Molecular surgery in colorectal cancer: Integrating genomics into operative decision-making

Colorectal cancer (CRC) surgery has traditionally been planned on the basis of anatomy and histopathology, with relatively standardised procedures applied across biologically heterogeneous disease. In contrast, systemic treatment has progressively incorporated molecular stratification into routine practice, including mismatch repair deficiency, microsatellite instability, germline susceptibility, and circulating tumour DNA (ctDNA). This divergence has created a growing disconnect between operative and systemic oncology, whereby surgical indications, timing, extent of resection, and postoperative surveillance remain largely anatomy-based despite major advances in tumour biology. In this Review, we propose the concept of molecular surgery in CRC, defined as the integration of genomic, germline, immunologic, and liquid-biopsy-derived information into surgical decision-making. We present a practical framework structured around four key domains: indication, timing, extent, and surveillance/reintervention. Within this framework, we discuss organ preservation and the transition from clinical to molecular complete response in rectal cancer, genotype-guided extent of surgery in hereditary CRC syndromes such as Lynch syndrome and familial adenomatous polyposis, the impact of neoadjuvant immunotherapy on surgical sequencing in dMMR/MSI-high disease, and the role of ctDNA-defined molecular residual disease in postoperative management. We also examine emerging tools, including multi-omic profiling, microbiome research, and artificial intelligence, as enabling technologies for future biology-informed surgical care. Finally, we address the educational, infrastructural, and ethical challenges of implementing molecular surgery in routine practice. CRC provides a timely model in which surgery is increasingly shaped not only by anatomical resectability, but also by tumour biology and treatment response. We argue that molecular data should be considered more systematically when defining surgical strategy in contemporary CRC care.