Neuro-Immune Crypt-Associated Cells Drive Colorectal Carcinogenesis via REST-Mediated Phenotypic Reprogramming: Implications for Tumorigenesis and Viral Susceptibility

Colorectal cancer (CRC) pathogenesis remains linked to poorly defined cellular origins and microenvironmental drivers. We identify Neuro-Immune Crypt-Associated (NICA) cells as a privileged pathogen portal and a plausible epithelial cell of origin. During carcinogenesis, the repressor REST drives a neuroendocrine-to-epithelial transition by silencing NICA-associated neuroendocrine markers, a lineage loss reversible via epigenetic modulation or genetic ablation in CRC models. This landscape is further shaped by EBV-infected B-lineage cells (BLEICS), which transactivate HERV-H/F elements in CRC cells through paracrine signaling, establishing a niche-restricted ‘viral scar’. While tumor crypts sense this retroviral pressure, they exhibit an abortive antiviral signature marked by RNase L downregulation, creating a functional execution gap. We propose a pathogen-first model where chronic inflammatory pressure triggers ‘mutation-silencing’ -the simultaneous genotoxic and epigenetic inactivation of tumor suppressors. Together, the convergence of NICA plasticity, BLEICS-mediated HERV induction, and compromised antiviral surveillance redefines CRC as a pathogen-driven disruption of the neuro-immune niche.