Recent clinical advances in nonconjugated antibodies and antibody-drug conjugates for colorectal cancer treatment.

BACKGROUND: The second most prevalent cause of cancer-related fatalities worldwide and the third most often diagnosed malignancy is colorectal cancer (CRC). The treatment of colorectal cancer has been transformed by recent developments in antibody-based therapeutics, such as antibody-drug conjugates (ADCs) and non-conjugated monoclonal antibodies (mAbs). This review aims to elucidate the most impactful therapeutic strategies in CRC immunotherapy, emphasizing both established and emerging approaches. MAIN BODY: With an emphasis on nonconjugated mAbs (such as bevacizumab and cetuximab) and ADCs (such as Ado-trastuzumab emtansine (T-DM1), Fam-trastuzumab deruxtecan), this study examines more than 150 clinical trials and peer-reviewed publications from sources including Scopus, PubMed, and Web of Science. The selection criteria included studies published within the last decade, emphasizing mechanisms of action, clinical efficacy, and safety profiles. Non-conjugated mAbs target specific tumor antigens to inhibit signaling pathways and stimulate immune-mediated cytotoxicity, while ADCs combine mAbs with cytotoxic payloads for precise tumor cell elimination. Clinical trials have demonstrated significant survival benefits with these agents in biomarker-selected populations, particularly in HER2-positive and microsatellite instability-high (MSI-H/dMMR) CRC subgroups. Challenges include drug resistance, variable antigen expression, and adverse effects, underscoring the need for biomarker-driven approaches and combination therapies. CONCLUSIONS: Immunotherapy, particularly non-conjugated mAbs and ADCs, transforms CRC treatment by improving survival and quality of life. Ongoing research is essential to address resistance mechanisms, optimize combination regimens, and integrate personalized therapies into clinical practice.