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Increasing evidence indicates that mature B cells in the adjacent tumor tissue, both as an intermediate state, are vital in advanced colorectal cancer (CRC), which is associated with a low survival rate. Developing predictive biomarkers that detect the tipping point of mature B cells before lymph node metastasis in CRC is critical to prevent irreversible deterioration. We analyzed B cells in the adjacent tissues of CRC samples from different stages using the dynamic network biomarker (DNB) method. Single-cell profiling of 725 CRC-derived B cells revealed the emergence of a mature B cell subtype. Using the DNB method, we identified stage II as a critical period before lymph node metastasis and that reversed difference genes triggered by DNBs were enriched in the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway involving B cell immune capability. DHX9 (DEAH-box helicase 9) was a specific para-cancerous tissue DNB key gene. The dynamic expression levels of DHX9 and its proximate network genes involved in B cell-related pathways were reversed at the network level from stage I to III. In summary, DHX9 in mature B cells of CRC-adjacent tissues may serve as a predictable biomarker and a potential immune target in CRC progression.