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Pathogenic bacteria adapt to distinct disease environments, but whether these adaptations create therapeutic vulnerabilities remains unclear. Fusobacterium nucleatum has emerged as a key microbial player in colorectal cancer (CRC), yet its strain-specific virulence mechanisms remain poorly defined. In this pilot study of 16 clinical F. nucleatum isolates from CRC patients (n=6), Crohn's disease patients (n=6), colon of healthy individuals (n=3) and an oral lesion (n=1), a subset of CRC-derived strains produced three- to fourfold higher levels of endogenous indole. Exogenous indole treatment differentially affected growth and biofilm formation, with some strains increasing biofilm despite growth inhibition. Notably, sensitivity to exogenous indole was independent of endogenous production and revealed that isolate 7-1 (EAVG002), a member of the tumourigenic Fna C2 clade, was uniquely hypersensitive to I3CA- and IPA-mediated stress. Invasion assays further showed that indole and its derivatives (I3A, I3CA) reduced the invasion of a highly indole-tolerant CRC-derived isolate (SB-CTX3Tcol3) into CRC cells by ~50%, comparable to antibiotic treatment. Furthermore, in two CRC cell lines, exposure to indole or indole derivatives resulted in substantial variability in adherens junction and tight junction transcript levels, with I3A having the strongest effect on tight junction (CLDN1, CLDN7) transcripts. Collectively, these findings reveal profound strain-level heterogeneity and indole derivative effects, highlighting vulnerabilities that could enable precision therapeutic targeting of pathogenic F. nucleatum populations within the host environment while preserving beneficial commensals.