Colorectal cancer(CRC) is the third most frequent malignant tumor. The gut microbiome acts as a vital component of CRC etiology. Fusobacterium nucleatum(Fn) is a key member of colorectal cancer-associated bacteria. But we lack a systematic and in-depth understanding on its role in CRC evolution. In this article, We reviewed the abundance changes and distribution of Fn in CRC occurrence and development, potential effect of Fn in the initiation of CRC, the source of intratumoral Fn and the cause of its tropism to CRC. In addition, We described the mechanism by which Fn promotes the malignant biological behavior of CRC, affects CRC response to therapy, and shapes the tumor immune microenvironment in great detail. Based on the relationship between Fn and CRC, we proposed strategies for CRC prevention and treatment, and discussed the feasibility and limitations of specific cases, to gain insights into further basic and clinical research in the future.

Background To construct a modified tumor‐node‐metastasis (TNM) staging system for stage I‐III colon cancer patients with lymph nodes examined (LNE) < 12. Methods The clinicopathological and survival data of 3870 stage I‐III colon cancer patients with LNE < 12 from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015 (development cohort) and 126 stage I‐III patients with LNE < 12 from the Second Affiliated Hospital of Harbin Medical University between 2011 and 2015 (validation cohort) were identified. The optimal stratification of LNR for cancer‐specific survival (CSS) was achieved using X‐tile software. The predictive accuracy of the modified stage (mStage) was determined by the concordance index (C‐index). Results The modified N stage (mN stage) was built based on the LNR (mN0: LNR = 0, mN1: 0 < LNR < 0.4 or cancer nodule formation and mN2: 0.4 ≤ LNR ≤ 1). Preferable C‐indices could be found for mStage compared with TNM stage in both development (0.750 vs 0.727) and validation cohorts (0.682 vs 0.646). Besides, patients with mStage A and B diseases could not benefit from adjuvant chemotherapy, while in patients with mStage C‐F diseases, those receiving radical surgery plus adjuvant chemotherapy presented better CSS than those with radical surgery alone. Conclusions The mStage system could predict the prognosis of colon cancer patients with LNE < 12 accurately and showed superior predictive power compared with conventional TNM staging system. Moreover, adjuvant chemotherapy might play inequable roles in patients with different mStage diseases.

Colorectal cancer (CRC) is the third most common malignant cancer worldwide with the second highest mortality. Gut microbiota can educate the tumor microenvironment (TME), consequently influencing the efficacy of immune checkpoint inhibitors (ICIs). Fusobacterium nucleatum is one of the most crucial bacteria contributing to colorectal tumorigenesis, but the molecular mechanisms between F. nucleatum and TME or ICIs are poorly investigated. In the present study, we firstly analyzed differentially expressed genes and the biological functions between F. nucleatum-infected and uninfected CRC cell lines, with the findings that CCL22 mRNA expression was markedly upregulated after F. nucleatum infection. Moreover, the survival analysis showed that CCL22 was significantly associated with the overall survival of CRC patients. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis suggested that CCL22 was related to immune-related terms. Furthermore, the ESTIMATE analysis indicated that the high-CCL22-expression subgroup had a higher immune/stromal/estimate score and lower tumor purity. The CIBERSORT analysis indicated that the high-CCL22-expression group had more immune-suppressive cells and less antitumor immune cells. In addition, immune checkpoint genes and cytotoxic genes were positively correlated with CCL22 expression. The immunophenoscore analysis suggested that CCL22 was associated with the IPS-CTLA4 and PD1/PD-L1/PD-L2 score. Interestingly, CCL22 expression in the KRAS and APC mutation groups was markedly reduced compared to that of the wild groups. In summary, our study provided evidence that CCL22 might play a crucial role in F. nucleatum-related colorectal tumorigenesis and correlate with TME and ICIs, which deserves further study.

Despite immune checkpoint blockade (ICB) therapy contributed to significant advances in cancer therapy, only a small percentage of patients with colorectal cancer (CRC) respond to it. Identification of these patients will facilitate ICB application in CRC. In this study, we integrated multiple CRC cohorts (2,078 samples) to construct tumor microenvironment (TME) subtypes using TME indices calculated by CIBERSORT and ESTIMATE algorithms. Furthermore, a surrogate quantitative indicator, a tumor microenvironment immune gene (TMEIG) score system, was established using the key immune genes between TME clusters 1 and 2. The subsequent analysis demonstrated that TME subtypes and the TMEIG score system correlated with clinical outcomes of patients in multiple CRC cohorts and exhibited distinct immune statuses. Furthermore, Tumor Immune Dysfunction and Exclusion (TIDE) analysis indicated that patients with low TMEIG scores were more likely to benefit from ICB therapy. A study on two ICB cohorts (GSE78220 and IMvigor210) also validated that patients with low TMEIG scores exhibited higher ICB response rates and better prognoses after ICB treatment. The biomarker evaluation module on the TIDE website revealed that the TMEIG score was a robust predictive biomarker. Moreover, differential expression analysis, immunohistochemistry, qPCR experiments, and gene set prioritization module on the TIDE website demonstrated that the five genes that constitute the TMEIG score system (SERPINE1, FABP4, SCG2, CALB2, and HOXC6) were closely associated with tumorigenesis, immune cells, and ICB response indices. Finally, TMEIG scores could accurately predict the prognosis and ICB response of patients with CRC. SERPINE1, FABP4, SCG2, CALB2, and HOXC6 might be potential targets related to ICB treatment. Furthermore, our study provided new insights into precision ICB therapy in CRC.