of MCAM was significantly downregulated in CRC, and low MCAM expression revealed poor prognosis in CRC patients. Moreover, MCAM overexpression inhibited the proliferation, migration, and invasive ability of CRC cells. Additionally, MCAM overexpression suppressed N-cadherin and MMP2/9 expression. Furthermore, MCAM impacted M1 macrophage polarization. MCAM is an independent predictor of CRC patient prognosis through Cox regression analysis. Lastly, TIDE score analysis indicated that elevated expression of MCAM increased immunotherapy efficacy. CONCLUSION:The findings of this research suggest that MCAM impacts M1 macrophage polarization and enhances immunotherapy efficacy, underscoring its potential as a therapeutic target for colorectal cancer.