Adjacent nontumor mucosa: The overlooked frontier in colorectal cancer prognostication

Figure 1 Paradigm shift in macrophage biology in colorectal cancer. From a tumor-centric view to an non-tumor mucosa (NM)-integrated, stage-specific model. Schematic illustration contrasting the traditional tumor-centric perspective with the proposed adjacent NM-integrated, stage-specific framework. Left panel (traditional tumor-centric view): Macrophage infiltration within the tumor center (TC) is relatively sparse and predominantly composed of M2-like macrophages (CD163⁺/CD206⁺), with limited M1-like macrophages (CD80⁺). Across stages, macrophage density within the TC is reduced compared with NM and is not associated with overall survival. Right panel (proposed NM-integrated model): In the adjacent NM, macrophages are more abundant and exhibit stage-specific prognostic associations. In stage I-III disease, higher densities of CD80⁺ M1-like macrophages in NM are associated with favorable prognosis and may reflect enhanced immune surveillance and cytotoxic support limiting metastatic dissemination. In contrast, in stage IV disease, increased CD163⁺/CD206⁺ M2-like macrophages in NM are associated with improved survival and may reflect tissue repair, vascular stabilization, and maintenance of epithelial integrity. Colored symbols represent macrophage subsets: M0 (CD68⁺, gray), M1-like (CD80⁺, orange), and M2-like (CD163⁺/CD206⁺, blue). The schematic reflects relative distribution patterns and conceptual associations rather than quantitative measurements.