Purpose <p>Chordoma, a rare malignancy of the axial skeleton and skull base, presents significant therapeutic challenges due to the high rates of tumor recurrence and resistance. While surgical resection and radiation therapy remain the gold standard of treatment, the lack of additional treatment options necessitates the exploration of novel therapies. Combinatorial therapies hold significant potential in shaping patient prognosis. By targeting the immunotherapeutic, epigenetic, and genetic landscapes of chordoma, these methods enable the more effective and personalized management of the diverse molecular mechanisms driving chordoma growth and resistance.</p> Methods <p>To elucidate such potential, we conducted a literature review of all published articles on the usage of immunotherapeutic, epigenetic, and genetic approaches for chordoma treatment from 2014 to 2024.</p> Results <p>Eighty-one papers were excluded based on our inclusion criteria. From the remaining thirty-nine publications, we found evidence supporting the efficacy of immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR) T-cell therapies, and monoclonal antibodies; the roles of DNA methylation patterns, histone modification pathways, and miRNA regulation; and the contribution of cancer stem-like cells (CSCs) to chordoma progression.</p> Conclusion <p>Our findings underscore the importance of a multidirectional approach in chordoma treatment throughout the disease progression to reduce morbidity and improve patient outcomes despite the heterogeneity of chordoma.</p> Graphical abstract <p></p>