Single‐Cell and Spatial Analysis Reveal the Differences Between Left‐Sided and Right‐Sided Colorectal Cancer

ABSTRACT Colorectal cancer (CRC) exhibits heterogeneity based on tumour laterality, with right‐sided tumours demonstrating distinct genetic, immunogenic and clinical behaviours compared to left‐sided counterparts. In this study, we conducted single‐cell RNA sequencing and spatial transcriptomics to dissect the distinct molecular landscapes of left‐ and right‐sided CRC. We identified enhanced germinal centre B cell infiltration and CXCL13 + T cell enrichment, features linked to adaptive immune priming and better immunotherapy responsiveness. Right‐sided CRC epithelial cells exhibited proliferative and immunogenic phenotypes, marked by upregulated immune‐related pathways and chemokine‐driven interactions with lymphocytes. Spatial analysis revealed organized tertiary lymphoid structure‐immune microenvironment crosstalk in right‐sided tumours, mediated by CCL19/21‐CCR7 signalling. In contrast, left‐sided CRC tumours displayed stromal‐epithelial interactions favouring angiogenesis and metabolic reprogramming. Our findings established a laterality‐specific immune microenvironment in CRC, providing insights for precise therapeutic strategies of left‐ and right‐sided CRC.