Oral mucositis in cancer therapy: A review of the clinical landscape and the emerging role of microbiome-host interactions

Oral mucositis (OM) is a debilitating toxicity of chemotherapy and radiotherapy that compromises nutrition, quality of life, treatment adherence, and overall cancer outcomes. Despite its clinical impact, therapeutic options remain limited, and our descriptive analysis of the clinical trial landscape reveals about 93.75% attrition rate from clinical success to regulatory approval, highlighting the limitations of single-pathway strategies that target epithelial injury alone. Emerging evidence implicates oral microbiome as an active contributor to OM initiation, inflammatory amplification, and delayed healing, interacting dynamically with host immune responses to shape disease trajectory. These insights support a shift toward multi-targeted therapeutic frameworks that concurrently address epithelial protection, host-immune modulation, and microbial dysbiosis. This approach is increasingly reflected in the growing pipeline shift toward multifunctional compounds and microbiome-based approaches. This suggests that successful OM management will require the integrated antimicrobial and anti-inflammatory approaches, potentially guided by patient-specific microbiome profiling. • Oral mucositis is a debilitating consequence of cancer therapies affecting >80% of patients, and yet lacks effective preventive or therapeutic approaches. • Therapeutic development for oral mucositis shows 93.75% failure rate from Phase 2 to regulatory approval. • The oral microbiome actively drives mucositis severity, creating treatment-resistant inflammation. • Successful treatment requires a multi-targeted strategy integrating antimicrobial and anti-inflammatory approaches.