Omics-Informed Resistance Reversal and Treatment Sensitization in Oral Squamous Cell Carcinoma: A Systematic Review and Structured Synthesis

Background/Objectives: High-throughput molecular profiling identifies potential determinants of treatment resistance, but the extent to which these discoveries support reversal of acquired resistance or enhanced treatment sensitivity in oral squamous cell carcinoma (OSCC) remains unclear. This review evaluated evidence linking molecular discovery, target-directed intervention, and improved anticancer treatment response. Methods: PubMed/MEDLINE, Scopus, and Embase were searched, supplemented by Google Scholar and citation searching. Two reviewers independently screened reports, extracted data, and assessed methodological limitations. Eligible investigations connected integrated multi-omics (Category A) or single-omics/broad functional screening (Category B) with target-specific perturbation and a treatment-response comparison. Evidence was synthesized without meta-analysis. Results: Of 1091 database records, 816 unique records were screened and 40 full-text reports assessed; 29 were excluded. Eleven reports were included from databases and two from backward citation searching (total, 13; Category A, four; Category B, nine). Nine reports examined acquired-resistance reversal, whereas four demonstrated sensitization without acquired-resistance reversal. The highest therapeutic evaluation setting was cell culture (three reports), patient-derived organoids (one), or animal models (nine). Randomization was explicitly described in three of nine animal-treatment reports; allocation concealment and outcome blinding were generally unclear. Conclusions: Omics-informed perturbations were associated with improved treatment responses in preclinical OSCC models. Heterogeneous interventions, uneven methodological safeguards, and limited independent validation prevent conclusions about clinical efficacy. Treatment-specific causal experiments and validation in authentic patient-derived systems are needed.