Background: Evidence suggests that the tumor microenvironment (TME) affects the tumor active response to immunotherapy. Tumor angiogenesis is closely related to the TME. Nonetheless, the effects of angiogenesis on the TME of colorectal cancer (CRC) remain unknown.

Methods: We comprehensively assessed the angiogenesis patterns in CRC based on 36 angiogenesis-related genes (ARGs). Subsequently, we evaluated the prognostic values and therapeutic sensitivities of angiogenesis patterns using multiple methods. We then performed the machine learning algorithm and functional experiments to identify the prognostic key ARGs. Ultimately, the regulation of gut microbiota on the expression of ARGs was further investigated by using whole genome sequencing.

Results: Two angiogenesis clusters were identified and angiogenesis cluster B was characterized by increased stromal and immunity activation with unfavorable odds of survival. Further, an ARG_score including 9 ARGs to predict recurrence-free survival (RFS) was established and its predominant predictive ability was confirmed. The low ARG_score patients were characterized by a high mutation burden, high microsatellite instability, and immune activation with better prognosis. Moreover, patients with high KLK10 expression were associated with a hot tumor immune microenvironment, poorer immune checkpoint blocking treatment, and shorter survival. The in vitro experiments also indicated that Fusobacterium nucleatum (F.n) infection significantly induced KLK10 expression in CRC.

Conclusions: The quantification of angiogenesis patterns could contribute to predict TME characteristics, prognosis, and individualized immunotherapy strategies. Furthermore, our findings suggest that F.n may influence CRC progression through ARGs, which could serve as a clinical biomarker and therapeutic target for F.n-infected CRC patients.