{
  "abstract": "Background Chronic inflammation is a well-established driver of colorectal cancer (CRC), with the resulting inflammatory microenvironment facilitating tumor initiation and progression. The integrin CD11b/CD18, a leukocyte-specific heterodimeric adhesion receptor, mediates critical immunoregulatory functions during inflammatory responses. However, the roles and mechanisms of CD11b/CD18 in colitis-associated colorectal cancer (CAC) remain unclear.Methods To investigate the impact of CD11b/CD18 deficiency on colorectal carcinogenesis, an azoxymethane/dextran sodium sulfate-induced CAC model was established with CD11b and CD18 single-knockout and double-knockout mice. The tumor immune microenvironment was characterized using multicolor flow cytometry. Transcriptomic changes in tumor-associated neutrophils (TANs) and macrophages (TAMs) on CD11b/CD18 ablation were profiled by RNA sequencing. Functional crosstalk between TANs and TAMs was assessed via co-culture experiments. The direct role of CD11b/CD18 in TAM polarization and antitumor activity was evaluated using in vitro agonist assays, and the involvement of the extracellular signal-regulated kinase (ERK)/signal transducer and activator of transcription 3 (STAT3) axis was validated with pathway-specific inhibitors.Results Bioinformatics analysis revealed significant downregulation of ITGAM (CD11b) and ITGB2 (CD18) expression in CRC tissues. In the CAC model, CD11b and CD18 exhibited non-redundant and cooperative functions, and double deficiency significantly exacerbated tumor progression, with increased STAT3 phosphorylation and reduced yes-associated protein phosphorylation. Flow cytometric analysis identified neutrophils as the predominant CD11b+CD18+ population within the tumor microenvironment (TME). Mechanistically, CD11b/CD18 deficiency promoted TME remodeling, including protumor skewing of TANs and TAMs, with TAM polarization mediated partly by TAN-TAM crosstalk. Beyond this indirect mechanism, direct activation of CD11b/CD18 in TAMs attenuated the immunosuppressive properties and enhanced their tumoricidal activity. At the molecular level, CD11b/CD18 deficiency activated janus kinase (JAK)-STAT and mitogen-activated protein kinase pathways in TAMs, whereas CD11b/CD18 activation effectively suppressed ERK1/2 and STAT3 signaling. Combined inhibition of ERK1/2 and STAT3 reversed M2 polarization and restored TAM-mediated tumor killing.Conclusions Our findings establish that integrin CD11b/CD18 orchestrates antitumor immunity by modulating the TME, particularly through direct TAM reprogramming and indirect TAN-TAM crosstalk, highlighting its potential as an immunotherapeutic target for CAC.",
  "authors": [
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China",
        "Department of Gastroenterology, Wenzhou Central Hospital, Affiliated to Wenzhou Medical University, Wenzhou, Zhejiang, China"
      ],
      "name": "Ying Lin"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China"
      ],
      "name": "Yuan-Kun Liu"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China"
      ],
      "name": "Peng Mi"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China"
      ],
      "name": "Xian-Ling Zhao"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China"
      ],
      "name": "Jun-Hui Lin"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China"
      ],
      "name": "Xiao-Shen Cheng"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China"
      ],
      "name": "Lai-Ying Liang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China"
      ],
      "name": "Yong-Dong Huang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China"
      ],
      "name": "Ya-Ni Huo"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China"
      ],
      "name": "Gui-Jing Xie"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China"
      ],
      "name": "Zhen-Yu Ye"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China",
        "Cancer Research Center, Department of Digestive Disease and Institute of Microbial Ecology, School of Medicine, Xiamen University, Xiamen, Fujian, China"
      ],
      "name": "Bayasi Guleng"
    }
  ],
  "title": "Integrin CD11b/CD18 reprograms macrophage polarization by suppressing ERK/STAT3 signaling to enhance antitumor immunity in colitis-associated colorectal cancer",
  "uid": "4ce9eb42-99c9-58ed-a0de-d322a7f16414"
}