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This review provides a comprehensive synthesis of integrated, multidisciplinary strategies for OMD-CRC, with particular emphasis on hepatic and pulmonary metastases. We examine the biological foundations that differentiate oligometastatic from polymetastatic disease, including molecular subtypes that inform prognosis and therapeutic responsiveness. Local treatment modalities are critically evaluated, ranging from surgical metastasectomy\u2014the standard of care in adequately selected patients\u2014to minimally invasive approaches such as thermal ablation and Stereotactic Body Radiotherapy (SBRT). Recent randomized trials and prospective studies have suggested possible non-inferiority of these alternatives to surgery in selected contexts, thereby broadening the spectrum of curative-intent interventions. Equally pivotal is the integration of systemic therapy. We discuss optimal timing (neoadjuvant, adjuvant, perioperative) and regimen selection for both resectable and initially unresectable disease. The role of conversion therapy, combining intensive chemotherapy with targeted agents guided by molecular determinants such as RAS\/BRAF mutational status and tumor sidedness, is highlighted as a cornerstone in expanding surgical eligibility. Looking ahead, emerging technologies\u2014including radiomics and liquid biopsy approaches such as circulating tumor DNA (ctDNA)\u2014hold promise for refining patient selection, detecting minimal residual disease, and further individualizing treatment pathways. The convergence of advanced local therapies, precision-guided systemic regimens, and novel biomarkers delineates the new frontier in optimizing outcomes for patients with OMD-CRC.<\/jats:p>","DOI":"10.3389\/or.2026.1932297","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T07:37:31Z","timestamp":1791185851000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Treatment of oligometastatic disease in colorectal cancer: from molecular biology to multimodal strategies"],"prefix":"10.3389","volume":"20","author":[{"given":"G.","family":"Arrichiello","sequence":"first","affiliation":[{"name":"Medical Oncology Unit, Azienda Ospedaliera di Rilievo Nazionale Sant\u2019Anna e San Sebastiano Caserta","place":["Casert, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Piccolo","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Azienda Ospedaliera di Rilievo Nazionale Sant\u2019Anna e San Sebastiano Caserta","place":["Casert, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F.","family":"Carlino","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Azienda Ospedaliera di Rilievo Nazionale Sant\u2019Anna e San Sebastiano Caserta","place":["Casert, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Franzese","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Azienda Ospedaliera di Rilievo Nazionale Sant\u2019Anna e San Sebastiano Caserta","place":["Casert, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Ventriglia","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Azienda Ospedaliera di Rilievo Nazionale Sant\u2019Anna e San Sebastiano Caserta","place":["Casert, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Annunziata","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Azienda Ospedaliera di Rilievo Nazionale Sant\u2019Anna e San Sebastiano Caserta","place":["Casert, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"Patan\u00e8","sequence":"additional","affiliation":[{"name":"Interventional Radiology Unit, Azienda Ospedaliera di Rilievo Nazionale Sant\u2019Anna e San Sebastiano Caserta","place":["Casert, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"De Siero","sequence":"additional","affiliation":[{"name":"Interventional Radiology Unit, Azienda Ospedaliera di Rilievo Nazionale Sant\u2019Anna e San Sebastiano Caserta","place":["Casert, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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