Sidedness matters: single-cell perspectives on left- and right-sided colorectal cancer

Frontiers in Cell and Developmental Biology. 2025. Vol. 13. Article 1720996.

Yanova M., Maltseva D., Tonevitsky A.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Tumor sidedness, distinguishing left- (LCRC) and right-sided (RCRC) cancers, has emerged as a critical clinical determinant, influencing patient prognosis and therapeutic response. However, the cellular and molecular mechanisms underlying these differences remain poorly understood. Recent advances in single-cell RNA sequencing (sc-seq) provide high-resolution insights into CRC heterogeneity, revealing distinct tumor, immune, and stromal cell populations and their context-specific interactions. In this review, we synthesize sc-seq studies that dissect the molecular programs driving progression, therapy resistance, and metastasis in CRC. We highlight malignant subclusters characterized by metabolic reprogramming and spatially organized oncogenic signaling; specialized immune cell states, including macrophage subsets, exhausted T cells, and mast cells, that shape tumor immunity; and stromal elements such as cancer-associated fibroblasts and endothelial tip cells that remodel the extracellular matrix, promote angiogenesis, and foster immune evasion. Importantly, sc-seq demonstrates that LCRC and RCRC represent distinct multicellular ecosystems with differential immune recruitment and stromal signaling, underscoring the need for sidedness-informed therapeutic strategies. We propose that future interventions should target cell-cell communication networks and spatially defined tumor–microenvironment interactions to overcome heterogeneity and improve clinical outcomes.

Keywords: колоректальный рак, Colorectal cancer, РНК-секвенирование единичных клеток, single-cell RNA sequencing, left-sided and right-sided colorectal cancer, cell-cell interactions, лево- и правосторонний колоректальный рак, межклеточные взаимодействия

Publication based on the results of: Microfluidic models (2025)