Single-cell RNA sequencing reveals pro-tumorigenic intestinal mast cell programs in colorectal cancer

Abstract Mast cells (MCs) are multifunctional immune cells with context-dependent functions in cancer. In colorectal cancer (CRC), their contribution remains debated, suggesting that distinct MC subsets may either support tumor progression or promote anti-tumor immunity. Using single-cell RNA sequencing in a mouse model of inflammation-driven CRC, we uncovered extensive MC plasticity during tumor progression. Transcriptomic profiling and pseudotime trajectory analysis revealed a transition from precursor-like MCs exclusively present in adjacent tissue to differentiated tumor-associated MC (TAMC) subsets. TAMCs displayed a distinct repertoire of proteases and pro-inflammatory cytokines, contributing to increased vascular permeability and recruitment of additional immune cells. Moreover, TAMCs exhibited upregulation of molecules with immunosuppressive potential and underwent a tumor microenvironment (TME)-driven metabolic reprogramming. Accordingly, antibody-mediated MC depletion reduced tumor burden. Notably, most of the transcriptional features identified in a murine CRC model were recapitulated in human CRC, supporting the translational relevance of this MC program. Our findings identify a tumor-adapted MC state that orchestrates immune evasion and tissue remodeling during CRC progression, supporting the notion that MC are reprogrammed toward an immune-suppressive and pro-tumorigenic phenotype.