Immune-epithelial crosstalk governs immune checkpoint inhibitor efficacy in colorectal cancer.

Colorectal cancer (CRC) with deficient DNA mismatch repair (dMMR) elicits a CD8+ T cell response. However, the magnitude and composition of this response vary among patients, influencing the efficacy of immune checkpoint inhibitors (ICIs). To investigate this heterogeneity, we integrated bulk transcriptomics with immune repertoire sequencing in dMMR CRC. We identified co-regulated gene modules associated with T- and B cell clonal expansion, immune-metabolic interactions, and therapeutic response. Key transcriptional programs linked to T cell clonality and ICI responsiveness were validated using spatial transcriptomics and the TCGA-CRC cohort. We observed an inverse relationship between immune activation and oxidative metabolism and identified immune-epithelial crosstalk as a determinant of ICI efficacy. These findings may inform biomarker development and patient stratification in both dMMR and mismatch repair-proficient CRC. Transcriptional programs linked to T cell clonality in dMMR CRC also define a subset of immunologically active microsatellite-stable tumors, supporting the rationale for extending ICI-based therapies to these patients.