Integrin CD11b/CD18 reprograms macrophage polarization by suppressing ERK/STAT3 signaling to enhance antitumor immunity in colitis-associated colorectal cancer.

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.