Fusobacterium nucleatum (F. nucleatum), a Gram-negative anaerobe, is increasingly implicated in the pathogenesis of colorectal cancer (CRC) and inflammatory bowel disease (IBD). Its adhesin FadA enables epithelial adherence and invasion, promoting inflammation and tumorigenesis. F. nucleatum has been shown to activate the NLRP3 inflammasome, leading to IL-1β release, and is associated with chemoresistance and poor prognosis in CRC. Additionally, lipid peroxidation markers such as malondialdehyde (MDA) and 4-hydroxy-nonenal (4-HNA) may contribute to inflammation-driven carcinogenesis. This study protocol aims to investigate the role of F. nucleatum in the development and progression of IBD and CRC through integrated clinical, molecular, and imaging approaches. The protocol involves quantifying F. nucleatum in tissue biopsies across disease stages and assessing correlations with inflammatory and oxidative markers. It will explore the bacterium’s involvement in NLRP3 inflammasome activation, IL-1β production, and autophagy, and its potential contribution to chemoresistance. Furthermore, radiomic analysis of computed tomography (CT) images will be performed to identify imaging phenotypes associated with microbial load and inflammatory activity. Although primarily a protocol, the study includes preliminary in vitro data showing that exposure to FadA significantly increases inflammatory markers in Caco-2 cells, supporting the hypothesis that F. nucleatum contributes to a pro-inflammatory, pro-tumorigenic microenvironment relevant to CRC progression.

Objectives: To evaluate and indirectly compare overall survival (OS) and safety of regorafenib, fruquintinib, and trifluridine/tipiracil (TAS-102) monotherapy in refractory metastatic colorectal cancer (mCRC) beyond the third line. Methods: A systematic review and meta-analysis of phase II/III randomized controlled trials was conducted according to PRISMA guidelines. PubMed/MEDLINE, Embase, and Cochrane CENTRAL were searched from inception. Eligible studies included patients with mCRC previously treated with standard chemotherapy and biologic agents, receiving regorafenib, fruquintinib, or TAS-102 as monotherapy in the fourth line or later. OS data were reconstructed from published Kaplan–Meier curves. Pooled median and mean OS were estimated using a random-effects model, and heterogeneity was assessed using the I² statistic. Safety outcomes were descriptively summarized. Results: Four RCTs were included. The pooled median OS was 7.83 months (95% CI: 6.98–8.80), and the pooled mean OS was 8.90 months (95% CI: 8.00–9.81), with no heterogeneity (I² = 0%). Survival gains versus placebo ranged from 1.4 to 2.6 months. Survival curves largely overlapped, with differences below one month. Safety was consistent with known profiles. Conclusions: These agents provide comparable efficacy with modest survival benefit in late-line mCRC, highlighting the need for improved strategies and better treatment sequencing.