CXCR2 associated neutrophil stromal interactions and immune exclusion in microsatellite stable colorectal cancer

Most microsatellite-stable or mismatch-repair-proficient colorectal cancers respond poorly to immune checkpoint monotherapy. This Mini Review examines whether C-X-C motif chemokine receptor 2 (CXCR2)-associated neutrophil recruitment and local stromal interactions contribute to immune exclusion: CD8+ T cells accumulate in stroma or at the tumor margin with limited entry into epithelial nests. We propose that, in a subset of excluded lesions, recruited neutrophils acquire local functions that impair T-cell activity or access. Human observations and experimental perturbations support parts of this model; the complete pathway has not been established as a major cause of checkpoint resistance. Recruitment dependence, tissue adaptation, and measured function provide a basis for comparing studies with different neutrophil labels. Lesions selected for mechanistic investigation would need confirmed microsatellite-stable or mismatch-repair-proficient status, spatial exclusion, and a relevant intratumoral CXCR2-associated neutrophil program. Primary tumors and metastatic sites require separate evaluation. The limited activity of navarixin plus pembrolizumab argues against unselected targeting. Combining CXCR2 inhibition, selected stromal or vascular modulation, and checkpoint blockade remains a preclinical hypothesis. Before clinical translation, comparative studies must link intratumoral target engagement to improved CD8+ T-cell access, function, and tumor control. The proposed tissue biomarkers are research tools whose predictive value requires validation.