Single-cell dissection reveals the role of DNA damage response patterns in tumor microenvironment components contributing to colorectal cancer progression and immunotherapy.

Colorectal cancer (CRC) is one of the leading malignant cancers. DNA damage response (DDR), referring to the molecular process of DNA damage, is emerging as a promising field in targeted cancer therapy. However, the engagement of DDR in the remodeling of the tumor microenvironment is rarely studied. In this study, by sequential nonnegative matrix factorization (NMF) algorithm, pseudotime analysis, cell-cell interaction analysis, and SCENIC analysis, we have shown that DDR genes demonstrate various patterns among different cell types in CRC TME (tumor microenvironment), especially in epithelial cells, cancer-associated fibroblasts, CD8+ T cells, tumor-associated macrophages, which enhance the intensity of intercellular communication and transcription factor activation. Furthermore, based on the newly identified DDR-related TME signatures, cell subtypes including MNAT+CD8+T_cells-C5, POLR2E+Mac-C10, HMGB2+Epi-C4, HMGB1+Mac-C11, PER1+Mac-C5, PER1+CD8+T_cells-C1, POLR2A+Mac-C1, TDG+Epi-C5, TDG+CD8+T_cells-C8 are determined as critical prognostic factors for CRC patients and predictors of immune checkpoint blockade (ICB) therapy efficacy in two public CRC cohorts, TCGA-COAD and GSE39582. Our novel and systematic analysis on the level of the single-cell analysis has revealed the unique role of DDR in remodeling CRC TME for the first time, facilitating the prediction of prognosis and guidance of personalized ICB regimens in CRC.